WorldWideScience

Sample records for neurodegenerative conditions including

  1. The Diagnosis and Understanding of Apraxia of Speech: Why Including Neurodegenerative Etiologies May Be Important

    Science.gov (United States)

    Duffy, Joseph R.; Josephs, Keith A.

    2012-01-01

    Purpose: To discuss apraxia of speech (AOS) as it occurs in neurodegenerative disease (progressive AOS [PAOS]) and how its careful study may contribute to general concepts of AOS and help refine its diagnostic criteria. Method: The article summarizes our current understanding of the clinical features and neuroanatomical and pathologic correlates…

  2. Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

    OpenAIRE

    Risacher, Shannon L.; Saykin, Andrew J.

    2013-01-01

    Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, famili...

  3. Energy principle with included boundary conditions

    International Nuclear Information System (INIS)

    Lehnert, B.

    1994-01-01

    Earlier comments by the author on the limitations of the classical form of the extended energy principle are supported by a complementary analysis on the potential energy change arising from free-boundary displacements of a magnetically confined plasma. In the final formulation of the extended principle, restricted displacements, satisfying pressure continuity by means of plasma volume currents in a thin boundary layer, are replaced by unrestricted (arbitrary) displacements which can give rise to induced surface currents. It is found that these currents contribute to the change in potential energy, and that their contribution is not taken into account by such a formulation. A general expression is further given for surface currents induced by arbitrary displacements. The expression is used to reformulate the energy principle for the class of displacements which satisfy all necessary boundary conditions, including that of the pressure balance. This makes a minimization procedure of the potential energy possible, for the class of all physically relevant test functions which include the constraints imposed by the boundary conditions. Such a procedure is also consistent with a corresponding variational calculus. (Author)

  4. Physiological Signals and Their Fractal Response to Stress Conditions, Environmental Changes and Neurodegenerative Diseases

    National Research Council Canada - National Science Library

    Scafetta, N; Moon, R. E; West, B. J

    2006-01-01

    .... Some of these studies have been intended to develop more reliable methodologies for understanding how biological systems respond to peculiar altered conditions induced by internal stress, environment...

  5. Essential Tremor: A Neurodegenerative Disease?

    Directory of Open Access Journals (Sweden)

    Julian Benito-Leon

    2014-07-01

    Full Text Available Background: Essential tremor (ET is one of the most common neurological disorders among adults, and is the most common of the many tremor disorders. It has classically been viewed as a benign monosymptomatic condition, yet over the past decade, a growing body of evidence indicates that ET is a progressive condition that is clinically heterogeneous, as it may be associated with a spectrum of clinical features, with both motor and non‐motor elements. In this review, I will describe the most significant emerging milestones in research which, when taken together, suggest that ET is a neurodegenerative condition.Methods: A PubMed search conducted in June 2014 crossing the terms “essential tremor” (ET and “neurodegenerative” yielded 122 entries, 20 of which included the term “neurodegenerative” in the article title. This was supplemented by articles in the author's files that pertained to this topic.Results/Discussion: There is an open and active dialogue in the medical community as to whether ET is a neurodegenerative disease, with considerable evidence in favor of this. Specifically, ET is a progressive disorder of aging associated with neuronal loss (reduction in Purkinje cells as well as other post‐mortem changes that occur in traditional neurodegenerative disorders. Along with this, advanced neuroimaging techniques are now demonstrating distinct structural changes, several of which are consistent with neuronal loss, in patients with ET. However, further longitudinal clinical and neuroimaging longitudinal studies to assess progression are required.

  6. Glutamate and Neurodegenerative Disease

    Science.gov (United States)

    Schaeffer, Eric; Duplantier, Allen

    As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

  7. Neurodegenerative Dementia

    International Nuclear Information System (INIS)

    Allard, Michelle

    2006-01-01

    Full text: With increasing life expectancy across the world, the number of elderly people at risk of developing dementia is growing rapidly. Thus, progressive neurodegenerative disorders such as dementia represent a growing public health concern. These diseases are characterized by a progressive loss in most of the cognitive functions. The promise, possibly in a near future, of disease-modifying therapies has made the characterization of the early stages of dementia a topic of major interest. The assessment of these early stages is a challenge for neuroimaging studies. In order to conceive prevention trials; it is of major outcome to fully understand the mechanisms of the cognitive system impairment and its evolution, with a particular reference to the symptomatic pre-dementia stage, when subjects just begin to depart from normality. In this article we review recent progress in neuroimaging, and their potentiality for increasing a diagnostic accuracy. (author)

  8. DNA damage in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

    2015-06-15

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  9. DNA damage in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Coppedè, Fabio; Migliore, Lucia

    2015-01-01

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  10. Global warming and neurodegenerative disorders: speculations on their linkage

    Science.gov (United States)

    Habibi, Laleh; Perry, George; Mahmoudi, Morteza

    2014-01-01

    Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders. PMID:25671171

  11. Global warming and neurodegenerative disorders: speculations on their linkage.

    Science.gov (United States)

    Habibi, Laleh; Perry, George; Mahmoudi, Morteza

    2014-01-01

    Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders.

  12. Amyloid PET in neurodegenerative diseases with dementia.

    Science.gov (United States)

    Camacho, V; Gómez-Grande, A; Sopena, P; García-Solís, D; Gómez Río, M; Lorenzo, C; Rubí, S; Arbizu, J

    2018-05-15

    Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive decline and memory loss, and is the most common form of dementia. Amyloid plaques with neurofibrillary tangles are a neuropathological hallmark of AD that produces synaptic dysfunction and culminates later in neuronal loss. Amyloid PET is a useful, available and non-invasive technique that provides in vivo information about the cortical amyloid burden. In the latest revised criteria for the diagnosis of AD biomarkers were defined and integrated: pathological and diagnostic biomarkers (increased retention on fibrillar amyloid PET or decreased Aβ 1-42 and increased T-Tau or P-Tau in CSF) and neurodegeneration or topographical biomarkers (temporoparietal hypometabolism on 18 F-FDG PET and temporal atrophy on MRI). Recently specific recommendations have been created as a consensus statement on the appropriate use of the imaging biomarkers, including amyloid PET: early-onset cognitive impairment/dementia, atypical forms of AD, mild cognitive impairment with early age of onset, and to differentiate between AD and other neurodegenerative diseases that occur with dementia. Amyloid PET is also contributing to the development of new therapies for AD, as well as in research studies for the study of other neurodegenerative diseases that occur with dementia where the deposition of Aβ amyloid is involved in its pathogenesis. In this paper, we review some general concepts and study the use of amyloid PET in depth and its relationship with neurodegenerative diseases and other diagnostic techniques. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Recommendations for the use of PET imaging biomarkers in the diagnosis of neurodegenerative conditions associated with dementia: SEMNIM and SEN consensus.

    Science.gov (United States)

    Arbizu, Javier; García-Ribas, Guillermo; Carrió, Ignasi; Garrastachu, Puy; Martínez-Lage, Pablo; Molinuevo, José Luis

    2015-01-01

    The new diagnostic criteria for Alzheimer's disease (AD) acknowledges the interest given to biomarkers to improve the specificity in subjects with dementia and to facilitate an early diagnosis of the pathophysiological process of AD in the prodromal or pre-dementia stage. The current availability of PET imaging biomarkers of synaptic dysfunction (PET-FDG) and beta amyloid deposition using amyloid-PET provides clinicians with the opportunity to apply the new criteria and improve diagnostic accuracy in their clinical practice. Therefore, it seems essential for the scientific societies involved to use the new clinical diagnostic support tools to establish clear, evidence-based and agreed set of recommendations for their appropriate use. The present work includes a systematic review of the literature on the utility of FDG-PET and amyloid-PET for the diagnosis of AD and related neurodegenerative diseases that occur with dementia. Thus, we propose a series of recommendations agreed on by the Spanish Society of Nuclear Medicine and Spanish Society of Neurology as a consensus statement on the appropriate use of PET imaging biomarkers. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  14. Autophagy and neurodegenerative disorders

    Institute of Scientific and Technical Information of China (English)

    Evangelia Kesidou; Roza Lagoudaki; Olga Touloumi; Kyriaki-Nefeli Poulatsidou; Constantina Simeonidou

    2013-01-01

    Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracel ular mechanism that removes damaged organelles and misfolded proteins in order to maintain cel homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.

  15. Aquatherapy for neurodegenerative disorders.

    Science.gov (United States)

    Plecash, Alyson R; Leavitt, Blair R

    2014-01-01

    Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.

  16. Curcumin and neurodegenerative diseases

    Science.gov (United States)

    Monroy, Adriana; Lithgow, Gordon J.; Alavez, Silvestre

    2013-01-01

    Over the last ten years curcumin has been reported to be effective against a wide variety of diseases and is characterized as having anti-carcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, and anti-infectious properties. Recent studies performed in both vertebrate and invertebrate models have been conducted to determine whether curcumin was also neuroprotective. The efficacy of curcumin in several pre-clinical trials for neurodegenerative diseases has created considerable excitement mainly due to its lack of toxicity and low cost. This suggests that curcumin could be a worthy candidate for nutraceutical intervention. Since aging is a common risk factor for neurodegenerative diseases, it is possible that some compounds that target aging mechanisms could also prevent these kinds of diseases. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent aging-associated changes in cellular proteins that lead to protein insolubility and aggregation. This loss in protein homeostasis is associated with several age-related diseases. Recently, curcumin has been found to help maintain protein homeostasis and extend lifespan in the model invertebrate Caenorhabditis elegans. Here, we review the evidence from several animal models that curcumin improves healthspan by preventing or delaying the onset of various neurodegenerative diseases. PMID:23303664

  17. Protection against neurodegenerative disease on Earth and in space

    Science.gov (United States)

    Takamatsu, Yoshiki; Koike, Wakako; Takenouchi, Takato; Sugama, Shuei; Wei, Jianshe; Waragai, Masaaki; Sekiyama, Kazunari; Hashimoto, Makoto

    2016-01-01

    All living organisms have evolutionarily adapted themselves to the Earth’s gravity, and failure to adapt to gravity changes may lead to pathological conditions. This perspective may also apply to abnormal aging observed in bedridden elderly patients with aging-associated diseases such as osteoporosis and sarcopenia. Given that bedridden elderly patients are partially analogous to astronauts in that both cannot experience the beneficial effects of gravity on the skeletal system and may suffer from bone loss and muscle weakness, one may wonder whether there are gravity-related mechanisms underlying diseases among the elderly. In contrast to numerous studies of the relevance of microgravity in skeletal disorders, little attention has been paid to neurodegenerative diseases. Therefore, the objective of this paper is to discuss the possible relevance of microgravity in these diseases. We particularly noted a proteomics paper showing that levels of hippocampal proteins, including β-synuclein and carboxyl-terminal ubiquitin hydrolase L1, which have been linked to familial neurodegenerative diseases, were significantly decreased in the hippocampus of mice subjected to hindlimb suspension, a model of microgravity. We suggest that microgravity-induced neurodegeneration may be further exacerbated by diabetes and other factors. On the basis of this view, prevention of neurodegenerative diseases through ‘anti-diabetes’ and ‘hypergravity’ approaches may be important as a common therapeutic approach on Earth and in space. Collectively, neurodegenerative diseases and space medicine may be linked to each other more strongly than previously thought. PMID:28725728

  18. 78 FR 68907 - Agency Information Collection (Foot (Including Flatfeet (pes planus)) Conditions Disability...

    Science.gov (United States)

    2013-11-15

    ... planus)) Conditions Disability Benefits Questionnaire). Type of Review: New data collection. Abstract... (Including Flatfeet (pes planus)) Conditions Disability Benefits Questionnaire) Under OMB Review AGENCY...)) Conditions Disability Benefits Questionnaire)'' in any correspondence. FOR FURTHER INFORMATION CONTACT...

  19. Tau imaging in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Dani, M.; Edison, P. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Brooks, D.J. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Aarhus University, Institute of Clinical Medicine, Aarhus (Denmark)

    2016-06-15

    Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [{sup 18}F]THK523, [{sup 18}F]THK5117, [{sup 18}F]THK5105 and [{sup 18}F]THK5351, [{sup 18}F]AV1451(T807) and [{sup 11}C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. (orig.)

  20. Flavonoid-Based Therapies in the Early Management of Neurodegenerative Diseases12

    Science.gov (United States)

    Solanki, Isha; Parihar, Priyanka; Mansuri, Mohammad Lukman; Parihar, Mordhwaj S

    2015-01-01

    During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases. PMID:25593144

  1. Progranulin in neurodegenerative disease.

    Science.gov (United States)

    Petkau, Terri L; Leavitt, Blair R

    2014-07-01

    Loss-of-function mutations in the progranulin gene are a common cause of familial frontotemporal dementia (FTD). The purpose of this review is to summarize the role of progranulin in health and disease, because the field is now poised to begin examining therapeutics that alter endogenous progranulin levels. We first review the clinical and neuropathological phenotype of FTD patients carrying mutations in the progranulin gene, which suggests that progranulin-mediated neurodegeneration is multifactorial and influenced by other genetic and/or environmental factors. We then examine evidence for the role of progranulin in the brain with a focus on mouse model systems. A better understanding of the complexity of progranulin biology in the brain will help guide the development of progranulin-modulating therapies for neurodegenerative disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. F1 occurrence including L condition in TUCUMAN and BUENOS AIRES

    International Nuclear Information System (INIS)

    Mosert Gonzalez, M. de; Ezquer, R.G.; Oviedo, R.V. del

    1997-01-01

    An analysis of the occurrence of the F1 layer including the L condition has been done, using data from two Argentine stations: TUCUMAN and BUENOS AIRES, at different seasons and solar activity conditions. The comparisons between observations and the F1 occurrence predicted by the IRI-90 model show the need of reviewing the use of the DuCharme et al. (1973) formula adopted by the model to predict the occurrence of the intermediate F1 layer including the L condition. (author). 6 refs, 6 figs, 2 tabs

  3. Predictors of activity and participation across neurodegenerative conditions: a comparison of people with motor neurone disease, multiple sclerosis and Parkinson's disease.

    Science.gov (United States)

    Morley, David; Dummett, Sarah; Kelly, Laura; Fitzpatrick, Ray; Jenkinson, Crispin

    2018-02-17

    Comparisons between neurological conditions have the potential to inform service providers by identifying particular areas of difficulty experienced by affected individuals. This study aimed to identify predictors of activity and participation in people with motor neurone disease (MND), people with multiple sclerosis (MS) and people with Parkinson's Disease (PD). The Oxford Participation and Activities Questionnaire (Ox-PAQ) and Medical Outcomes Study 36-Item Short Form Survey (MOS SF-36) were administered by postal survey to 386 people with a confirmed diagnosis of MND, MS or PD. Data analyses focused on stepwise regression analyses in order to identify predictors of activity and participation in the three conditions assessed. Three hundred and thirty four participants completed the survey, a response rate of 86.5%. Regression analyses identified multiple predictors of activity and participation dependent on Ox-PAQ domain and disease group, the most prominent being social and physical functioning as measured by the MOS SF-36. Results indicate that the physical and social consequences of neurological illness are of greatest relevance to people experiencing the conditions assessed. Whilst the largely inevitable physical implications of disease take hold, emphasis should be placed on the avoidance of social withdrawal and isolation, and the maintenance of social engagement should become a significant priority.

  4. Oxidative stress treatment for clinical trials in neurodegenerative diseases.

    Science.gov (United States)

    Ienco, Elena Caldarazzo; LoGerfo, Annalisa; Carlesi, Cecilia; Orsucci, Daniele; Ricci, Giulia; Mancuso, Michelangelo; Siciliano, Gabriele

    2011-01-01

    Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine.

  5. [Circadian blood pressure variation under several pathophysiological conditions including secondary hypertension].

    Science.gov (United States)

    Imai, Yutaka; Hosaka, Miki; Satoh, Michihiro

    2014-08-01

    Abnormality of circadian blood pressure (BP) variation, i.e. non-dipper, riser, nocturnal hypertension etc, is brought by several pathophysiological conditions especially by secondary hypertension. These pathophysiological conditions are classified into several categories, i.e. disturbance of autonomic nervous system, metabolic disorder, endocrine disorder, disorder of Na and water excretion (e.g. sodium sensitivity), severe target organ damage and ischemia, cardiovascular complications and drug induced hypertension. Each pathophysiological condition which brings disturbance of circadian BP variation is included in several categories, e.g. diabetes mellitus is included in metabolic disorder, autonomic imbalance, sodium sensitivity and endocrine disorder. However, it seems that unified principle of the genesis of disturbance of circadian BP variation in many pathophysiological conditions is autonomic imbalance. Thus, it is concluded that disturbance of circadian BP variation is not purposive biological behavior but the result of autonomic imbalance which looks as if compensatory reaction such as exaggerated Na-water excretion during night in patient with Na-water retention who reveals disturbed circadian BP variation.

  6. Neuroregeneration in neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Mureşanu Dafin F

    2011-06-01

    Full Text Available Abstract Background Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach. Discussion Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies. Summary In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.

  7. Aptamer and its applications in neurodegenerative diseases.

    Science.gov (United States)

    Qu, Jing; Yu, Shuqing; Zheng, Yuan; Zheng, Yan; Yang, Hui; Zhang, Jianliang

    2017-02-01

    Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathy, Huntington's disease and multiple sclerosis.

  8. Convergent molecular defects underpin diverse neurodegenerative diseases.

    Science.gov (United States)

    Tofaris, George K; Buckley, Noel J

    2018-02-19

    In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood?

    Science.gov (United States)

    Faa, G; Marcialis, M A; Ravarino, A; Piras, M; Pintus, M C; Fanos, V

    2014-01-01

    In recent years, evidence is growing on the role played by gestational factors in shaping brain development and on the influence of intrauterine experiences on later development of neurodegenerative diseases including Parkinson's (PD) and Alzheimer's disease (AD). The nine months of intrauterine development and the first three years of postnatal life are appearing to be extremely critical for making connections among neurons and among neuronal and glial cells that will shape a lifetime of experience. Here, the multiple epigenetic factors acting during gestation - including maternal diet, malnutrition, stress, hypertension, maternal diabetes, fetal hypoxia, prematurity, low birth weight, prenatal infection, intrauterine growth restriction, drugs administered to the mother or to the baby - are reported, and their ability to modulate brain development, resulting in interindividual variability in the total neuronal and glial burden at birth is discussed. Data from recent literature suggest that prevention of neurodegeneration should be identified as the one method to halt the diffusion of neurodegenerative diseases. The "two hits" hypothesis, first introduced for PD and successfully applied to AD and other neurodegenerative human pathologies, should focus our attention on a peculiar period of our life: the intrauterine and perinatal periods. The first hit to our nervous system occurs early in life, determining a PD or AD imprinting to our brain that will condition our resistance or, alternatively, our susceptibility to develop a neurodegenerative disease later in life. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including PD and AD, is emerging as a new fascinating research focus. This assumption implies that research on prevention of neurodegenerative diseases should center on events taking place early in life, during gestation and in the perinatal periods, thus presenting a new challenge to

  10. A new wall function boundary condition including heat release effect for supersonic combustion flows

    International Nuclear Information System (INIS)

    Gao, Zhen-Xun; Jiang, Chong-Wen; Lee, Chun-Hian

    2016-01-01

    Highlights: • A new wall function including heat release effect is theoretically derived. • The new wall function is a unified form holding for flows with/without combustion. • The new wall function shows good results for a supersonic combustion case. - Abstract: A new wall function boundary condition considering combustion heat release effect (denoted as CWFBC) is proposed, for efficient predictions of skin friction and heat transfer in supersonic combustion flows. Based on a standard flow model including boundary-layer combustion, the Shvab–Zeldovich coupling parameters are introduced to derive a new velocity law-of-the-wall including the influence of combustion. For the temperature law-of-the-wall, it is proposed to use the enthalpy–velocity relation, instead of the Crocco–Busemann equation, to eliminate explicit influence of chemical reactions. The obtained velocity and temperature law-of-the-walls constitute the CWFBC, which is a unified form simultaneously holding for single-species, multi-species mixing and multi-species reactive flows. The subsequent numerical simulations using this CWFBC on an experimental case indicate that the CWFBC could accurately reflect the influences on the skin friction and heat transfer by the chemical reactions and heat release, and show large improvements compared to previous WFBC. Moreover, the CWFBC can give accurate skin friction and heat flux for a coarse mesh with y"+ up to 200 for the experimental case, except for slightly larger discrepancy of the wall heat flux around ignition position.

  11. Molecular diagnostics of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Megha eAgrawal

    2015-09-01

    Full Text Available Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer’s and Parkinson’s disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.

  12. Molecular diagnostics of neurodegenerative disorders.

    Science.gov (United States)

    Agrawal, Megha; Biswas, Abhijit

    2015-01-01

    Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.

  13. Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases.

    Science.gov (United States)

    Martin-Jiménez, Cynthia A; García-Vega, Ángela; Cabezas, Ricardo; Aliev, Gjumrakch; Echeverria, Valentina; González, Janneth; Barreto, George E

    2017-11-01

    Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Transcranial Direct Current Stimulation in Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Argye E. Hillis

    2014-04-01

    Full Text Available We review rationale, challenges, study designs, reported results, and future directions in the use of transcranial direct cranial stimulation (tDCS in neurodegenerative disease, focusing on treatment of spelling in primary progressive aphasia (PPA. Rationale Evidence from both animal studies and human studies indicates that anodal and cathodal tDCS over the brain result in a temporary change in membrane potentials, reducing the threshold for long-term potentiation of neurons in the affected area. This may allow unaffected brain regions to assume functions of diseased regions. Challenges Special challenges in treating individuals with progressive conditions include altered goals of treatment and the possibility that participants may accumulate new deficits over the course of the treatment program that interfere with their ability to understand, retain, or cooperate with aspects of the program. The most serious challenge – particularly for single case designs - is that there may be no stable baseline against which to measure change with treatment. Thus, it is essential to demonstrate that treatment results in a statistically significant change in the slope of decline or improvement. Therefore, demonstration of a significant difference between tDCS and control (sham requires either a large number of participants or a large effect size. Designs The choice of a treatment design reflects these limitations. Group studies with a randomized, double-blind, sham control trial design (without cross-over provide the greatest power to detect a difference between intervention and control conditions, with the fewest participants. A cross-over design, in which all participants (from 1 to many receive both active and sham conditions, in randomized order, requires a larger effect size for the active condition relative to the control condition (or little to no maintenance of treatment gains or carry-over effect to show significant differences between treatment

  15. Heat shock protein 90 in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Rodina Anna

    2010-06-01

    Full Text Available Abstract Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1, the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

  16. Chameleon sequences in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Bahramali, Golnaz; Goliaei, Bahram; Minuchehr, Zarrin; Salari, Ali

    2016-01-01

    Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to “helix to strand (HE)”, “helix to coil (HC)” and “strand to coil (CE)” alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases.

  17. Chameleon sequences in neurodegenerative diseases.

    Science.gov (United States)

    Bahramali, Golnaz; Goliaei, Bahram; Minuchehr, Zarrin; Salari, Ali

    2016-03-25

    Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to "helix to strand (HE)", "helix to coil (HC)" and "strand to coil (CE)" alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Chameleon sequences in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Bahramali, Golnaz [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Goliaei, Bahram, E-mail: goliaei@ut.ac.ir [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Minuchehr, Zarrin, E-mail: minuchehr@nigeb.ac.ir [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of); Salari, Ali [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of)

    2016-03-25

    Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to “helix to strand (HE)”, “helix to coil (HC)” and “strand to coil (CE)” alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases.

  19. Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI).

    Science.gov (United States)

    Montero-Odasso, Manuel; Pieruccini-Faria, Frederico; Bartha, Robert; Black, Sandra E; Finger, Elizabeth; Freedman, Morris; Greenberg, Barry; Grimes, David A; Hegele, Robert A; Hudson, Christopher; Kleinstiver, Peter W; Lang, Anthony E; Masellis, Mario; McLaughlin, Paula M; Munoz, Douglas P; Strother, Stephen; Swartz, Richard H; Symons, Sean; Tartaglia, Maria Carmela; Zinman, Lorne; Strong, Michael J; McIlroy, William

    2017-01-01

    The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

  20. Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia.

    Science.gov (United States)

    Chiang, Shannon; Kalinowski, Danuta S; Jansson, Patric J; Richardson, Des R; Huang, Michael L-H

    2017-08-04

    Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. The role of thiamine in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Irena Bubko

    2015-09-01

    Full Text Available Vitamin B1 (thiamine plays an important role in metabolism. It is indispensable for normal growth and development of the organism. Thiamine has a favourable impact on a number of systems, including the digestive, cardiovascular and nervous systems. It also stimulates the brain and improves the psycho-emotional state. Hence it is often called the vitamin of “reassurance of the spirit”. Thiamine is a water-soluble vitamin. It can be present in the free form as thiamine or as its phosphate esters: mono-, di- or triphosphate. The main source of thiamine as an exogenous vitamin is certain foodstuffs, but trace amounts can be synthesised by microorganisms of the large intestine. The recommended daily intake of thiamine is about 2.0 mg. Since vitamin B1 has no ability to accumulate in the organism, manifestations of its deficiency begin to appear very quickly. The chronic state of thiamine deficiency, to a large extent, because of its function, contributes to the development of neurodegenerative diseases. It was proved that supporting vitamin B1 therapy not only constitutes neuroprotection but can also have a favourable impact on advanced neurodegenerative diseases. This article presents the current state of knowledge as regards the effects of thiamine exerted through this vitamin in a number of diseases such as Parkinson’s disease, Alzheimer’s disease, Wernicke’s encephalopathy or Wernicke-Korsakoff syndrome and Huntington’s disease.

  2. TRPM2, calcium and neurodegenerative diseases

    Science.gov (United States)

    Xie, Yu-Feng; MacDonald, John F; Jackson, Michael F

    2010-01-01

    NMDA receptor overactivation triggers intracellular Ca2+ dysregulation, which has long been thought to be critical for initiating excitotoxic cell death cascades associated with stroke and neurodegenerative disease. The inability of NMDA receptor antagonists to afford neuroprotection in clinical stroke trials has led to a re-evaluation of excitotoxic models of cell death and has focused research efforts towards identifying additional Ca2+ influx pathways. Recent studies indicate that TRPM2, a member of the TRPM subfamily of Ca2+-permeant, non-selective cation channel, plays an important role in mediating cellular responses to a wide range of stimuli that, under certain situations, can induce cell death. These include reactive oxygen and nitrogen species, tumour necrosis factor as well as soluble oli-gomers of amyloid beta. However, the molecular basis of TRPM2 channel involvement in these processes is not fully understood. In this review, we summarize recent studies about the regulation of TRPM2, its interaction with calcium and the possible implications for neurodegenerative diseases. PMID:21383889

  3. Ghrelin and Neurodegenerative Disorders-a Review.

    Science.gov (United States)

    Shi, Limin; Du, Xixun; Jiang, Hong; Xie, Junxia

    2017-03-01

    Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor 1a (GHS-R1a), is a gut-derived, orexigenic peptide hormone that primarily regulates growth hormone secretion, food intake, and energy homeostasis. With the wide expression of GHS-R1a in extra-hypothalamic regions, the physiological role of ghrelin is more extensive than solely its involvement in metabolic function. Ghrelin has been shown to be involved in numerous higher brain functions, such as memory, reward, mood, and sleep. Some of these functions are disrupted in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This link between ghrelin and these neurodegenerative diseases is supported by numerous studies. This review aims to provide a comprehensive overview of the most recent evidence of the novel neuromodulatory role of ghrelin in PD, AD, and HD. Moreover, the changes in circulating and/or central ghrelin levels that are associated with disease progression are also postulated to be a biomarker for clinical diagnosis and therapy.

  4. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases.

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-04-01

    A small proportion of cases seen in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), Parkinson\\'s disease and Alzheimer disease are familial. These familial cases are usually clinically indistinguishable from sporadic cases. Identifying familial cases is important both in terms of clinical guidance for family members and for gene discovery.

  5. The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

    Science.gov (United States)

    Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

    2016-10-15

    One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Role of sigma-1 receptors in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Linda Nguyen

    2015-01-01

    Full Text Available Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

  7. Role of Ionizing Radiation in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Neel K. Sharma

    2018-05-01

    Full Text Available Ionizing radiation (IR from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR.

  8. Role of Ionizing Radiation in Neurodegenerative Diseases

    Science.gov (United States)

    Sharma, Neel K.; Sharma, Rupali; Mathur, Deepali; Sharad, Shashwat; Minhas, Gillipsie; Bhatia, Kulsajan; Anand, Akshay; Ghosh, Sanchita P.

    2018-01-01

    Ionizing radiation (IR) from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR. PMID:29867445

  9. Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

    Science.gov (United States)

    de Souza, Jessica M.; Goncalves, Bruno D. C.; Gomez, Marcus V.; Vieira, Luciene B.; Ribeiro, Fabiola M.

    2018-01-01

    Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, brain

  10. A Lumped Thermal Model Including Thermal Coupling and Thermal Boundary Conditions for High Power IGBT Modules

    DEFF Research Database (Denmark)

    Bahman, Amir Sajjad; Ma, Ke; Blaabjerg, Frede

    2018-01-01

    Detailed thermal dynamics of high power IGBT modules are important information for the reliability analysis and thermal design of power electronic systems. However, the existing thermal models have their limits to correctly predict these complicated thermal behavior in the IGBTs: The typically used...... thermal model based on one-dimensional RC lumps have limits to provide temperature distributions inside the device, moreover some variable factors in the real-field applications like the cooling and heating conditions of the converter cannot be adapted. On the other hand, the more advanced three......-dimensional thermal models based on Finite Element Method (FEM) need massive computations, which make the long-term thermal dynamics difficult to calculate. In this paper, a new lumped three-dimensional thermal model is proposed, which can be easily characterized from FEM simulations and can acquire the critical...

  11. In silico studies in drug research against neurodegenerative diseases.

    Science.gov (United States)

    Makhouri, Farahnaz Rezaei; Ghasemi, Jahan B

    2017-08-22

    Neurodegenerative diseases such as Alzheimer's disease (AD), progressive neurodegenerative forms of Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective dysfunction and degeneration of neurons and axons in the central nervous system (CNS). Computer-aided or in silico design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays. In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches. Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Redox Imbalance and Viral Infections in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-01-01

    Full Text Available Reactive oxygen species (ROS are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD, Alzheimer’s disease (AD, and amyotrophic lateral sclerosis (ALS.

  13. Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Kurt A. Jellinger

    2011-01-01

    Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

  14. Neuroproteases in peptide neurotransmission and neurodegenerative diseases: applications to drug discovery research.

    Science.gov (United States)

    Hook, Vivian Y H

    2006-01-01

    The nervous system represents a key area for development of novel therapeutic agents for the treatment of neurological and neurodegenerative diseases. Recent research has demonstrated the critical importance of neuroproteases for the production of specific peptide neurotransmitters and for the production of toxic peptides in major neurodegenerative diseases that include Alzheimer, Huntington, and Parkinson diseases. This review illustrates the successful criteria that have allowed identification of proteases responsible for converting protein precursors into active peptide neurotransmitters, consisting of dual cysteine protease and subtilisin-like protease pathways in neuroendocrine cells. These peptide neurotransmitters are critical regulators of neurologic conditions, including analgesia and cognition, and numerous behaviors. Importantly, protease pathways also represent prominent mechanisms in neurodegenerative diseases, especially Alzheimer, Huntington, and Parkinson diseases. Recent studies have identified secretory vesicle cathepsin B as a novel beta-secretase for production of the neurotoxic beta-amyloid (Abeta) peptide of Alzheimer disease. Moreover, inhibition of cathepsin B reduces Abeta peptide levels in brain. These neuroproteases potentially represent new drug targets that should be explored in future pharmaceutical research endeavors for drug discovery.

  15. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders

    International Nuclear Information System (INIS)

    Agarwal, Swati; Yadav, Anuradha; Chaturvedi, Rajnish Kumar

    2017-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models. - Highlights: • Peroxisome -activated receptors (PPARs) serve to be a promising therapeutic target for several neurodegenerative disorders. • PPAR agonist as well as provides neuroprotection in vitro as well as in vivo animal models of neurodegenerative disorders. • PPAR activating anti-inflammatory drugs use is effective in decreasing progression of neurodegenerative diseases.

  16. Nanobiomaterials' applications in neurodegenerative diseases.

    Science.gov (United States)

    Silva Adaya, Daniela; Aguirre-Cruz, Lucinda; Guevara, Jorge; Ortiz-Islas, Emma

    2017-02-01

    The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.

  17. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders

    NARCIS (Netherlands)

    Stoyanova, Irina

    2014-01-01

    Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics:

  18. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

    Science.gov (United States)

    Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

    2016-06-01

    Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Comparative Incidence of Conformational, Neurodegenerative Disorders.

    Directory of Open Access Journals (Sweden)

    Jesús de Pedro-Cuesta

    Full Text Available The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs.We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD. We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD forms, amyotrophic lateral sclerosis (ALS, and sporadic rapidly progressing neurodegenerative dementia (sRPNDd. For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined.Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD, to 1589 and 2589 for AMD and Alzheimer's disease (AD respectively. Age-specific profiles varied from (a symmetrical, inverted V-shaped curves for low incidences to (b those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration.These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might

  20. Comparative Incidence of Conformational, Neurodegenerative Disorders

    Science.gov (United States)

    de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

    2015-01-01

    Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to

  1. Neurodegenerative Disorders Treatment: The MicroRNA Role.

    Science.gov (United States)

    Ridolfi, Barbara; Abdel-Haq, Hanin

    2017-01-01

    Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and prion disease are not timely and effectively treated using conventional therapies. This emphasizes the need for alternative therapeutic approaches. In this respect, gene-based therapies have been adopted as potentially feasible alternative therapies, where the microRNA (miRNA) approach has experienced a great explosion in recent years. Because miRNAs have been shown to be implicated in the pathogenesis of several diseases including neurodegenerative diseases, they are intensely studied as candidates for diagnostic and prognostic biomarkers, as predictors of drug response and as therapeutic agents. In this review, we evaluate the feasibility of both direct and indirect miRNA mimics and inhibitors toward the regulation of neurodegenerative-related genes both in vivo and in vitro models, highlight the advantages and drawbacks associated with miRNA-based therapy, and summarize the relevant techniques and approaches attempted to deliver miRNAs to the central nervous system for therapeutic purposes, with particular regard to the exosomes. Additionally, we describe a new approach that holds great promise for the treatment of a wide range of diseases including neurodegenerative disorders. This approach is based on addressing the incorporation of miRNAs into exosomes to increase the quantity and quality of miRNA packed and delivered to the central nervous system and other sites of action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Quantitative analysis on electrooculography (EOG) for neurodegenerative disease

    Science.gov (United States)

    Liu, Chang-Chia; Chaovalitwongse, W. Art; Pardalos, Panos M.; Seref, Onur; Xanthopoulos, Petros; Sackellares, J. C.; Skidmore, Frank M.

    2007-11-01

    Many studies have documented abnormal horizontal and vertical eye movements in human neurodegenerative disease as well as during altered states of consciousness (including drowsiness and intoxication) in healthy adults. Eye movement measurement may play an important role measuring the progress of neurodegenerative diseases and state of alertness in healthy individuals. There are several techniques for measuring eye movement, Infrared detection technique (IR). Video-oculography (VOG), Scleral eye coil and EOG. Among those available recording techniques, EOG is a major source for monitoring the abnormal eye movement. In this real-time quantitative analysis study, the methods which can capture the characteristic of the eye movement were proposed to accurately categorize the state of neurodegenerative subjects. The EOG recordings were taken while 5 tested subjects were watching a short (>120 s) animation clip. In response to the animated clip the participants executed a number of eye movements, including vertical smooth pursued (SVP), horizontal smooth pursued (HVP) and random saccades (RS). Detection of abnormalities in ocular movement may improve our diagnosis and understanding a neurodegenerative disease and altered states of consciousness. A standard real-time quantitative analysis will improve detection and provide a better understanding of pathology in these disorders.

  3. Cerebral correlates of psychotic syndromes in neurodegenerative diseases

    OpenAIRE

    Jellinger, Kurt A

    2012-01-01

    Abstract Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer?s disease, synucleinopathies (Parkinson?s disease, dementia with Lewy bodies), Huntington?s disease, frontotemporal degenerations, motoneuron and prion...

  4. Transmission of Neurodegenerative Disorders Through Blood Transfusion

    DEFF Research Database (Denmark)

    Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus

    2016-01-01

    BACKGROUND: The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health...... implications. OBJECTIVE: To investigate possible transfusion transmission of neurodegenerative disorders. DESIGN: Retrospective cohort study. SETTING: Nationwide registers of transfusions in Sweden and Denmark. PARTICIPANTS: 1 465 845 patients who received transfusions between 1968 and 2012. MEASUREMENTS.......9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy...

  5. The aging brain and neurodegenerative disorders

    International Nuclear Information System (INIS)

    Braffman, B.H.; Trojanowski, J.Q.; Atlas, S.W.

    1991-01-01

    Both the aging brain and neurodegenerative disorders are characterized by a lack of vital endurance of affected neurons resulting in their premature death. Neuronal shrinkage or atrophy and death are normal and inevitable aspects of normal or successful aging; this is unexpected, excessive, and premature in neurodegenerative disorders. These histologic changes result in the neuroimaging findings of focal and/or diffuse atrophy with consequent enlargement of cerebrospinal fluid (CSF) spaces. The aging brain and neurodegenerative disorders share other magnetic resonance (MR) changes, i.e., markedly hypointense extrapyramidal nuclei and hyperintense white matter foci. The sequelae of senescent vascular changes result in additional characteristic features of the aging brain. This paper presents the MR and neuropathologic manifestations of both the normal aging brain and the brain affected by neurodegenerative disorders

  6. Sleep and caregiving : sleeping practices of couples facing neurodegenerative diseases

    OpenAIRE

    Casini , Elisa

    2017-01-01

    This doctoral dissertation in sociology examines the sleep practices of ageing couples confronted with neuro-degenerative conditions. It aims to understand the time- and space-related aspects of these sleep practices, so central to couples’ lives, throughout the different stages of illness, and places particular emphasis on gender-based relations. Thirty couples were interviewed in their homes, 12 of whom were affected by Lewy Body Dementia and 18 by Alzheimer’s Disease. Empirical methods suc...

  7. Coenzyme Q10 effects in neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Meredith Spindler

    2009-11-01

    Full Text Available Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10 is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.Keywords: coenzyme Q10, neurodegenerative disease, Parkinson’s disease, Huntington’s disease, mitochondrial dysfunction

  8. Expression of Nrf2 in neurodegenerative diseases.

    Science.gov (United States)

    Ramsey, Chenere P; Glass, Charles A; Montgomery, Marshall B; Lindl, Kathryn A; Ritson, Gillian P; Chia, Luis A; Hamilton, Ronald L; Chu, Charleen T; Jordan-Sciutto, Kelly L

    2007-01-01

    In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

  9. Folic acid, neurodegenerative and neuropsychiatric disease.

    Science.gov (United States)

    Kronenberg, Golo; Colla, Michael; Endres, Matthias

    2009-04-01

    Folic acid plays an important role in neuroplasticity and in the maintenance of neuronal integrity. Folate is a co-factor in one-carbon metabolism during which it promotes the regeneration of methionine from homocysteine, a highly reactive sulfur-containing amino acid. Methionine may then be converted to S-adenosylmethionine (SAM), the principal methyl donor in most biosynthetic methylation reactions. On the cellular level, folate deficiency and hyperhomocysteinemia exert multiple detrimental effects. These include induction of DNA damage, uracil misincorporation into DNA and altered patterns of DNA methylation. Low folate status and elevated homocysteine increase the generation of reactive oxygen species and contribute to excitotoxicity and mitochondrial dysfunction which may lead to apoptosis. Strong epidemiological and experimental evidence links derangements of one-carbon metabolism to vascular, neurodegenerative and neuropsychiatric disease, including most prominently cerebral ischemia, Alzheimer's dementia and depression. Although firm evidence from controlled clinical trials is largely lacking, B-vitamin supplementation and homocysteine reduction may have a role especially in the primary prevention of stroke and dementia as well as as an adjunct to antidepressant pharmacotherapy.

  10. Progranulin: at the interface of neurodegenerative and metabolic diseases.

    Science.gov (United States)

    Nguyen, Andrew D; Nguyen, Thi A; Martens, Lauren Herl; Mitic, Laura L; Farese, Robert V

    2013-12-01

    Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor-like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. We review here progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight the growth factor-like, trophic, and anti-inflammatory properties of progranulin as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Health benefits of methylxanthines in neurodegenerative diseases.

    Science.gov (United States)

    Oñatibia-Astibia, Ainhoa; Franco, Rafael; Martínez-Pinilla, Eva

    2017-06-01

    Methylxanthines (MTXs) are consumed by almost everybody in almost every area of the world. Caffeine, theophylline and theobromine are the most well-known members of this family of compounds; they are present, inter alia, in coffee, tea, cacao, yerba mate and cola drinks. MTXs are readily absorbed in the gastrointestinal tract and are able to penetrate into the central nervous system, where they exert significant psychostimulant actions, which are more evident in acute intake. Coffee has been paradigmatic, as its use was forbidden in many diseases, however, this negative view has radically changed; evidence shows that MTXs display health benefits in diseases involving cell death in the nervous system. This paper reviews data that appraise the preventive and even therapeutic potential of MTXs in a variety of neurodegenerative diseases. Future perspectives include the use of MTXs to advance the understanding the pathophysiology of, inter alia, Alzheimer's disease (AD) and Parkinson's disease (PD), and the use of the methylxanthine chemical moiety as a basis for the development of new and more efficacious drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Mapping Neurodegenerative Disease Onset and Progression.

    Science.gov (United States)

    Seeley, William W

    2017-08-01

    Brain networks have been of long-standing interest to neurodegeneration researchers, including but not limited to investigators focusing on conventional prion diseases, which are known to propagate along neural pathways. Tools for human network mapping, however, remained inadequate, limiting our understanding of human brain network architecture and preventing clinical research applications. Until recently, neuropathological studies were the only viable approach to mapping disease onset and progression in humans but required large autopsy cohorts and laborious methods for whole-brain sectioning and staining. Despite important advantages, postmortem studies cannot address in vivo, physiological, or longitudinal questions and have limited potential to explore early-stage disease except for the most common disorders. Emerging in vivo network-based neuroimaging strategies have begun to address these issues, providing data that complement the neuropathological tradition. Overall, findings to date highlight several fundamental principles of neurodegenerative disease anatomy and pathogenesis, as well as some enduring mysteries. These principles and mysteries provide a road map for future research. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  13. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

    Science.gov (United States)

    Simon, Matthew J; Iliff, Jeffrey J

    2016-03-01

    Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

    Science.gov (United States)

    Jellinger, Kurt A

    2012-05-01

    Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general. © 2011 The Author Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  15. Cannabinoids and value-based decision making: Implications for neurodegenerative disorders

    NARCIS (Netherlands)

    Lee, AM; Oleson, E.B.; Diergaarde, L.; Cheer, J.F.; Pattij, T.

    2012-01-01

    In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson's disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired

  16. The ubiquitin proteasome system in glia and its role in neurodegenerative diseases

    NARCIS (Netherlands)

    Jansen, Anne H. P.; Reits, Eric A. J.; Hol, Elly M.

    2014-01-01

    The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's,

  17. Excitatory amino acid neurotoxicity and neurodegenerative disease.

    Science.gov (United States)

    Meldrum, B; Garthwaite, J

    1990-09-01

    The progress over the last 30 years in defining the role of excitatory amino acids in normal physiological function and in the abnormal neuronal activity of epilepsy has been reviewed in earlier articles in this series. In the last five years it has become clear that excitatory amino acids also play a role in a wide range of neurodegenerative processes. The evidence is clearest where the degenerative process is acute, but is more controversial for slow degenerative processes. In this article Brian Meldrum and John Garthwaite review in vivo and in vitro studies of the cytotoxicity of amino acids and summarize the contribution of such toxicity to acute and chronic neurodegenerative disorders.

  18. Olfactory memory impairment in neurodegenerative diseases.

    Science.gov (United States)

    Bahuleyan, Biju; Singh, Satendra

    2012-10-01

    Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the present review was to discuss the available scientific knowledge on the olfactory memory and to relate its impairment with neurodegenerative diseases.

  19. Olfaction in Neurologic and Neurodegenerative Diseases: A Literature Review

    Directory of Open Access Journals (Sweden)

    Godoy, Maria Dantas Costa Lima

    2015-01-01

    Full Text Available Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia.

  20. LSTM for diagnosis of neurodegenerative diseases using gait data

    Science.gov (United States)

    Zhao, Aite; Qi, Lin; Li, Jie; Dong, Junyu; Yu, Hui

    2018-04-01

    Neurodegenerative diseases (NDs) usually cause gait disorders and postural disorders, which provides an important basis for NDs diagnosis. By observing and analyzing these clinical manifestations, medical specialists finally give diagnostic results to the patient, which is inefficient and can be easily affected by doctors' subjectivity. In this paper, we propose a two-layer Long Short-Term Memory (LSTM) model to learn the gait patterns exhibited in the three NDs. The model was trained and tested using temporal data that was recorded by force-sensitive resistors including time series, such as stride interval and swing interval. Our proposed method outperforms other methods in literature in accordance with accuracy of the predicted diagnostic result. Our approach aims at providing the quantitative assessment so that to indicate the diagnosis and treatment of these neurodegenerative diseases in clinic

  1. Sublethal RNA Oxidation as a Mechanism for Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Mark A. Smith

    2008-05-01

    Full Text Available Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.

  2. Medicinal Plants in Neurodegenerative Diseases: Perspective of Traditional Persian Medicine.

    Science.gov (United States)

    Farzaei, Mohammad Hosein; Shahpiri, Zahra; Mehri, Mohammad Reza; Bahramsoltani, Roodabeh; Rezaei, Mahdi; Raeesdana, Azade; Rahimi, Roja

    2018-01-01

    Neurodegenerative diseases are a progressive loss of structure and/or function of neurons. Weak therapeutic response and progressive nature of the diseases, as well as a wide range of side effects caused by conventional therapeutic approaches make patients seek for complementary and alternative medicine. The aim of the present paper is to discuss the neuropharmacological basis of medicinal plants and their principle phytochemicals which have been used in traditional Persian medicine for different types of neurodegenerative diseases. Medicinal plants introduced in traditional Persian medicine perform beneficial effects in neurodegenerative diseases via various cellular and molecular mechanisms including suppression of apoptosis mediated by an increase in the expression of anti-apoptotic agents (e.g. Bcl-2) as well as a decrease in the expression and activity of proapoptotic proteins (e.g. Bax, caspase 3 and 9). Alleviating inflammatory responses and suppressing the expression and function of pro-inflammatory cytokines like Tumor necrosis factor α and interleukins, as well as improvement in antioxidative performance mediated by superoxide dismutase and catalase, are among other neuroprotective mechanisms of traditional medicinal plants. Modulation of transcription, transduction, intracellular signaling pathways including ERK, p38, and MAPK, with upstream regulatory activity on inflammatory cascades, apoptosis and oxidative stress associated pathways, play an essential role in the preventive and therapeutic potential of the plants in neurodegenerative diseases. Medicinal plants used in traditional Persian medicine along with their related phytochemicals by affecting various neuropharmacological pathways can be considered as future drugs or adjuvant therapies with conventional pharmacotherapeutics; though, further clinical studies are necessary for the confirmation of their safety and efficacy. Copyright© Bentham Science Publishers; For any queries, please email at

  3. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

    Science.gov (United States)

    Bellingham, Shayne A; Guo, Belinda B; Coleman, Bradley M; Hill, Andrew F

    2012-01-01

    Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

  4. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jocelyn M Madeira

    2015-01-01

    Full Text Available Neurodegenerative disorders including Alzheimer′s disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

  5. Neural Substrates of Spontaneous Narrative Production in Focal Neurodegenerative Disease

    Science.gov (United States)

    Gola, Kelly A.; Thorne, Avril; Veldhuisen, Lisa D.; Felix, Cordula M.; Hankinson, Sarah; Pham, Julie; Shany-Ur, Tal; Schauer, Guido P.; Stanley, Christine M.; Glenn, Shenly; Miller, Bruce L.; Rankin, Katherine P.

    2016-01-01

    Conversational storytelling integrates diverse cognitive and socio-emotional abilities that critically differ across neurodegenerative disease groups and may have diagnostic relevance and predict anatomic changes. The present study employed mixed methods discourse and quantitative analyses to delineate patterns of storytelling across focal neurodegenerative disease groups, and to clarify the neuroanatomical contributions to common storytelling characteristics in these patients. Transcripts of spontaneous social interactions of 46 participants (15 behavioral variant frontotemporal dementia (bvFTD), 7 semantic variant primary progressive aphasia (svPPA), 12 Alzheimer's disease (AD), and 12 healthy older normal controls) were analysed for storytelling characteristics and frequency, and videos of the interactions were rated for patients' social attentiveness. Compared to controls, svPPAs also told more stories and autobiographical stories, and perseverated on aspects of self during storytelling. ADs told fewer autobiographical stories than NCs, and svPPAs and bvFTDs failed to attend to social cues. Storytelling characteristics were associated with a processing speed and mental flexibility, and voxel-based anatomic analysis of structural magnetic resonance imaging revealed that temporal organization, evaluations, and social attention correlated with atrophy corresponding to known intrinsic connectivity networks, including the default mode, limbic, salience, and stable task control networks. Differences in spontaneous storytelling among neurodegenerative groups elucidated diverse cognitive, socio-emotional, and neural contributions to narrative production, with implications for diagnostic screening and therapeutic intervention. PMID:26485159

  6. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

    Directory of Open Access Journals (Sweden)

    Jose A. Santiago

    2017-05-01

    Full Text Available Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer’s (AD, Parkinson’s (PD and Huntington’s diseases (HD. We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

  7. On one-loop corrections to matching conditions of lattice HQET including 1/m{sub b} terms

    Energy Technology Data Exchange (ETDEWEB)

    Korcyl, Piotr [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC

    2013-12-15

    HQET is an effective theory for QCD with N{sub f} light quarks and a massive valence quark if the mass of the latter is much bigger than LQCD. As any effective theory, HQET is predictive only when a set of parameters has been determined through a process called matching. The non-perturbative matching procedure including 1/m{sub b} terms, developed by the ALPHA collaboration, consists of 19 carefully chosen observables which are precisely computable in lattice QCD as well as in lattice HQET. The matching conditions are then a set of 19 equations which relate the QCD and HQET values of these observables. We present a study of one-loop corrections to two generic matching observables involving correlation function with an insertion of the A{sub 0} operator. Our results enable us to quantify the quality of the relevant observables in view of the envisaged nonperturbative implementation of this matching procedure.

  8. Applications of the conjugate gradient FFT method in scattering and radiation including simulations with impedance boundary conditions

    Science.gov (United States)

    Barkeshli, Kasra; Volakis, John L.

    1991-01-01

    The theoretical and computational aspects related to the application of the Conjugate Gradient FFT (CGFFT) method in computational electromagnetics are examined. The advantages of applying the CGFFT method to a class of large scale scattering and radiation problems are outlined. The main advantages of the method stem from its iterative nature which eliminates a need to form the system matrix (thus reducing the computer memory allocation requirements) and guarantees convergence to the true solution in a finite number of steps. Results are presented for various radiators and scatterers including thin cylindrical dipole antennas, thin conductive and resistive strips and plates, as well as dielectric cylinders. Solutions of integral equations derived on the basis of generalized impedance boundary conditions (GIBC) are also examined. The boundary conditions can be used to replace the profile of a material coating by an impedance sheet or insert, thus, eliminating the need to introduce unknown polarization currents within the volume of the layer. A general full wave analysis of 2-D and 3-D rectangular grooves and cavities is presented which will also serve as a reference for future work.

  9. Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

    Science.gov (United States)

    Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E

    2017-03-01

    Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of

  10. Synaptic activity and bioenergy homeostasis: implications in brain trauma and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Natasha eKhatri

    2013-12-01

    Full Text Available Powered by glucose metabolism, the brain is the most energy-demanding organ in our body, accounting for a quarter of total oxygen consumption. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport and mitochondria translocation. Energy insufficiency will be sensed by the AMP-activated dependent protein kinase (AMPK, a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries.

  11. Retrospective cohort study shows that the risks for retinopathy of prematurity included birth age and weight, medical conditions and treatment.

    Science.gov (United States)

    Ali, Aliaa A; Gomaa, Nancy A S; Awadein, Ahmed R; Al-Hayouti, Huda H; Hegazy, Ahmed I

    2017-12-01

    This study described the characteristics and risk factors of neonates who developed retinopathy of prematurity (ROP) and severe treatable ROP in two Egyptian neonatal intensive care units (NICUs). This retrospective cohort study comprised 108 preterm neonates who were screened for ROP after being admitted to the two NICUs run by Cairo University Hospital from June 2014 to May 2015. Patients were examined using digital fundus photography and indirect ophthalmoscopy was performed if ROP was detected. Retinopathy of prematurity occurred in 75 patients. Late-onset sepsis, ventilation and hypercapnia were independently associated with ROP. Patients who developed severe treatable ROP had a younger gestational age (GA) than patients who did not develop ROP or developed mild or moderate ROP (29 weeks, range 27-33 weeks versus 32 weeks, range 28-36 weeks, p = 0.002) and a lower birthweight (1200 g, range 980-1590 g versus 1460 g, range 770-2475 g, p = 0.029). The risk factors associated with severe treatable ROP included the duration of admission, the duration of incubator oxygen, late-onset sepsis, intraventricular haemorrhage, total parenteral nutrition and the duration of caffeine citrate therapy. This study showed that the risks for ROP were wide-ranging and included GA and weight, medical conditions and treatment. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  12. Pain in Neurodegenerative Disease : Current Knowledge and Future Perspectives

    NARCIS (Netherlands)

    de Tommaso, Marina; Arendt-Nielsen, Lars; Defrin, Ruth; Kunz, Miriam; Pickering, Gisele; Valeriani, Massimiliano

    2016-01-01

    Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington's disease (HD),

  13. Olfactory Memory Impairment in Neurodegenerative Diseases

    OpenAIRE

    Bahuleyan, Biju; Singh, Satendra

    2012-01-01

    Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the prese...

  14. Synthetic prions and other human neurodegenerative proteinopathies.

    Science.gov (United States)

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-02

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Methods for the prognosus and suagnosis of neurodegenerative diseases

    OpenAIRE

    Naranjo, José Ramón; Mellström, Britt; Rábano, Alberto

    2014-01-01

    [EN] The present invention corresponds to the field of neurobiology and relates to methods for predicting the appearance of a neurodegenerative disease in a subject, for diagnosing the prodromic stage of a neurodegenerative disease in a subject, for predicting whether a subject diagnosed of a prodromic stage of a neurodegenerative disease will develop said neurodegenerative disease and for selecting a subject for a therapy for the prevention and/or treatment of a prodromic stage of a neurode...

  16. The early warning system of landslides and sediment runoffs using meteorological condition including rainfall-soil moisture index (Invited)

    Science.gov (United States)

    Kubota, T.; Silva, I. C.; Hasnawir, H.

    2009-12-01

    The research including observation of rain, soil moisture content and sediment discharge is conducted on a torrent in northern Kyushu whose geology consists of Paleozoic metamorphic rocks (mainly schist) and whose vegetation consists of mainly Japanese cypress and cedar. Soil depth is approximately 50cm in average and permeability k is 0.1~0.01 order. With data obtained by the observation for more than 4 years, standard rainfalls of warning and evacuation against the sudden sediment runoffs are analyzed. Then, the result was compared with the ones in Nuevo Leon Mexico (geology of schist, slate, k=0.01~0.001 order) and in southern Sulawesi Island Indonesia (volcanic geology, k=0.001~0.0001 order). Hitherto, various methods were proposed to analyze the warning critical standard for landslide disaster or large sediment discharge. In this study, we employed Hirano's element slope runoff theory, the Self Organized Criticality Assumption (SOC), and the Elementary Catastrophe Theory (ETC) to analyze the data, although the soil moisture fluctuation, meteorological condition such as upper air wind and dew point depression, the rainfall-soil moisture index provided by Japan Meteorological Agency was considered. The last one is a cutting edge technology based on the tank model calculation of soil moisture content combined with short term rainfall prediction which is a product of numerical simulation using radar image advection analysis compensated with surface rain data and with orographic rain effect. In Hirano's theory, we can describe the critical rain Rc and rain intensity Ric as following equation. Q/A/M/ cosθ = Ri ∫(r*cosθ)dt = Ri*R (1) ∴ Ric*Rc = C (2) Here, Q: sediment runoff or debris flow discharge, A: watershed area, M: function concerning with sediment deposit features on the upstream torrents or slopes (porosity, torrent bed slope gradient, sediment accumulation length and depth, cohesion), t: time, θ: torrent bed or hillside slope gradient, r: instant

  17. Effect of roasting conditions on color and volatile profile including HMF level in sweet almonds (Prunus dulcis).

    Science.gov (United States)

    Agila, Amal; Barringer, Sheryl

    2012-04-01

    Microwave, oven, and oil roasting of almonds were used to promote almond flavor and color formation. Raw pasteurized almonds were roasted in a microwave for 1 to 3 min, in an oven at 177 °C for 5, 10, 15, and 20 min; and at 135 and 163 °C for 20 min, and in oil at 135, 163, and 177 °C for 5 min and 177 °C for 10 min. Volatile compounds were quantified in the headspace of ground almonds, both raw and roasted, by selected ion flow tube mass spectrometry. Strong correlations were found between L value, chroma, and 5-(hydroxy methyl)-2- furfural; and were independent of roasting method. Raw almonds had lower concentrations of most volatiles than roasted almonds. Conditions that produced color equivalent to commercial samples were 2 min in the microwave, 5 min at 177 °C in the oven, and 5 min at 135 °C in oil. Microwave heating produced higher levels of most volatiles than oven and oil roasting at commercial color. Sensory evaluation indicated that microwave-roasted almonds had the strongest aroma and were the most preferred. Oil-roasted almonds showed significantly lower levels of volatiles than other methods, likely due to loss of these volatiles into the oil. Alcohols such as benzyl alcohols and strecker aldehydes including benzaldehyde and methional were at higher concentrations than other volatiles in roasted almonds. The oxidation of lipids to form alkanals such as nonanal and degradation of sugars to form furan type compounds was also observed. The Maillard reaction contributed to the formation of more of the total volatiles in almonds than the lipid oxidation reaction. The level of 5-(hydroxy methyl)-2- furfural (HMF), color, volatile profile, and sensory perception can be used to develop the best roasting method, time, and temperature for almonds. The rate of color development and the production of volatiles differ under different roasting conditions. Based on the color, volatile, and sensory assessments of the 3 almonds, the use of microwave technology

  18. Evidence-based therapy for sleep disorders in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    LIU Ling

    2013-08-01

    Full Text Available Objective To evaluate the effectiveness of the treatments for sleep disorders in neurodegenerative diseases so as to provide the best therapeutic regimens for the evidence-based treatment. Methods Search PubMed, MEDLINE, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases with "sleep disorder or sleep disturbance", "neurodegenerative diseases", "Parkinson's disease or PD", "Alzheimer's disease or AD", "multiple system atrophy or MSA" as retrieval words. The quality of the articles were evaluated with Jadad Scale. Results A total of 35 articles, including 2 systematic reviews, 5 randomized controlled trials, 13 clinical controlled trials, 13 case series and 2 epidemiological investigation studies were included for evaluation, 13 of which were high grade and 22 were low grade articles. Clinical evidences showed that: 1 advice on sleep hygiene, careful use of dopaminergic drugs and hypnotic sedative agents should be considered for PD. Bright light therapy (BLT may improve circadian rhythm sleep disorders and clonazepam may be effective for rapid eye movement sleep behavior disorder (RBD. However, to date, very few controlled studies are available to make a recommendation for the management of sleep disorders in PD; 2 treatments for sleep disorders in AD include drug therapy (e.g. melatonin, acetylcholinesterase inhibitors, antipsychotic drugs, antidepressants and non-drug therapy (e.g. BLT, behavior therapy, but very limited evidence shows the effectiveness of these treatments; 3 the first line treatment for sleep-related breathing disorder in MSA is nasal continuous positive airway pressure (nCPAP, and clonazepam is effective for RBD in MSA; 4 there is rare evidence related to the treatment of sleep disorders in dementia with Lewy body (DLB and amyotrophic lateral sclerosis (ALS. Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment in neurodegenerative

  19. Beneficial Effects of Green Tea Catechins on Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Monira Pervin

    2018-05-01

    Full Text Available Tea is one of the most consumed beverages in the world. Green tea, black tea, and oolong tea are made from the same plant Camellia sinensis (L. O. Kuntze. Among them, green tea has been the most extensively studied for beneficial effects on diseases including cancer, obesity, diabetes, and inflammatory and neurodegenerative diseases. Several human observational and intervention studies have found beneficial effects of tea consumption on neurodegenerative impairment, such as cognitive dysfunction and memory loss. These studies supported the basis of tea’s preventive effects of Parkinson’s disease, but few studies have revealed such effects on Alzheimer’s disease. In contrast, several human studies have not reported these favorable effects with regard to tea. This discrepancy may be due to incomplete adjustment of confounding factors, including the method of quantifying consumption, beverage temperature, cigarette smoking, alcohol consumption, and differences in genetic and environmental factors, such as race, sex, age, and lifestyle. Thus, more rigorous human studies are required to understand the neuroprotective effect of tea. A number of laboratory experiments demonstrated the benefits of green tea and green tea catechins (GTCs, such as epigallocatechin gallate (EGCG, and proposed action mechanisms. The targets of GTCs include the abnormal accumulation of fibrous proteins, such as Aβ and α-synuclein, inflammation, elevated expression of pro-apoptotic proteins, and oxidative stress, which are associated with neuronal cell dysfunction and death in the cerebral cortex. Computational molecular docking analysis revealed how EGCG can prevent the accumulation of fibrous proteins. These findings suggest that GTCs have the potential to be used in the prevention and treatment of neurodegenerative diseases and could be useful for the development of new drugs.

  20. Including local rainfall dynamics and uncertain boundary conditions into a 2-D regional-local flood modelling cascade

    Science.gov (United States)

    Bermúdez, María; Neal, Jeffrey C.; Bates, Paul D.; Coxon, Gemma; Freer, Jim E.; Cea, Luis; Puertas, Jerónimo

    2016-04-01

    Flood inundation models require appropriate boundary conditions to be specified at the limits of the domain, which commonly consist of upstream flow rate and downstream water level. These data are usually acquired from gauging stations on the river network where measured water levels are converted to discharge via a rating curve. Derived streamflow estimates are therefore subject to uncertainties in this rating curve, including extrapolating beyond the maximum observed ratings magnitude. In addition, the limited number of gauges in reach-scale studies often requires flow to be routed from the nearest upstream gauge to the boundary of the model domain. This introduces additional uncertainty, derived not only from the flow routing method used, but also from the additional lateral rainfall-runoff contributions downstream of the gauging point. Although generally assumed to have a minor impact on discharge in fluvial flood modeling, this local hydrological input may become important in a sparse gauge network or in events with significant local rainfall. In this study, a method to incorporate rating curve uncertainty and the local rainfall-runoff dynamics into the predictions of a reach-scale flood inundation model is proposed. Discharge uncertainty bounds are generated by applying a non-parametric local weighted regression approach to stage-discharge measurements for two gauging stations, while measured rainfall downstream from these locations is cascaded into a hydrological model to quantify additional inflows along the main channel. A regional simplified-physics hydraulic model is then applied to combine these inputs and generate an ensemble of discharge and water elevation time series at the boundaries of a local-scale high complexity hydraulic model. Finally, the effect of these rainfall dynamics and uncertain boundary conditions are evaluated on the local-scale model. Improvements in model performance when incorporating these processes are quantified using observed

  1. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Tansey Malú G

    2008-10-01

    Full Text Available Abstract The role of tumor necrosis factor (TNF as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1 is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF or transmembrane TNF (tmTNF, with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD, Parkinson's (PD, amyotrophic lateral sclerosis (ALS, and multiple sclerosis (MS. The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

  2. Neuronal network disintegration: common pathways linking neurodegenerative diseases.

    Science.gov (United States)

    Ahmed, Rebekah M; Devenney, Emma M; Irish, Muireann; Ittner, Arne; Naismith, Sharon; Ittner, Lars M; Rohrer, Jonathan D; Halliday, Glenda M; Eisen, Andrew; Hodges, John R; Kiernan, Matthew C

    2016-11-01

    Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Samantha Giordano

    2014-01-01

    Full Text Available Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1 radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2 radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3 since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.

  4. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies

    Directory of Open Access Journals (Sweden)

    Maria Carmela Tartaglia

    2014-01-01

    Full Text Available Chronic traumatic encephalopathy (CTE is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer’s disease and frontotemporal lobar degeneration. The aim of this perspective is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

  5. 40 CFR 142.307 - What terms and conditions must be included in a small system variance?

    Science.gov (United States)

    2010-07-01

    ... that may affect proper and effective operation and maintenance of the technology; (2) Monitoring... effective installation, operation and maintenance of the applicable small system variance technology in... health, which may include: (i) Public education requirements; and (ii) Source water protection...

  6. Influence of probiotics, included in peanut butter, on the fate of selected Salmonella and Listeria strains under simulated gastrointestinal conditions.

    Science.gov (United States)

    Klu, Y A K; Chen, J

    2016-04-01

    This study observed the behaviour of probiotics and selected bacterial pathogens co-inoculated into peanut butter during gastrointestinal simulation. Peanut butter homogenates co-inoculated with Salmonella/Listeria strains (5 log CFU ml(-1) ) and lyophilized or cultured probiotics (9 log CFU ml(-1) ) were exposed to simulated gastrointestinal conditions for 24 h at 37°C. Sample pH, titratable acidity and pathogen populations were determined. Agar diffusion assay was performed to assess the inhibitory effect of probiotic culture supernatants with either natural (3·80 (Lactobacillus), 3·78 (Bifidobacteirum) and 5·17 (Streptococcus/Lactococcus)) or neutralized (6·0) pH. Antibacterial effect of crude bacteriocin extracts were also evaluated against the pathogens. After 24 h, samples with probiotics had lower pH and higher titratable acidity than those without probiotics. The presence of probiotics caused a significant reduction (P Probiotics in 'peanut butter' survived simulated gastrointestinal conditions and inhibited the growth of Salmonella/Listeria. Peanut butter is a plausible carrier to deliver probiotics to improve the gastrointestinal health of children in developing countries. © 2016 The Society for Applied Microbiology.

  7. Circulating progranulin as a biomarker for neurodegenerative diseases.

    Science.gov (United States)

    Ghidoni, Roberta; Paterlini, Anna; Benussi, Luisa

    2012-01-01

    Progranulin is a growth factor involved in the regulation of multiple processes including tumorigenesis, wound repair, development, and inflammation. The recent discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD), and other neurodegenerative diseases leading to dementia, has brought renewed interest in progranulin and its functions in the central nervous system. GRN null mutations cause protein haploinsufficiency, leading to a significant decrease in progranulin levels that can be detected in plasma, serum and cerebrospinal fluid (CSF) of mutation carriers. The dosage of circulating progranulin sped up the identification of GRN mutations thus favoring genotype-phenotype correlation studies. Researchers demonstrated that, in GRN null mutation carriers, the shortage of progranulin invariably precedes clinical symptoms and thus mutation carriers are "captured" regardless of their disease status. GRN is a particularly appealing gene for drug targeting, in the way that boosting its expression may be beneficial for mutation carriers, preventing or delaying the onset of GRN-related neurodegenerative diseases. Physiological regulation of progranulin expression level is only partially known. Progranulin expression reflects mutation status and, intriguingly, its levels can be modulated by some additional factor (i.e. genetic background; drugs). Thus, factors increasing the production and secretion of progranulin from the normal gene are promising potential therapeutic avenues. In conclusion, peripheral progranulin is a nonintrusive highly accurate biomarker for early identification of mutation carriers and for monitoring future treatments that might boost the level of this protein.

  8. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.

    Science.gov (United States)

    Quigley, Eamonn M M

    2017-10-17

    The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.

  9. Guide for Operational Configuration Management Program including the adjunct programs of design reconstitution and material condition and aging management

    International Nuclear Information System (INIS)

    1993-11-01

    This standard presents program criteria and implementation guidance for an operational configuration management program for DOE nuclear and non-nuclear facilities in the operational phase. Portions of this standard are also useful for other DOE processes, activities, and programs. This Part 1 contains foreword, glossary, acronyms, bibliography, and Chapter 1 on operational configuration management program principles. Appendices are included on configuration management program interfaces, and background material and concepts for operational configuration management

  10. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases.

    Science.gov (United States)

    Kuboyama, Tomoharu; Tohda, Chihiro; Komatsu, Katsuko

    2014-01-01

    Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

  11. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

    Science.gov (United States)

    Damiani, Ernesto; Bosco, Gerardo

    2014-01-01

    An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review. PMID:25101284

  12. Neurodegenerative diseases: exercising towards neurogenesis and neuroregeneration

    Directory of Open Access Journals (Sweden)

    Eng-Tat Ang

    2010-07-01

    Full Text Available Currently, there is still no effective therapy for neurodegenerative diseases (NDD such as Alzheimer’s disease (AD and Parkinson’s disease (PD despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician’s and the scientist’s needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

  13. Transgenic nonhuman primates for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Chan Anthony WS

    2004-06-01

    Full Text Available Abstract Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD, Parkinson's disease (PD and Huntington's disease (HD have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which

  14. Glial hemichannels and their involvement in aging and neurodegenerative diseases.

    Science.gov (United States)

    Orellana, Juan A; von Bernhardi, Rommy; Giaume, Christian; Sáez, Juan C

    2012-01-26

    During the last two decades, it became increasingly evident that glial cells accomplish a more important role in brain function than previously thought. Glial cells express pannexins and connexins, which are member subunits of two protein families that form membrane channels termed hemichannels. These channels communicate intra- and extracellular compartments and allow the release of autocrine/paracrine signaling molecules [e.g., adenosine triphosphate (ATP), glutamate, nicotinamide adenine dinucleotide, and prostaglandin E2] to the extracellular milieu, as well as the uptake of small molecules (e.g., glucose). An increasing body of evidence has situated glial hemichannels as potential regulators of the beginning and maintenance of homeostatic imbalances observed in diverse brain diseases. Here, we review and discuss the current evidence about the possible role of glial hemichannels on neurodegenerative diseases. A subthreshold pathological threatening condition leads to microglial activation, which keeps active defense and restores the normal function of the central nervous system. However, if the stimulus is deleterious, microglial cells and the endothelium become overactivated, both releasing bioactive molecules (e.g., glutamate, cytokines, prostaglandins, and ATP), which increase the activity of glial hemichannels, reducing the astroglial neuroprotective functions, and further reducing neuronal viability. Because ATP and glutamate are released via glial hemichannels in neurodegenerative conditions, it is expected that they contribute to neurotoxicity. More importantly, toxic molecules released via glial hemichannels could increase the Ca2+ entry in neurons also via neuronal hemichannels, leading to neuronal death. Therefore, blockade of hemichannels expressed by glial cells and/or neurons during neuroinflammation might prevent neurodegeneration.

  15. Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2011-01-01

    Full Text Available Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB. Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.

  16. [Sense of smell, physiological ageing and neurodegenerative diseases: II. Ageing and neurodegenerative diseases].

    Science.gov (United States)

    Fusari, A; Molina, J A

    The sense of smell, which was once studied because of its biological and evolutionary significance, is today one of the centres of interest in research on normal and pathological ageing. The latest scientific developments point to an inversely proportional relationship between age and olfactory sensitivity. In certain neurodegenerative diseases this sensory decline is one of the first symptoms of the disorder and is correlated with the progression of the disease. In this work we are going to review the scientific knowledge on loss of sense of smell in ageing and in neurodegenerative diseases, with special attention given to Alzheimer's and Parkinson's diseases. A survey of studies that have examined the olfactory deficits in ageing and in some neurodegenerative diseases offers conclusive results about the presence of these impairments in the early stages of these disorders and even among healthy elderly persons. Although a number of causes contribute to these sensory losses in physiological ageing, a common neurological foundation has been proposed for Alzheimer's and Parkinson's diseases. Nevertheless, despite certain initial similarities, the olfactory deficits shown in these disorders seem to be qualitatively different.

  17. Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Masaaki Akagi

    2015-02-01

    Full Text Available Developed regions, including Japan, have become “aged societies,” and the number of adults with senile dementias, such as Alzheimer's disease (AD, Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs may play a role in the treatment of AD because endogenous neurotrophic factors (NFs prevent neuronal death. However, peptidyl compounds have been unable to cross the blood–brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE, which may have potential therapeutic applications in various neurodegenerative disorders.

  18. Progress of the relationship between serum uric acid and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Yang FU

    2018-04-01

    Full Text Available Serum uric acid (sUA, a natural antioxidant in human body, has been found to be related to the occurrence and development of various neurodegenerative diseases in recent years, including Parkinson's disease (PD, multiple system atrophy (MSA, Alzheimer's disease (AD and amyotrophic lateral sclerosis (ALS. Increasing of sUA level has been found to reduce the incidence of PD and ALS, but the relationship between sUA and AD, MSA remains largely unknown. The in vitro studies and animal experiments revealed that sUA can enhance the antioxidant capacity of neurons and delay neurodegeneration and apoptosis. This paper mainly reviews the progress in epidemiological and basic studies of the relationship between sUA and neurodegenerative diseases in recent years, and aims to provide a reference for future novel prevention and treatment strategies for neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2018.03.010

  19. Statistics concerning the Apollo command module water landing, including the probability of occurrence of various impact conditions, sucessful impact, and body X-axis loads

    Science.gov (United States)

    Whitnah, A. M.; Howes, D. B.

    1971-01-01

    Statistical information for the Apollo command module water landings is presented. This information includes the probability of occurrence of various impact conditions, a successful impact, and body X-axis loads of various magnitudes.

  20. S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding.

    Science.gov (United States)

    Nakamura, T; Lipton, S A

    2007-07-01

    Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca(2+) influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins - can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

  1. High-school football and late-life risk of neurodegenerative syndromes, 1956–1970

    Science.gov (United States)

    Janssen, Pieter HH; Mandrekar, Jay; Mielke, Michelle M; Ahlskog, J. Eric; Boeve, Bradley F; Josephs, Keith; Savica, Rodolfo

    2017-01-01

    BACKGROUND Repeated head trauma has been associated with risk of neurodegenerative diseases. Few studies have evaluated the long-term risk of neurodegenerative diseases in collision sports like football. OBJECTIVE To assess whether athletes who played American varsity high-school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. PATIENTS AND METHODS We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, compared to non-football-playing male varsity swimmers, wrestlers or basketball players. Using the records-linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, or amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. RESULTS We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than one year. Compared to non-football athletes, football players did not have an increased risk of neurodegenerative disease overall, nor the individual conditions of dementia, parkinsonism, or amyotrophic lateral sclerosis. CONCLUSION In this community based study, varsity high school football players from 1956 to 1970 did not have an increased risk of developing neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era where there was a generally nihilistic view of concussion dangers, less protective equipment and without prohibition of spearing (head-first tackling). However, size and strength of players from prior eras may not be comparable to current high-school athletes. PMID:27979411

  2. The Role of Copper in Neurodegenerative Disease

    Science.gov (United States)

    Rose, Francis M.

    My research concerns the fundamental atomistic mechanisms of neurodegenerative diseases and the methodologies by which they may be discerned. This thesis consists of three primary parts. The introductory material is the raison d'etre for this work and a critical overview of the specific physics, mathematics and algorithms used in this research. The methods are presented along with specific details in order to facilitate future replication and enhancement. With the groundwork of mechanisms and methods out of the way, we then explore a nouveau atomistic mechanism describing the onset of Parkinson's disease, a disease that has been closely linked to misfolded metalloproteins. Further exploration of neurodegeneration takes place in the following chapter, where a remedial approach to Alzheimer's disease via a simulated chelation of a metalloprotein is undertaken. Altogether, the methods and techniques applied here allow for simulated exploration of both the atomistic mechanisms of neurodegeneration and their potential remediation strategies. The beginning portion of the research efforts explore protein misfolding dynamics in the presence a copper ion. Misfolding of the human alpha-synuclein (aS) protein has been implicated as a central constituent in neurodegenerative disease. In Parkinson's disease (PD) in particular, aS is thought to be the causative participant when found concentrated into neuritic plaques. Here we propose a scenario involving the metal ion Cu2+ as the protein misfolding initiator of fibrillized aS, the chief component of neuritic plaques. From experimental results we know these misfolded proteins have a rich beta--sheet signature, a marker that we reproduce with our simulated model. This model identifies a process of structural modifications to a natively unfolded alpha-synuclein resulting in a partially folded intermediate with a well defined nucleation site. It serves as a precursor to the fully misfolded protein. Understanding the nucleation

  3. Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases.

    Science.gov (United States)

    Madeira, Maria H; Boia, Raquel; Ambrósio, António F; Santiago, Ana R

    2017-01-01

    Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A 2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

  4. Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Maria H. Madeira

    2017-01-01

    Full Text Available Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

  5. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Federica Ciregia

    2017-08-01

    Full Text Available Extracellular vesicles (EVs can be classified into apoptotic bodies, microvesicles (MVs, and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM, neuroblastoma (NB, medulloblastoma (MB, and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS, amyotrophic lateral sclerosis (ALS, Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis.

  6. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Hall, Vanessa Jane

    2016-01-01

    Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease......, frontotemporal dementia and Parkinson’s disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only...... that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about...

  7. Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Tarozzi

    2013-01-01

    Full Text Available A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer’s disease, and Parkinson's disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration.

  8. Visual dysfunction, neurodegenerative diseases, and aging.

    Science.gov (United States)

    Jackson, Gregory R; Owsley, Cynthia

    2003-08-01

    The four most common sight-threatening conditions in older adults in North America are cataract, ARM, glaucoma, and diabetic retinopathy. Even in their moderate stages, these conditions cause visual sensory impairments and reductions in health-related quality of life, including difficulties in daily tasks and psychosocial problems. Many older adults are free from these conditions, yet still experience a variety of visual perceptual problems resulting from aging-related changes in the optics of the eye and degeneration of the visual neural pathways. These problems consist of impairments in visual acuity, contrast sensitivity, color discrimination, temporal sensitivity, motion perception, peripheral visual field sensitivity, and visual processing speed. PD causes a progressive loss of dopaminergic cells predominantly in the retina and possibly in other areas of the visual system. This retinal dopamine deficiency produces selective spatial-temporal abnormalities in retinal ganglion cell function, probably arising from altered receptive field organization in the PD retina. The cortical degeneration characteristics of AD, including neurofibrillary tangles and neuritic plaques, also are present in the visual cortical areas, especially in the visual association areas. The most prominent electrophysiologic change in AD is a delay in the P2 component of the flash VEP. Deficits in higher-order visual abilities typically are compromised in AD, including problems with visual attention, perceiving structure from motion, visual memory, visual learning, reading, and object and face perception. There have been reports of a visual variant of AD in which these types of visual problems are the initial and most prominent signs of the disease. Visual sensory impairments (e.g., contrast sensitivity or achromatopsia) also have been reported but are believed more reflective of cortical disturbances than of AD-associated optic neuropathy.

  9. THE MITOCHONDRIAL DERANGEMENTS IN NEURONAL DEGENER ATION AND NEURODEGENERATIVE DISEASES

    Institute of Scientific and Technical Information of China (English)

    Xue, Qi-ming; Gao, Feng; Chen, Qin-tang

    2000-01-01

    @@There are diverse concepts on the pathogenesis of neuronal degeneration and the neurodegenerative diseases. Among them there are different factors which might influence the initiation of neuronal degeneration as well as the pathogenesis of neurodegenerative diseases, such as Alzheimer′s disease, Parkinson′s disease, motor neuron disease, and so on.

  10. Neurodegenerative diseases of the central motor system in MRI

    International Nuclear Information System (INIS)

    Alfke, K.

    2005-01-01

    Neurodegenerative diseases of the central motor system often lead to discrete but functionally important parenchymal abnormalities in various parts of the brain. MRI is the most sensitive imaging method to detect these abnormalities. Various neurodegenerative diseases are presented with their clinical symptoms and MRI findings. Criteria for differential diagnosis are provided as well. (orig.)

  11. Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

    2016-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

  12. A neurodegenerative vascular burden index and the impact on cognition

    Directory of Open Access Journals (Sweden)

    Sebastian eHeinzel

    2014-07-01

    Full Text Available A wide range of vascular burden factors have been identified to impact vascular function and structure as indicated by carotid intima-media thickness (IMT. On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI. Since many vascular factors increase the risk of Alzheimer's disease (AD, a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages.We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102 for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication and/or blood marker data were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT and the CERAD neuropsychological battery.IMT was significantly predicted by age (standardized β = .26, sex (.09; males > females and the factors included in the VBI: obesity (.18, hypertension (.14, smoking (.08, diabetes (.07, and atherosclerosis (.05, whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT (≥1.0 mm. The VBI showed an impact on executive control (log(TMT B-A, p = .047 and a trend towards decreased global cognitive function (CERAD total score, p = .057 independent of age, sex and education.A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and

  13. Seeking environmental causes of neurodegenerative disease and envisioning primary prevention.

    Science.gov (United States)

    Spencer, Peter S; Palmer, Valerie S; Kisby, Glen E

    2016-09-01

    Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer's disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of

  14. Computed tomography of neurodegenerative disease in childhood

    International Nuclear Information System (INIS)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-01-01

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author)

  15. Neurodegenerative diseases : Lessons from genome-wide screens in small model organisms

    NARCIS (Netherlands)

    van Ham, Tjakko J.; Breitling, Rainer; Swertz, Morris A.; Nollen, Ellen A. A.

    2009-01-01

    Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly

  16. Combination Comprising Parthenolide For Use In The Treatment Of Alzheimer's Disease And Other Neurodegenerative Disorders

    KAUST Repository

    Bajic, Vladimir B.

    2015-06-18

    The present invention generally concerns particular methods and compositions for treatment of a neurodegenerative disease, such as Alzheimer\\'s Disease. In particular embodiments, there is a composition comprising Parthenolide and a second agent, including an inhibitor of TLR4/MD-2/CD14, nAChR agonist, Resatorvid, Curcumin, Tilorone or a Tilorone analog, or a combination thereof.

  17. Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis.

    Directory of Open Access Journals (Sweden)

    Elena Sieni

    Full Text Available Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy.We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI (group 1 or specific risk factors for (diabetes insipidus, craniofacial bone lesions, but no evidence of, neurodegenerative MRI changes (group 2. All patients underwent clinical, neurophysiological and MRI studies.Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs, and five had abnormal brainstem auditory evoked potentials (BAEPs. MR spectroscopy (MRS showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV and negative predictive value (NPV for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%, 100% (69.2%-100%, 100% (73.5%-100%, and 66.7% (38.4%-88.2%, respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient.A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.

  18. Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

    Science.gov (United States)

    Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

    2018-02-12

    There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since

  19. High School Football and Late-Life Risk of Neurodegenerative Syndromes, 1956-1970.

    Science.gov (United States)

    Janssen, Pieter H H; Mandrekar, Jay; Mielke, Michelle M; Ahlskog, J Eric; Boeve, Bradley F; Josephs, Keith; Savica, Rodolfo

    2017-01-01

    To assess whether athletes who played American varsity high school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, and non-football-playing male varsity swimmers, wrestlers, and basketball players. Using the medical records linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, and amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than 1 year. Compared with nonfootball athletes, football players did not have an increased risk of neurodegenerative disease overall or of the individual conditions of dementia, parkinsonism, and amyotrophic lateral sclerosis. In this community-based study, varsity high school football players from 1956 to 1970 did not have an increased risk of neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era when there was a generally nihilistic view of concussion dangers, less protective equipment, and no prohibition of spearing (head-first tackling). However, the size and strength of players from previous eras may not be comparable with that of current high school athletes. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  20. Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Marjana Brkic

    2015-01-01

    Full Text Available Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs, a protein family of zinc-containing endopeptidases, are essential in (neuroinflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer’s disease (AD, Parkinson’s disease (PD, amyotrophic lateral sclerosis (ALS, Huntington’s disease (HD, and multiple sclerosis (MS. We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.

  1. Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases.

    Science.gov (United States)

    Brkic, Marjana; Balusu, Sriram; Libert, Claude; Vandenbroucke, Roosmarijn E

    2015-01-01

    Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS) functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs), a protein family of zinc-containing endopeptidases, are essential in (neuro)inflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.

  2. Ocimum basilicum improve chronic stress-induced neurodegenerative changes in mice hippocampus.

    Science.gov (United States)

    Ayuob, Nasra Naeim; El Wahab, Manal Galal Abd; Ali, Soad Shaker; Abdel-Tawab, Hanem Saad

    2018-01-22

    Alzheimer's disease (AD), one of the progressive neurodegenerative diseases might be associated with exposure to stress and altered living conditions. This study aimed to evaluate the effectiveness of Ocimum basilicum (OB) essential oils in improving the neurodegenerative-like changes induced in mice after exposed to chronic unpredictable mild stress (CUMS). Forty male Swiss albino mice divided into four groups (n = 10); the control, CUMS, CUMS + Fluoxetine, CUMS + OB were used. Behavioral tests, serum corticosterone level, hippocampus protein level of the glucocorticoid receptors (GRs) and brain-dreived neurotropic factor (BDNF) were determined after exposure to CUMS. Hippocampus was histopathologically examined. Data were analyzed using statistical package for the social sciences (SPSS) and P value of less than 0.05 was considered significant. OB diminished the depression manifestation as well as impaired short term memory observed in the mice after exposure to the CUMS as evidenced by the forced swimming and elevated plus maze test. OB also up-regulated the serum corticosterone level, hippocampal protein level of the glucocorticoid receptor and the brain-derived neurotropic factor and reduced the neurodegenerative and atrophic changes induced in the hippocampus after exposure to CUMS. Essential oils of OB alleviated the memory impairment and hippocampal neurodegenerative changes induced by exposure to the chronic unpredictable stress indicating that it is the time to test its effectiveness on patients suffering from Alzheimer disease.

  3. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Alana M. Horowitz

    2017-08-01

    Full Text Available Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

  4. Non-coding RNA and pseudogenes in neurodegenerative diseases: "The (unUsual Suspects"

    Directory of Open Access Journals (Sweden)

    Valerio eCosta

    2012-10-01

    Full Text Available Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration.Alteration in regulatory networks affecting gene expression contribute to human diseases' onset, including neurodegenerative disorders, and deregulation of non-coding RNAs - particularly microRNAs - is supposed to have a significant impact.Recently, competitive endogenous RNAs - acting as sponges - have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of microRNAs in neurogenesis, we hypothesize competitive endogenous RNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed.

  5. Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders.

    Science.gov (United States)

    Singh, Abhijeet; Chokriwal, Ankit; Sharma, Madan Mohan; Jain, Devendra; Saxena, Juhi; Stephen, Bjorn John

    2017-08-16

    Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions.

  6. Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

    Science.gov (United States)

    Luchowska-Kocot, Dorota; Kiełczykowska, Małgorzata; Musik, Irena; Kurzepa, Jacek

    2017-01-01

    Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. PMID:28654017

  7. Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

    Science.gov (United States)

    Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo

    2016-01-01

    Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.

  8. Beneficial Role of Coffee and Caffeine in Neurodegenerative Diseases: A Minireview

    Directory of Open Access Journals (Sweden)

    Yenisetti SC

    2016-06-01

    Full Text Available Coffee is among the most widespread and healthiest beverages in the world. Coffee typically contains more caffeine than most other beverages, and is widely and frequently consumed. Thus, it contributes significantly to the overall caffeine consumption within the general population, particularly in adults. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health-promoting potential. Several lines of evidence have highlighted the beneficial effects towards several disease conditions including Type II diabetes, hepatitis C virus, hepatocellular carcinoma, nonalcoholic fatty liver disease and neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's disease (PD and Amyotrophic Lateral Sclerosis (ALS. The health-promoting properties of coffee are largely attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, and hydroxy hydroquinone. In this minireview, an attempt has been made to discuss the various evidences which are mainly derived from animal and cell models. Various mechanisms chiefly responsible for the beneficial effects of caffeine have also been briefly outlined. A short note on the undesirable effects of excessive coffee intakes is also presented.

  9. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.

    Science.gov (United States)

    Josephs, Keith A; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Master, Ankit V; Lowe, Val J; Jack, Clifford R; Whitwell, Jennifer L

    2012-05-01

    Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [(18)F]-fluorodeoxyglucose and [(11)C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49-82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy

  10. Neuroanatomy of Shared Conversational Laughter in Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Peter S. Pressman

    2018-06-01

    Full Text Available Perceiving another person's emotional expression often sparks a corresponding signal in the observer. Shared conversational laughter is a familiar example. Prior studies of shared laughter have made use of task-based functional neuroimaging. While these methods offer insight in a controlled setting, the ecological validity of such controlled tasks has limitations. Here, we investigate the neural correlates of shared laughter in patients with one of a variety of neurodegenerative disease syndromes (N = 75, including Alzheimer's disease (AD, behavioral variant frontotemporal dementia (bvFTD, right and left temporal variants of semantic dementia (rtvFTD, svPPA, nonfluent/agrammatic primary progressive aphasia (nfvPPA, corticobasal syndrome (CBS, and progressive supranuclear palsy (PSP. Patients were recorded in a brief unrehearsed conversation with a partner (e.g., a friend or family member. Laughter was manually labeled, and an automated system was used to assess the timing of that laughter relative to the partner's laughter. The probability of each participant with neurodegenerative disease laughing during or shortly after his or her partners' laughter was compared to differences in brain morphology using voxel-based morphometry, thresholded based on cluster size and a permutation method and including age, sex, magnet strength, disease-specific atrophy and total intracranial volumes as covariates. While no significant correlations were found at the critical T value, at a corrected voxelwise threshold of p < 0.005, a cluster in the left posterior cingulate gyrus demonstrated a trend at p = 0.08 (T = 4.54. Exploratory analysis with a voxelwise threshold of p = 0.001 also suggests involvement of the left precuneus (T = 3.91 and right fusiform gyrus (T = 3.86. The precuneus has been previously implicated in the detection of socially complex laughter, and the fusiform gyrus has a well-described role in the recognition and processing of others

  11. Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Hideyuki eTakeuchi

    2014-09-01

    Full Text Available Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS. Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g. minocycline have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.

  12. C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Paulo Victor Sgobbi de Souza

    2015-03-01

    Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

  13. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

    Science.gov (United States)

    Akizu, Naiara; Cantagrel, Vincent; Schroth, Jana; Cai, Na; Vaux, Keith; McCloskey, Douglas; Naviaux, Robert K; Van Vleet, Jeremy; Fenstermaker, Ali G; Silhavy, Jennifer L; Scheliga, Judith S; Toyama, Keiko; Morisaki, Hiroko; Sonmez, Fatma M; Celep, Figen; Oraby, Azza; Zaki, Maha S; Al-Baradie, Raidah; Faqeih, Eissa A; Saleh, Mohammed A M; Spencer, Emily; Rosti, Rasim Ozgur; Scott, Eric; Nickerson, Elizabeth; Gabriel, Stacey; Morisaki, Takayuki; Holmes, Edward W; Gleeson, Joseph G

    2013-08-01

    Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. AMPD2 Regulates GTP Synthesis and is Mutated in a Potentially-Treatable Neurodegenerative Brainstem Disorder

    Science.gov (United States)

    Akizu, Naiara; Cantagrel, Vincent; Schroth, Jana; Cai, Na; Vaux, Keith; McCloskey, Douglas; Naviaux, Robert K.; Vleet, Jeremy Van; Fenstermaker, Ali G.; Silhavy, Jennifer L.; Scheliga, Judith S.; Toyama, Keiko; Morisaki, Hiroko; Sonmez, Fatma Mujgan; Celep, Figen; Oraby, Azza; Zaki, Maha S.; Al-Baradie, Raidah; Faqeih, Eissa; Saleh, Mohammad; Spencer, Emily; Rosti, Rasim Ozgur; Scott, Eric; Nickerson, Elizabeth; Gabriel, Stacey; Morisaki, Takayuki; Holmes, Edward W.; Gleeson, Joseph G.

    2013-01-01

    Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a new distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new, potentially treatable early-onset neurodegenerative disease. PMID:23911318

  15. The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Sahar eAl-Mahdawi

    2014-12-01

    Full Text Available DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC, which is formed by oxidation of 5mC by ten-eleven translocation (TET enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS. The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer’s disease (AD, amyotrophic lateral sclerosis (ALS, fragile X-associated tremor/ataxia syndrome (FXTAS, Friedreich ataxia (FRDA, Huntington’s disease (HD, and Parkinson’s disease (PD.

  16. Living conditions, including life style, in primary-care patients with nonacute, nonspecific spinal pain compared with a population-based sample: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Odd Lindell

    2010-11-01

    Full Text Available Odd Lindell, Sven-Erik Johansson, Lars-Erik Strender1Center for Family and Community Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, SwedenBackground: Nonspecific spinal pain (NSP, comprising back and/or neck pain, is one of the leading disorders behind long-term sick-listing, including disability pensions. Early interventions to prevent long-term sick-listing require the identification of patients at risk. The aim of this study was to compare living conditions associated with long-term sick-listing for NSP in patients with nonacute NSP, with a nonpatient population-based sample. Nonacute NSP is pain that leads to full-time sick-listing>3 weeks.Methods: One hundred and twenty-five patients with nonacute NSP, 2000–2004, were included in a randomized controlled trial in Stockholm County with the objective of comparing cognitive–behavioral rehabilitation with traditional primary care. For these patients, a cross-sectional study was carried out with baseline data. Living conditions were compared between the patients and 338 nonpatients by logistic regression. The conditions from univariate analyses were included in a multivariate analysis. The nonsignificant variables were excluded sequentially to yield a model comprising only the significant factors (P <0.05. The results are shown as odds ratios (OR with 95% confidence intervals.Results: In the univariate analyses, 13 of the 18 living conditions had higher odds for the patients with a dominance of physical work strains and Indication of alcohol over-consumption, odds ratio (OR 14.8 (95% confidence interval [CI] 3.2–67.6. Five conditions qualified for the multivariate model: High physical workload, OR 13.7 (CI 5.9–32.2; Hectic work tempo, OR 8.4 (CI 2.5–28.3; Blue-collar job, OR 4.5 (CI 1.8–11.4; Obesity, OR 3.5 (CI 1.2–10.2; and Low education, OR 2.7 (CI 1.1–6.8.Conclusions: As most of the living conditions have previously been

  17. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease.

    Science.gov (United States)

    Chitramuthu, Babykumari P; Bennett, Hugh P J; Bateman, Andrew

    2017-12-01

    Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer's disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Modelling iron mismanagement in neurodegenerative disease in vitro: paradigms, pitfalls, possibilities & practical considerations.

    Science.gov (United States)

    Healy, Sinead; McMahon, Jill M; FitzGerald, Una

    2017-11-01

    Although aberrant metabolism and deposition of iron has been associated with aging and neurodegeneration, the contribution of iron to neuropathology is unclear. Well-designed model systems that are suited to studying the putative pathological effect of iron are likely to be essential if such unresolved details are to be clarified. In this review, we have evaluated the utility and effectiveness of the reductionist in vitro platform to study the molecular mechanisms putatively underlying iron perturbations of neurodegenerative disease. The expression and function of iron metabolism proteins in glia and neurons and the extent to which this iron regulatory system is replicated in in vitro models has been comprehensively described, followed by an appraisal of the inherent suitability of different in vitro and ex vivo models that have been, or might be, used for iron loading. Next, we have identified and critiqued the relevant experimental parameters that have been used in in vitro iron loading experiments, including the choice of iron reagent, relevant iron loading concentrations and supplementation with serum or ascorbate, and propose optimal iron loading conditions. Finally, we have provided a synthesis of the differential iron accumulation and toxicity in glia and neurons from reported iron loading paradigms. In summary, this review has amalgamated the findings and paradigms of the published reports modelling iron loading in monocultures, discussed the limitations and discrepancies of such work to critically propose a robust, relevant and reliable model of iron loading to be used for future investigations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.

    Science.gov (United States)

    Bicchi, Ilaria; Emiliani, Carla; Vescovi, Angelo; Martino, Sabata

    2015-01-01

    Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. © 2015 S. Karger AG, Basel.

  20. Numerical simulation of CO2 leakage from a geologic disposal reservoir, including transitions from super- to sub-critical conditions, and boiling of liquid of CO2

    International Nuclear Information System (INIS)

    Pruess, Karsten

    2003-01-01

    The critical point of CO 2 is at temperature and pressure conditions of T crit = 31.04 C, P crit = 73.82 bar. At lower (subcritical) temperatures and/or pressures, CO 2 can exist in two different phase states, a liquid and a gaseous state, as well as in two-phase mixtures of these states. Disposal of CO 2 into brine formations would be made at supercritical pressures. However, CO 2 escaping from the storage reservoir may migrate upwards towards regions with lower temperatures and pressures, where CO 2 would be in subcritical conditions. An assessment of the fate of leaking CO 2 requires a capability to model not only supercritical but also subcritical CO 2 , as well as phase changes between liquid and gaseous CO 2 in sub-critical conditions. We have developed a methodology for numerically simulating the behavior of water-CO 2 mixtures in permeable media under conditions that may include liquid, gaseous, and supercritical CO 2 . This has been applied to simulations of leakage from a deep storage reservoir in which a rising CO 2 plume undergoes transitions from supercritical to subcritical conditions. We find strong cooling effects when liquid CO 2 rises to elevations where it begins to boil and evolve a gaseous CO 2 phase. A three-phase zone forms (aqueous - liquid - gas), which over time becomes several hundred meters thick as decreasing temperatures permit liquid CO 2 to advance to shallower elevations. Fluid mobilities are reduced in the three-phase region from phase interference effects. This impedes CO 2 upflow, causes the plume to spread out laterally, and gives rise to dispersed CO 2 discharge at the land surface. Our simulation suggests that temperatures along a CO 2 leakage path may decline to levels low enough so that solid water ice and CO 2 hydrate phases may be formed

  1. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

    Science.gov (United States)

    King, Oliver D.; Gitler, Aaron D.; Shorter, James

    2012-01-01

    Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease and Huntington’s disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the

  2. Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    G. Natale

    2013-03-01

    Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

  3. The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Yajin Liao

    2017-02-01

    Full Text Available The mitochondrial calcium uniporter (MCU—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP; however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders.

  4. Sleep disturbance in mental health problems and neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Anderson KN

    2013-05-01

    Full Text Available Kirstie N Anderson1 Andrew J Bradley2,3 1Department of Neurology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK; 2Eli Lilly and Company Limited, Lilly House, Basingstoke, UK; 3Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK Abstract: Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour processes and is vital for normal brain function. This review will outline the normal sleep–wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed. Keywords: sleep, mental health, neurodegenerative disorders, cognition

  5. Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases.

    Science.gov (United States)

    Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C

    2018-04-03

    Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Graciela Cristina dos Santos

    2009-12-01

    Full Text Available According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10 has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP. The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.De acordo com estudos clínicos e pré-clínicos, o estresse oxidativo e suas conseqüências podem ser a causa, ou, no mínimo, o fator que contribui para grande número de doenças degenerativas. Estas doenças incluem problemas comuns e debilitantes, caracterizados por perda progressiva e irreversível de neurônios em regiões específicas do cérebro. As doenças degenerativas mais comuns são doença de Parkinson, de Hutington, de Alzheimer e esclerose amiotrófica lateral. A Coenzima Q10 (CoQ10 tem sido intensamente estudada desde sua descoberta, em 1957. É um componente da cadeia de transporte eletrônico e participa da respiração aeróbica celular, gerando energia na forma de trifosfato de

  7. Nanomedicine and neurodegenerative disorders: so close yet so far.

    Science.gov (United States)

    Tosi, Giovanni; Vandelli, Maria Angela; Forni, Flavio; Ruozi, Barbara

    2015-07-01

    This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases.

  8. Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Sibongile R. Sibambo

    2009-06-01

    Full Text Available The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.

  9. Iron in neurodegenerative disorders: being in the wrong place at the wrong time?

    Science.gov (United States)

    Apostolakis, Sotirios; Kypraiou, Anna-Maria

    2017-11-27

    Brain iron deposits have been reported consistently in imaging and histologic examinations of patients with neurodegenerative disorders. While the origins of this finding have not been clarified yet, it is speculated that impaired iron homeostasis or deficient transport mechanisms result in the accumulation of this highly toxic metal ultimately leading to formation of reactive oxygen species and cell death. On the other hand, there are also those who support that iron is just an incidental finding, a by product of neuronal loss. A literature review has been performed in order to present the key findings in support of the iron hypothesis of neurodegeneration, as well as to identify conditions causing or resulting from iron overload and compare and contrast their features with the most prominent neurodegenerative disorders. There is an abundance of experimental and observational findings in support of the hypothesis in question; however, as neurodegeneration is a rare incident of commonly encountered iron-associated disorders of the nervous system, and this metal is found in non-neurodegenerative disorders as well, it is possible that iron is the result or even an incidental finding in neurodegeneration. Understanding the underlying processes of iron metabolism in the brain and particularly its release during cell damage is expected to provide a deeper understanding of the origins of neurodegeneration in the years to come.

  10. Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders

    DEFF Research Database (Denmark)

    Winge, Kristian

    2015-01-01

    of incontinence in Alzheimer's disease, but higher cognitive function including attention and self-management may play a role. Incontinence is a major risk factor for loss of independence. The complex pathophysiologic mechanisms of neurodegenerative disorders and hence complex symptoms play important roles......Progressive neurodegenerative disorders are devastating diseases with often fatal outcomes. Lower urinary tract symptoms (LUTS) add to morbidity and increase the risk of becoming dependent on the help of others (e.g., nursing-home referral). In Parkinson's disease (PD), the specific loss...... in LUTS and patient quality of life. Nocturia, incontinence, and urgency as well as poor bladder emptying are the most common symptoms. These symptoms may interact with the core symptoms of the disorders, increasing the risk of incontinence and infection. In rarer neurogenerative disorder LUTS may...

  11. Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases.

    Science.gov (United States)

    Dodge, James C

    2017-01-01

    Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

  12. Cell ageing: a flourishing field for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Dora Brites

    2015-06-01

    Full Text Available Cellular senescence is viewed as an irreversible cell-cycle arrest mechanism involving a complexity of biological progressive processes and the acquisition of diverse cellular phenotypes. Several cell-intrinsic and extrinsic causes (stresses may lead to diverse cellular signaling cascades that include oxidative stress, mitochondrial dysfunction, DNA damage, excessive accumulation of misfolded proteins, impaired microRNA processing and inflammation. Here we review recent advances in the causes and consequences of brain cell ageing, including the senescence of endothelial cells at the central nervous system barriers, as well as of neurons and glial cells. We address what makes ageing an important risk factor for neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and cerebrovascular disease. In particular, we highlight the importance of defects in mitochondrial dynamics, in the cathepsin activity imbalance, in cell-cell communication, in the accumulation of misfolded and unfolded proteins and in the microRNA profiling as having potential impact on cellular ageing processes. Another important aspect is that the absence of specific senescence biomarkers has hampered the characterization of senescent cells in ageing and age-associated diseases. In accordance, the senescence-associated secretory phenotype (SASP or secretome was shown to vary in distinct cell types and upon different stressors, and SASP heterogeneity is believed to create subsets of senenescent cells. In addition to secreted proteins, we then place extracellular vesicles (exosomes and ectosomes as important mediators of intercellular communication with pathophysiological roles in disease spreading, and as emerging targets for therapeutic intervention. We also discuss the application of engineered extracellular vesicles as vehicles for drug delivery. Finally, we summarize current knowledge on methods to rejuvenate senescent cells

  13. Mass spectrometry-based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders.

    Science.gov (United States)

    Luan, Hemi; Wang, Xian; Cai, Zongwei

    2017-11-12

    Metabolomics seeks to take a "snapshot" in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry-based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry-based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the

  14. Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.

    Science.gov (United States)

    Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Flávia; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andréia; Gonçalves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, Márcia

    2015-08-18

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

  15. Mechanisms of action of brain insulin against neurodegenerative diseases.

    Science.gov (United States)

    Ramalingam, Mahesh; Kim, Sung-Jin

    2014-06-01

    Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.

  16. Prediction of neurodegenerative diseases from functional brain imaging data

    NARCIS (Netherlands)

    Mudali, Deborah

    2016-01-01

    Neurodegenerative diseases are a challenge, especially in the developed society where life expectancy is high. Since these diseases progress slowly, they are not easy to diagnose at an early stage. Moreover, they portray similar disease features, which makes them hard to differentiate. In this

  17. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

    Directory of Open Access Journals (Sweden)

    Panchanan Maiti

    2014-01-01

    Full Text Available The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

  18. Predictive gene testing for Huntington disease and other neurodegenerative disorders.

    Science.gov (United States)

    Wedderburn, S; Panegyres, P K; Andrew, S; Goldblatt, J; Liebeck, T; McGrath, F; Wiltshire, M; Pestell, C; Lee, J; Beilby, J

    2013-12-01

    Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  19. NSAIDs and cardiovascular drugs in neurodegenerative and cerebrovascular diseases

    NARCIS (Netherlands)

    M.D.M. Haag (Mendel)

    2009-01-01

    textabstractNeurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer disease (AD)), Parkinson disease (PD) and stroke. The prevalence of these neurological disorders rises with older age. From 55 years to 90 years and

  20. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

    Science.gov (United States)

    Morgan, Neil V; Westaway, Shawn K; Morton, Jenny E V; Gregory, Allison; Gissen, Paul; Sonek, Scott; Cangul, Hakan; Coryell, Jason; Canham, Natalie; Nardocci, Nardo; Zorzi, Giovanna; Pasha, Shanaz; Rodriguez, Diana; Desguerre, Isabelle; Mubaidin, Amar; Bertini, Enrico; Trembath, Richard C; Simonati, Alessandro; Schanen, Carolyn; Johnson, Colin A; Levinson, Barbara; Woods, C Geoffrey; Wilmot, Beth; Kramer, Patricia; Gitschier, Jane; Maher, Eamonn R; Hayflick, Susan J

    2007-01-01

    Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis. PMID:16783378

  1. Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment

    Science.gov (United States)

    Li, Min; Wang, Li; Liu, Jiang-Hong; Zhan, Shu-Qin

    2018-01-01

    Objective: Rapid eye movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. Data Sources: Using the combined keywords: “RBD”, “neurodegenerative disease”, “Parkinson disease”, and “magnetic resonance imaging”, the PubMed/MEDLINE literature search was conducted up to January 1, 2018. Study Selection: A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. Results: Single-nucleotide polymorphisms in SCARB2 (rs6812193) and MAPT (rs12185268) were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. Conclusions: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated

  2. Potential application of lithium in Parkinson’s and other neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Carol A Lazzara

    2015-10-01

    Full Text Available Lithium, the long-standing hallmark treatment for bipolar disorder, has recently been identified as a potential neuroprotective agent in neurodegeneration. Here we focus on introducing numerous in vitro and in vivo studies that have shown lithium treatment to be efficacious in reducing oxidative stress and inflammation, increasing autophagy, inhibiting apoptosis, and decreasing the accumulation of α-synulcein, with an emphasis on Parkinson’s disease. A number of biological pathways have been shown to be involved in causing these neuroprotective effects. The inhibition of GSK-3β has been the mechanism most studied; however, other modes of action include the regulation of apoptotic proteins and glutamate excitotoxicity as well as down-regulation of Calpain-1. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side-effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases.

  3. The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?

    Science.gov (United States)

    Doty, Kevin R; Guillot-Sestier, Marie-Victoire; Town, Terrence

    2015-08-18

    Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases.

    Science.gov (United States)

    Phan, Chia-Wei; David, Pamela; Sabaratnam, Vikineswary

    2017-01-01

    There is an exponential increase in dementia in old age at a global level because of increasing life expectancy. The prevalence of neurodegenerative diseases such as dementia and Alzheimer's disease (AD) will continue to rise steadily, and is expected to reach 42 million cases worldwide in 2020. Despite the advancement of medication, the management of these diseases remains largely ineffective. Therefore, it is vital to explore novel nature-based nutraceuticals to mitigate AD and other age-related neurodegenerative disorders. Mushrooms and their extracts appear to hold many health benefits, including immune-modulating effects. A number of edible mushrooms have been shown to contain rare and exotic compounds that exhibit positive effects on brain cells both in vitro and in vivo. In this review, we summarize the scientific information on edible and culinary mushrooms with regard to their antidementia/AD active compounds and/or pharmacological test results. The bioactive components in these mushrooms and the underlying mechanism of their activities are discussed. In short, these mushrooms may be regarded as functional foods for the mitigation of neurodegenerative diseases.

  5. Effect of electromagnetic radiations on neurodegenerative diseases- technological revolution as a curse in disguise.

    Science.gov (United States)

    Hasan, Gulam M; Sheikh, Ishfaq A; Karim, Sajjad; Haque, Absarul; Kamal, Mohammad A; Chaudhary, Adeel G; Azhar, Essam; Mirza, Zeenat

    2014-01-01

    In the present developed world, all of us are flooded with electromagnetic radiations (EMR) emanating from generation and transmission of electricity, domestic appliances and industrial equipments, to telecommunications and broadcasting. We have been exposed to EMR for last many decades; however their recent steady increase from artificial sources has been reported as millions of antennas and satellites irradiate the global population round the clock, year round. Needless to say, these are so integral to modern life that interaction with them on a daily basis is seemingly inevitable; hence, the EMR exposure load has increased to a point where their health effects are becoming a major concern. Delicate and sensitive electrical system of human body is affected by consistent penetration of electromagnetic frequencies causing DNA breakages and chromosomal aberrations. Technological innovations came with Pandora's Box of hazardous consequences including neurodegenerative disorders, hearing disabilities, diabetes, congenital abnormalities, infertility, cardiovascular diseases and cancer to name few, all on a sharp rise. Electromagnetic non-ionizing radiations pose considerable health threat with prolonged exposure. Mobile phones are usually held near to the brain and manifest progressive structural or functional alterations in neurons leading to neurodegenerative diseases and neuronal death. This has provoked awareness among both the general public and scientific community and international bodies acknowledge that further systematic research is needed. The aim of the present review was to have an insight in whether and how cumulative electro-magnetic field exposure is a risk factor for neurodegenerative disorders.

  6. Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges.

    Science.gov (United States)

    Poon, Anna; Zhang, Yu; Chandrasekaran, Abinaya; Phanthong, Phetcharat; Schmid, Benjamin; Nielsen, Troels T; Freude, Kristine K

    2017-10-25

    The rising prevalence of progressive neurodegenerative diseases coupled with increasing longevity poses an economic burden at individual and societal levels. There is currently no effective cure for the majority of neurodegenerative diseases and disease-affected tissues from patients have been difficult to obtain for research and drug discovery in pre-clinical settings. While the use of animal models has contributed invaluable mechanistic insights and potential therapeutic targets, the translational value of animal models could be further enhanced when combined with in vitro models derived from patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls generated using CRISPR-Cas9 mediated genome editing. The iPSCs are self-renewable and capable of being differentiated into the cell types affected by the diseases. These in vitro models based on patient-derived iPSCs provide the opportunity to model disease development, uncover novel mechanisms and test potential therapeutics. Here we review findings from iPSC-based modeling of selected neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and spinocerebellar ataxia. Furthermore, we discuss the possibilities of generating three-dimensional (3D) models using the iPSCs-derived cells and compare their advantages and disadvantages to conventional two-dimensional (2D) models. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Tetsuro Tago

    2018-01-01

    Full Text Available Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs, which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET. We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.

  8. Head trauma in sport and neurodegenerative disease: an issue whose time has come?

    Science.gov (United States)

    Pearce, Neil; Gallo, Valentina; McElvenny, Damien

    2015-03-01

    A number of small studies and anecdotal reports have been suggested that sports involving repeated head trauma may have long-term risks of neurodegenerative disease. There are now plausible mechanisms for these effects, and a recognition that these problems do not just occur in former boxers, but in a variety of sports involving repeated concussions, and possibly also in sports in which low-level head trauma is common. These neurodegenerative effects potentially include increased risks of impaired cognitive function and dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Many would argue for taking a precautionary approach and immediately banning or restricting sports such as boxing. However, there are important public health issues in terms of how wide the net should be cast in terms of other sports, and what remedial measures could be taken? This in turn requires a major research effort involving both clinical and basic research to understand the underlying mechanisms, leading from head trauma to neurodegenerative disease and epidemiologic studies to assess the long-term consequences. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. The Progression of Posterior Cortical Atrophy to Corticobasal Syndrome: Lumping or Splitting Neurodegenerative Diseases?

    Directory of Open Access Journals (Sweden)

    Maurizio Giorelli

    2014-06-01

    Full Text Available Background: Posterior cortical atrophy is a clinical syndrome that is characterized by the progressive loss of visuospatial integration and is associated with neurodegenerative conditions.Case Report: We describe a 60‐year‐old female with simultanagnosia, oculomotor apraxia, and optic ataxia for which she received an initial clinical diagnosis of posterior cortical atrophy. Three years later, she developed Balint's syndrome, Gerstmann's syndrome, left alien hand syndrome, smooth asymmetric (left rigidity, cortical sensory loss, and spontaneous myoclonic jerks of the left arm, which suggested a final diagnosis of corticobasal syndrome.Discussion: This case report indicates that corticobasal syndrome may present with visuospatial deficits.

  10. Association between environmental exposure to pesticides and neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Parron, Tesifon [University of Almeria, Department of Neurosciences and Health Sciences, Almeria (Spain); Andalusian Council of Health at Almeria province, Almeria (Spain); Requena, Mar [Andalusian Council of Health at Almeria province, Almeria (Spain); Hernandez, Antonio F., E-mail: ajerez@ugr.es [University of Granada School of Medicine, Granada (Spain); Alarcon, Raquel [Andalusian Council of Health at Almeria province, Almeria (Spain)

    2011-11-15

    Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: Black-Right-Pointing-Pointer Environmental exposure to pesticides and neurodegenerative-psychiatric disorders. Black-Right-Pointing-Pointer Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. Black

  11. A knowledge based approach to matching human neurodegenerative disease and animal models

    Directory of Open Access Journals (Sweden)

    Maryann E Martone

    2013-05-01

    Full Text Available Neurodegenerative diseases present a wide and complex range of biological and clinical features. Animal models are key to translational research, yet typically only exhibit a subset of disease features rather than being precise replicas of the disease. Consequently, connecting animal to human conditions using direct data-mining strategies has proven challenging, particularly for diseases of the nervous system, with its complicated anatomy and physiology. To address this challenge we have explored the use of ontologies to create formal descriptions of structural phenotypes across scales that are machine processable and amenable to logical inference. As proof of concept, we built a Neurodegenerative Disease Phenotype Ontology and an associated Phenotype Knowledge Base using an entity-quality model that incorporates descriptions for both human disease phenotypes and those of animal models. Entities are drawn from community ontologies made available through the Neuroscience Information Framework and qualities are drawn from the Phenotype and Trait Ontology. We generated ~1200 structured phenotype statements describing structural alterations at the subcellular, cellular and gross anatomical levels observed in 11 human neurodegenerative conditions and associated animal models. PhenoSim, an open source tool for comparing phenotypes, was used to issue a series of competency questions to compare individual phenotypes among organisms and to determine which animal models recapitulate phenotypic aspects of the human disease in aggregate. Overall, the system was able to use relationships within the ontology to bridge phenotypes across scales, returning non-trivial matches based on common subsumers that were meaningful to a neuroscientist with an advanced knowledge of neuroanatomy. The system can be used both to compare individual phenotypes and also phenotypes in aggregate. This proof of concept suggests that expressing complex phenotypes using formal

  12. Maillard reaction versus other nonenzymatic modifications in neurodegenerative processes.

    Science.gov (United States)

    Pamplona, Reinald; Ilieva, Ekaterina; Ayala, Victoria; Bellmunt, Maria Josep; Cacabelos, Daniel; Dalfo, Esther; Ferrer, Isidre; Portero-Otin, Manuel

    2008-04-01

    Nonenzymatic protein modifications are generated from direct oxidation of amino acid side chains and from reaction of the nucleophilic side chains of specific amino acids with reactive carbonyl species. These reactions give rise to specific markers that have been analyzed in different neurodegenerative diseases sharing protein aggregation, such as Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis. Collectively, available data demonstrate that oxidative stress homeostasis, mitochondrial function, and energy metabolism are key factors in determining the disease-specific pattern of protein molecular damage. In addition, these findings suggest the lack of a "gold marker of oxidative stress," and, consequently, they strengthen the need for a molecular dissection of the nonenzymatic reactions underlying neurodegenerative processes.

  13. Transposable elements in TDP-43-mediated neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Wanhe Li

    Full Text Available Elevated expression of specific transposable elements (TEs has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.

  14. Advances in epigenetics and epigenomics for neurodegenerative diseases.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2011-10-01

    In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.

  15. Astrocytes in neurodegenerative diseases (I): function and molecular description.

    Science.gov (United States)

    Guillamón-Vivancos, T; Gómez-Pinedo, U; Matías-Guiu, J

    2015-03-01

    Astrocytes have been considered mere supporting cells in the CNS. However, we now know that astrocytes are actively involved in many of the functions of the CNS and may play an important role in neurodegenerative diseases. This article reviews the roles astrocytes play in CNS development and plasticity; control of synaptic transmission; regulation of blood flow, energy, and metabolism; formation of the blood-brain barrier; regulation of the circadian rhythms, lipid metabolism and secretion of lipoproteins; and in neurogenesis. Astrocyte markers and the functions of astrogliosis are also described. Astrocytes play an active role in the CNS. A good knowledge of astrocytes is essential to understanding the mechanisms of neurodegenerative diseases. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  16. The effectiveness of extracorporeal shockwave therapy in common lower limb conditions: a systematic review including quantification of patient-rated pain reduction.

    Science.gov (United States)

    Korakakis, Vasileios; Whiteley, Rodney; Tzavara, Alexander; Malliaropoulos, Nikolaos

    2018-03-01

    To evaluate extracorporeal shockwave therapy (ESWT) in treating Achilles tendinopathy (AT), greater trochanteric pain syndrome (GTPS), medial tibial stress syndrome (MTSS), patellar tendinopathy (PT) and proximal hamstring tendinopathy (PHT). Systematic review. Randomised and non-randomised studies assessing ESWT in patients with AT, GTPS, MTSS, PT and PHT were included. Risk of bias and quality of studies were evaluated. Moderate-level evidence suggests (1) no difference between focused ESWT and placebo ESWT at short and mid-term in PT and (2) radial ESWT is superior to conservative treatment at short, mid and long term in PHT. Low-level evidence suggests that ESWT (1) is comparable to eccentric training, but superior to wait-and-see policy at 4 months in mid-portion AT; (2) is superior to eccentric training at 4 months in insertional AT; (3) less effective than corticosteroid injection at short term, but ESWT produced superior results at mid and long term in GTPS; (4) produced comparable results to control treatment at long term in GTPS; and (5) is superior to control conservative treatment at long term in PT. Regarding the rest of the results, there was only very low or no level of evidence. 13 studies showed high risk of bias largely due to methodology, blinding and reporting. Low level of evidence suggests that ESWT may be effective for some lower limb conditions in all phases of the rehabilitation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  17. Styrene-spaced copolymers including anthraquinone and β-O-4 lignin model units: synthesis, characterization and reactivity under alkaline pulping conditions.

    Science.gov (United States)

    Megiatto, Jackson D; Cazeils, Emmanuel; Ham-Pichavant, Frédérique; Grelier, Stéphane; Gardrat, Christian; Castellan, Alain

    2012-05-14

    A series of random copoly(styrene)s has been synthesized via radical polymerization of functionalized anthraquinone (AQ) and β-O-4 lignin model monomers. The copolymers were designed to have a different number of styrene spacer groups between the AQ and β-O-4 lignin side chains aiming at investigating the distance effects on AQ/β-O-4 electron transfer mechanisms. A detailed molecular characterization, including techniques such as size exclusion chromatography, MALDI-TOF mass spectrometry, and (1)H, (13)C, (31)P NMR and UV-vis spectroscopies, afforded quantitative information about the composition of the copolymers as well as the average distribution of the AQ and β-O-4 groups in the macromolecular structures. TGA and DSC thermal analysis have indicated that the copolymers were thermally stable under regular pulping conditions, revealing the inertness of the styrene polymer backbone in the investigation of electron transfer mechanisms. Alkaline pulping experiments showed that close contact between the redox active side chains in the copolymers was fundamental for an efficient degradation of the β-O-4 lignin model units, highlighting the importance of electron transfer reactions in the lignin degradation mechanisms catalyzed by AQ. In the absence of glucose, AQ units oxidized phenolic β-O-4 lignin model parts, mainly by electron transfer leading to vanillin as major product. By contrast, in presence of glucose, anthrahydroquinone units (formed by reduction of AQ) reduced the quinone-methide units (issued by dehydration of phenolic β-O-4 lignin model part) mainly by electron transfer leading to guaiacol as major product. Both processes were distance dependent.

  18. Memory in neurodegenerative disease: biological, cognitive, and clinical perspectives

    National Research Council Canada - National Science Library

    Tröster, Alexander I

    1998-01-01

    ... of memory dysfunction in neurodegenerative disease  . ,  . ,     .  100 6 Functional neuroimaging correlates...

  19. Progranulin: At the interface of neurodegenerative and metabolic diseases

    OpenAIRE

    Nguyen, Andrew D.; Nguyen, Thi A.; Martens, Lauren Herl; Mitic, Laura L.; Farese, Robert V.

    2013-01-01

    Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor–like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin’s function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic fun...

  20. [Caregivers of people with neurodegenerative diseases: from help to delegation].

    Science.gov (United States)

    Delzescaux, Sabine; Blondel, Frédéric

    2015-01-01

    Being a caregiver is difficult, even more so when it comes to helping people with a neurodegenerative disease. These caregivers, either family members or close friends, are confronted with an unexpected delegation which can prove to be highly complex as the pitfalls can indeed be significant. Moreover, the support the caregivers can provide depends on the support they can get for themselves. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. EMAP/NOAA 2003 SURVEY OF ECOLOGICAL CONDITIONS OF THE WESTERN U.S. CONTINENTAL SHELF, INCLUDING GULF OF FARALLONES NATIONAL MARINE SANCTUARY

    Science.gov (United States)

    In June of 2003 a partnership between EPA, NOAA, and the western coastal states conducted a joint survey of ecological condition of aquatic resources along the U.S. western continental shelf (30-120 m), using multiple indicators of ecological condition. The study is an element o...

  2. The emergence of designed multiple ligands for neurodegenerative disorders.

    Science.gov (United States)

    Geldenhuys, Werner J; Youdim, Moussa B H; Carroll, Richard T; Van der Schyf, Cornelis J

    2011-09-01

    The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. Copyright © 2011. Published by Elsevier Ltd.

  3. Drosophila as an In Vivo Model for Human Neurodegenerative Disease

    Science.gov (United States)

    McGurk, Leeanne; Berson, Amit; Bonini, Nancy M.

    2015-01-01

    With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research. PMID:26447127

  4. Implications of glial nitric oxyde in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jose Enrique eYuste

    2015-08-01

    Full Text Available Nitric oxide (NO is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

  5. Differential diagnosis of neurodegenerative dementias with nuclear medicine methods

    International Nuclear Information System (INIS)

    Kluge, R.

    2015-01-01

    Full text: Neurodegenerative dementias (NDD) are characterized by insidious onset and gradual progression of cognitive dysfunction, initially relatively focal with respect to cognitive domains and brain regions involved. Nuclear medicine techniques help to clarify differential diagnoses of syndromes such as Alzheimer’s disease (AD), dementia with Lewy bodies (DlB), posterior cortical atrophy (PCA), logopenic primary progressive aphasia (PPA), agrammatic PPA, semantic dementia (SD), behavioral variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy syndrome (PSPS). The process of pathologic changes in the brain may start decades before first clinical symptoms become evident. An early diagnosis already in the pre-clinical phase of the diseases will be of immense importance when expected effective therapeutic options have been introduced. NDDs are histopathologically characterized by accumulation of pathological proteins in the brain like beta amyloid or protein tau. While radiotracers for labeling of protein tau are in preclinical evaluation, different radiotracers labeling amyloid plaques ([11C]PIB, [18F]Florbetapir (Amyvid, Fa. EliLilly), [18F]Florbetaben (Neuraceq, Fa. Piramal), [18F]Flutemetamol (vVzamyl, Fa. Ge) have already been established in clinical use during the last years. In AD these tracers are intensively accumulated in the whole cortical brain. Even an early disease can be excluded in case of a negative amyloid PET. The method is, however, not highly specific since amyloid plaques may also be present in DlB (70 – 80%), FTD (30%) orlogopenicPPA (100%). Neuronal dysfunction goes along with decreased glucose consumption. Different diseases are characterized by different topographical zones of reduced [18F]FDG uptake. In AD the posterior cingular, temporopariatal and (later) frontal cortex are affected, in DlB the pattern is similar, including the occipital cortex, in FTD the frontal cortex is affected, in nonfluent PPA the

  6. New Therapeutic Drugs from Bioactive Natural Molecules: the Role of Gut Microbiota Metabolism in Neurodegenerative Diseases.

    Science.gov (United States)

    Di Meo, Francesco; Donato, Stella; Di Pardo, Alba; Maglione, Vittorio; Filosa, Stefania; Crispi, Stefania

    2018-04-03

    The gut-brain axis is considered a neuroendocrine system, which connects brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for healthy conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. Gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Recent advances in gut microbiota analyses indicate that the gut bacterial community plays a key role in maintaining normal brain functions. Recent metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both gut bacterial composition and brain biochemistry. Modifications of microbiota composition by natural bioactive molecules could be used to restore the altered brain functions, which characterize neurodegenerative diseases, leading to consider these compounds as novel therapeutic strategies for the treatment of neuropathologies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Assessing Executive Dysfunction in Neurodegenerative Disorders: A Critical Review of Brief Neuropsychological Tools

    Directory of Open Access Journals (Sweden)

    Helena S. Moreira

    2017-11-01

    Full Text Available Executive function (EF has been defined as a multifaceted construct that involves a variety of high-level cognitive abilities such as planning, working memory, mental flexibility, and inhibition. Being able to identify deficits in EF is important for the diagnosis and monitoring of several neurodegenerative disorders, and thus their assessment is a topic of much debate. In particular, there has been a growing interest in the development of neuropsychological screening tools that can potentially provide a reliable quick measure of EF. In this review, we critically discuss the four screening tools of EF currently available in the literature: Executive Interview-25 (EXIT 25, Frontal Assessment Battery (FAB, INECO Frontal Screening (IFS, and FRONTIER Executive Screen (FES. We first describe their features, and then evaluate their psychometric properties, the existing evidence on their neural correlates, and the empirical work that has been conducted in clinical populations. We conclude that the four screening tools generally present appropriate psychometric properties, and are sensitive to impairments in EF in several neurodegenerative conditions. However, more research will be needed mostly with respect to normative data and neural correlates, and to determine the extent to which these tools add specific information to the one provided by global cognition screening tests. More research directly comparing the available tools with each other will also be important to establish in which conditions each of them can be most useful.

  8. Emulation of Physician Tasks in Eye-Tracked Virtual Reality for Remote Diagnosis of Neurodegenerative Disease.

    Science.gov (United States)

    Orlosky, Jason; Itoh, Yuta; Ranchet, Maud; Kiyokawa, Kiyoshi; Morgan, John; Devos, Hannes

    2017-04-01

    For neurodegenerative conditions like Parkinson's disease, early and accurate diagnosis is still a difficult task. Evaluations can be time consuming, patients must often travel to metropolitan areas or different cities to see experts, and misdiagnosis can result in improper treatment. To date, only a handful of assistive or remote methods exist to help physicians evaluate patients with suspected neurological disease in a convenient and consistent way. In this paper, we present a low-cost VR interface designed to support evaluation and diagnosis of neurodegenerative disease and test its use in a clinical setting. Using a commercially available VR display with an infrared camera integrated into the lens, we have constructed a 3D virtual environment designed to emulate common tasks used to evaluate patients, such as fixating on a point, conducting smooth pursuit of an object, or executing saccades. These virtual tasks are designed to elicit eye movements commonly associated with neurodegenerative disease, such as abnormal saccades, square wave jerks, and ocular tremor. Next, we conducted experiments with 9 patients with a diagnosis of Parkinson's disease and 7 healthy controls to test the system's potential to emulate tasks for clinical diagnosis. We then applied eye tracking algorithms and image enhancement to the eye recordings taken during the experiment and conducted a short follow-up study with two physicians for evaluation. Results showed that our VR interface was able to elicit five common types of movements usable for evaluation, physicians were able to confirm three out of four abnormalities, and visualizations were rated as potentially useful for diagnosis.

  9. No Geographic Correlation between Lyme Disease and Death Due to 4 Neurodegenerative Disorders, United States, 2001-2010.

    Science.gov (United States)

    Forrester, Joseph D; Kugeler, Kiersten J; Perea, Anna E; Pastula, Daniel M; Mead, Paul S

    2015-11-01

    Associations between Lyme disease and certain neurodegenerative diseases have been proposed, but supportive evidence for an association is lacking. Similar geographic distributions would be expected if 2 conditions were etiologically linked. Thus, we compared the distribution of Lyme disease cases in the United States with the distributions of deaths due to Alzheimer disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson disease; no geographic correlations were identified. Lyme disease incidence per US state was not correlated with rates of death due to ALS, MS, or Parkinson disease; however, an inverse correlation was detected between Lyme disease and Alzheimer disease. The absence of a positive correlation between the geographic distribution of Lyme disease and the distribution of deaths due to Alzheimer disease, ALS, MS, and Parkinson disease provides further evidence that Lyme disease is not associated with the development of these neurodegenerative conditions.

  10. The ELISA-measured increase in cerebrospinal fluid tau that discriminates Alzheimer's disease from other neurodegenerative disorders is not attributable to differential recognition of tau assembly forms.

    Science.gov (United States)

    O'Dowd, Seán T; Ardah, Mustafa T; Johansson, Per; Lomakin, Aleksey; Benedek, George B; Roberts, Kinley A; Cummins, Gemma; El Agnaf, Omar M; Svensson, Johan; Zetterberg, Henrik; Lynch, Timothy; Walsh, Dominic M

    2013-01-01

    Elevated cerebrospinal fluid concentrations of tau discriminate Alzheimer's disease from other neurodegenerative conditions. The reasons for this are unclear. While commercial assay kits are widely used to determine total-tau concentrations, little is known about their ability to detect different aggregation states of tau. We demonstrate that the leading commercial enzyme-linked immunosorbent assay reliably detects aggregated and monomeric tau and evinces good recovery of both species when added into cerebrospinal fluid. Hence, the disparity between total-tau levels encountered in Alzheimer's disease and other neurodegenerative conditions is not due to differential recognition of tau assembly forms or the extent of degeneration.

  11. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

    Science.gov (United States)

    Liu, Ying; Deng, Wenbin

    2016-05-01

    With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

  12. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.

    Science.gov (United States)

    LaMarca, Elizabeth A; Powell, Samuel K; Akbarian, Schahram; Brennand, Kristen J

    2018-01-01

    Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional "mini-brains" and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson's disease, and consider the future of this groundbreaking research.

  13. Clinical neurogenetics: behavioral management of inherited neurodegenerative disease.

    Science.gov (United States)

    Wexler, Eric

    2013-11-01

    Psychiatric symptoms often manifest years before overt neurologic signs in patients with inherited neurodegenerative disease. The most frequently cited example of this phenomenon is the early onset of personality changes in "presymptomatic" Huntington patients. In some cases the changes in mood and cognition are even more debilitating than their neurologic symptoms. The goal of this article is to provide the neurologist with a concise primer that can be applied in a busy clinic or private practice. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. REM behaviour disorder detection associated with neurodegenerative diseases

    DEFF Research Database (Denmark)

    Kempfner, Jacob; Sorensen, Gertrud; Zoetmulder, Marielle

    2010-01-01

    Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection......, a computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance...

  15. Modelling neurodegenerative diseases in vitro: Recent advances in 3D iPSC technologies

    Directory of Open Access Journals (Sweden)

    Elodie J Siney

    2018-03-01

    Full Text Available The discovery of induced pluripotent stem cells (iPSC 12 years ago has fostered the development of innovative patient-derived in vitro models for better understanding of disease mechanisms. This is particularly relevant to neurodegenerative diseases, where availability of live human brain tissue for research is limited and post-mortem interval changes influence readouts from autopsy-derived human tissue. Hundreds of iPSC lines have now been prepared and banked, thanks to several large scale initiatives and cell banks. Patient- or engineered iPSC-derived neural models are now being used to recapitulate cellular and molecular aspects of a variety of neurodegenerative diseases, including early and pre-clinical disease stages. The broad relevance of these models derives from the availability of a variety of differentiation protocols to generate disease-specific cell types and the manipulation to either introduce or correct disease-relevant genetic modifications. Moreover, the use of chemical and physical three-dimensional (3D matrices improves control over the extracellular environment and cellular organization of the models. These iPSC-derived neural models can be utilised to identify target proteins and, importantly, provide high-throughput screening for drug discovery. Choosing Alzheimer’s disease (AD as an example, this review describes 3D iPSC-derived neural models and their advantages and limitations. There is now a requirement to fully characterise and validate these 3D iPSC-derived neural models as a viable research tool that is capable of complementing animal models of neurodegeneration and live human brain tissue. With further optimization of differentiation, maturation and aging protocols, as well as the 3D cellular organisation and extracellular matrix to recapitulate more closely, the molecular extracellular-environment of the human brain, 3D iPSC-derived models have the potential to deliver new knowledge, enable discovery of novel

  16. Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.

    Science.gov (United States)

    Ayyadevara, Srinivas; Balasubramaniam, Meenakshisundaram; Kakraba, Samuel; Alla, Ramani; Mehta, Jawahar L; Shmookler Reis, Robert J

    2017-12-10

    Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets. Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides. Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions. These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio

  17. The interplay between iron accumulation, mitochondrial dysfunction and inflammation during the execution step of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Pamela J. Urrutia

    2014-03-01

    Full Text Available A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich’s ataxia and Parkinson’s disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson’s disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

  18. MRI Markers of Neurodegenerative and Neurovascular Changes in Relation to Postoperative Delirium and Postoperative Cognitive Decline.

    Science.gov (United States)

    Kant, Ilse M J; de Bresser, Jeroen; van Montfort, Simone J T; Slooter, Arjen J C; Hendrikse, Jeroen

    2017-10-01

    Postoperative delirium (POD) and postoperative cognitive decline (POCD) are common in elderly patients. The aim of the present review was to explore the association of neurodegenerative and neurovascular changes with the occurrence of POD and POCD. Fifteen MRI studies were identified by combining multiple search terms for POD, POCD, and brain imaging. These studies described a total of 1,422 patients and were all observational in design. Neurodegenerative changes (global and regional brain volumes) did not show a consistent association with the occurrence of POD (four studies) or POCD (two studies). In contrast, neurovascular changes (white matter hyperintensities and cerebral infarcts) were more consistently associated with the occurrence of POD (seven studies) and POCD (five studies). In conclusion, neurovascular changes appear to be consistently associated with the occurrence of POD and POCD, and may identify patients at increased risk of these conditions. Larger prospective studies are needed to study the consistency of these findings and to unravel the underlying pathophysiological mechanisms. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. [Changes in olfaction during ageing and in certain neurodegenerative diseases: up-to-date].

    Science.gov (United States)

    Bianchi, A-J; Guépet-Sordet, H; Manckoundia, P

    2015-01-01

    Olfaction is a complex sensory system, and increasing interest is being shown in the link between olfaction and cognition, notably in the elderly. In this literature review, we revisit the specific neurophysiological features of the olfactory system and odorants that lead to a durable olfactory memory and an emotional memory, for which the implicit component produces subconscious olfactory conditioning. Olfaction is known to affect cognitive abilities and mood. We also consider the impairment of olfactory function due to ageing and to neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, through anatomopathological changes in the peripheral and central olfactory structures. The high frequency of these olfactory disorders as well as their early occurrence in Alzheimer disease and Parkinson disease are in favour of their clinical detection in subjects suffering from these two neurodegenerative diseases. Finally, we analyse the impact of olfactory stimulation on cognitive performance and attention. Current observational data from studies in elderly patients with Alzheimer-type dementia are limited to multiple sensory stimulation methods, such as the Snoezelen method, and aromatherapy. These therapies have shown benefits for dementia-related mood and behaviour disorders in the short term, with few side effects. Since olfactory chemosensory stimulation may be beneficial, it may be proposed in patients with dementia, especially Alzheimer-type dementia, as a complementary or even alternative therapy to existing medical strategies. Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  20. Examination of Gelatinase Isoforms in Rodent Models of Acute Neurodegenerative Diseases Using Two-Dimensional Zymography.

    Science.gov (United States)

    Chen, Shanyan; Meng, Fanjun; Chen, Zhenzhou; Qu, Zhe; Cui, Jiankun; Gu, Zezong

    2017-01-01

    Pathological activation of gelatinases (matrix metalloproteinase-2 and -9; MMP-2/-9) has been shown to cause a number of detrimental outcomes in neurodegenerative diseases. In gel gelatin zymography is a highly sensitive methodology commonly used in revealing levels of gelatinase activity and in separating the proform and active form of gelatinases, based on their different molecular weights. However, this methodology is inadequate in resolving complex enzyme isoforms, because gelatinase expression and activity can be regulated at transcriptional and/or post-translational levels under in vivo conditions resulting in alternation of their isoelectric focusing (IEF) points. In this chapter, we describe an advanced methodology, termed two-dimensional zymography, combining IEF with zymographic electrophoresis under non-reducing conditions to achieve significant improvement in separation of the gelatinase isoforms in both cell-based and in vivo models for acute brain injuries and neuroinflammation.

  1. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.

    Science.gov (United States)

    Ciechanover, Aaron; Kwon, Yong Tae

    2015-03-13

    Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

  2. Prions, prion-like prionoids, and neurodegenerative disordersVacancy

    Directory of Open Access Journals (Sweden)

    Ashok Verma

    2016-01-01

    Full Text Available Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like “prionoids” are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

  3. The epigenetic bottleneck of neurodegenerative and psychiatric diseases.

    Science.gov (United States)

    Sananbenesi, Farahnaz; Fischer, Andre

    2009-11-01

    The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases.

  4. Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders.

    Science.gov (United States)

    Jęśko, Henryk; Wencel, Przemysław; Strosznajder, Robert P; Strosznajder, Joanna B

    2017-03-01

    Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD + levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD + -dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer's disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.

  5. Congo red and protein aggregation in neurodegenerative diseases.

    Science.gov (United States)

    Frid, Petrea; Anisimov, Sergey V; Popovic, Natalija

    2007-01-01

    Congo red is a commonly used histological dye for amyloid detection. The specificity of this staining results from Congo red's affinity for binding to fibril proteins enriched in beta-sheet conformation. Unexpectedly, recent investigations indicate that the dye also possesses the capacity to interfere with processes of protein misfolding and aggregation, stabilizing native protein monomers or partially folded intermediates, while reducing concentration of more toxic protein oligomers. Inhibitory effects of Congo red upon amyloid toxicity may also range from blockade of channel formation and interference with glycosaminoglycans binding or immune functions, to the modulation of gene expression. Particularly, Congo red exhibits ameliorative effect in models of neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's and prion diseases. Another interesting application of Congo red analogues is the development of imaging probes. Based on their small molecular size and penetrability through blood-brain barrier, Congo red congeners can be used for both antemortem and in vivo visualization and quantification of brain amyloids. Therefore, understanding mechanisms involved in dye-amyloidal fibril binding and inhibition of aggregation will provide instructive guides for the design of future compounds, potentially useful for monitoring and treating neurodegenerative diseases.

  6. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Lee J. Martin

    2010-03-01

    Full Text Available Alzheimer’s disease (AD, Parkinson’s disease (PD and amyotrophic lateral sclerosis (ALS are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.

  7. Development of a kinetic model, including rate constant estimations, on iodine and caesium behaviour in the primary circuit of LWR's under accident conditions

    International Nuclear Information System (INIS)

    Alonso, A.; Buron, J.M.; Fernandez, S.

    1991-07-01

    In this report, a kinetic model has been developed with the aim to try to reproduce the chemical phenomena that take place in a flowing system containing steam, hydrogen and iodine and caesium vapours. The work is divided into two different parts. The first part consists in the estimation, through the Activited Complex Theory, of the reaction rate constants, for the chosen reactions, and the development of the kinetic model based on the concept of ideal tubular chemical reactor. The second part deals with the application of such model to several cases, which were taken from the Phase B 'Scoping Calculations' of the Phebus-FP Project (sequence AB) and the SFD-ST and SFD1.1 experiments. The main conclusion obtained from this work is that the assumption of instantaneous equilibrium could be inacurrate in order to estimate the iodine and caesium species distribution under severe accidents conditions

  8. A Design Study of the Inflated Sphere Landing Vehicle, Including the Landing Performance and the Effects of Deviations from Design Conditions

    Science.gov (United States)

    Martin, E. Dale

    1961-01-01

    The impact motion of the inflated sphere landing vehicle with a payload centrally supported from the spherical skin by numerous cords has been determined on the assumption of uniform isentropic gas compression during impact. The landing capabilities are determined for a system containing suspension cords of constant cross section. The effects of deviations in impact velocity and initial gas temperature from the design conditions are studied. Also discussed are the effects of errors in the time at which the skin is ruptured. These studies indicate how the design parameters should be chosen to insure reliability of the landing system. Calculations have been made and results are presented for a sphere inflated with hydrogen, landing on the moon in the absence of an atmosphere. The results are presented for one value of the skin-strength parameter.

  9. Actual Condition of Paddy Field Levee Maintenance by Various Farm Households including Large-scale Farming in the Developed Land Renting Area

    Science.gov (United States)

    Sakata, Yasuyo

    The survey of interview, resource acquisition, photographic operation, and questionnaire were carried out in the “n” Community in the “y” District in Hakusan City in Ishikawa Prefecture to investigate the actual condition of paddy field levee maintenance in the area where land-renting market was proceeding, large-scale farming was dominant, and the problems of geographically scattered farm-land existed. In the study zone, 1) an agricultural production legal person rent-cultivated some of the paddy fields and maintained the levees, 2) another agricultural production legal person rent-cultivated some of the soy bean fields for crop changeover and land owners maintained the levees. The results indicated that sufficient maintenance was executed on the levees of the paddy fields cultivated by the agricultural production legal person, the soy bean fields for crop changeover, and the paddy fields cultivated by the land owners. Each reason is considered to be the managerial strategy, the economic incentive, the mutual monitoring and cross-regulatory mechanism, etc.

  10. A pacemaker powered by an implantable biofuel cell operating under conditions mimicking the human blood circulatory system--battery not included.

    Science.gov (United States)

    Southcott, Mark; MacVittie, Kevin; Halámek, Jan; Halámková, Lenka; Jemison, William D; Lobel, Robert; Katz, Evgeny

    2013-05-07

    Biocatalytic electrodes made of buckypaper were modified with PQQ-dependent glucose dehydrogenase on the anode and with laccase on the cathode and were assembled in a flow biofuel cell filled with serum solution mimicking the human blood circulatory system. The biofuel cell generated an open circuitry voltage, Voc, of ca. 470 mV and a short circuitry current, Isc, of ca. 5 mA (a current density of 0.83 mA cm(-2)). The power generated by the implantable biofuel cell was used to activate a pacemaker connected to the cell via a charge pump and a DC-DC converter interface circuit to adjust the voltage produced by the biofuel cell to the value required by the pacemaker. The voltage-current dependencies were analyzed for the biofuel cell connected to an Ohmic load and to the electronic loads composed of the interface circuit, or the power converter, and the pacemaker to study their operation. The correct pacemaker operation was confirmed using a medical device - an implantable loop recorder. Sustainable operation of the pacemaker was achieved with the system closely mimicking human physiological conditions using a single biofuel cell. This first demonstration of the pacemaker activated by the physiologically produced electrical energy shows promise for future electronic implantable medical devices powered by electricity harvested from the human body.

  11. Behavior and failure of uniformly hydrided Zircaloy-4 fuel claddings between 25 C and 480 C under various stress states, including RIA loading conditions

    International Nuclear Information System (INIS)

    Le Saux, M.; Carassou, S.; Averty, X.; Le Saux, M.; Besson, J.; Poussard, C.

    2010-01-01

    The anisotropic plastic behavior and the fracture of as-received and hydrided Cold-Worked Stress Relieved Zircaloy-4 cladding tubes are investigated under thermal-mechanical loading conditions representative of Pellet-Clad Mechanical Interaction during Reactivity Initiated Accidents in Pressurized Water Reactors. In order to study the combined effects of temperature, hydrogen content, loading direction and stress state, Axial Tensile, Hoop Tensile, Expansion Due to Compression and hoop Plane Strain Tensile tests are performed at room temperature, 350 C and 480 C on the material containing various hydrogen contents up to 1200 wt. ppm (hydrides are circumferential and homogeneously distributed). These tests are combined with digital image correlation and metallographic and fractographic observations at different scales. The flow stress of the material decreases with increasing temperature. The material is either strengthened or softened by hydrogen depending on temperature and hydrogen content. Plastic anisotropy depends on temperature but not on hydrogen content. The ductility of the material decreases with increasing hydrogen content at room temperature due to damage nucleation by hydride cracking. The plastic strain that leads to hydride fracture at room temperature decreases with increasing hydrogen content. The influence of stress triaxiality on hydride cracking is negligible in the studied range. The influence of hydrogen on material ductility is negligible at 350 C and 480 C since hydrides do not crack at these temperatures. The ductility of the material increases with increasing temperature. The evolution of material ductility is associated with a change in both the macroscopic fracture mode of the specimens and the microscopic failure mechanisms. (authors)

  12. Effects of Cd and Ni toxicity to Ceratophyllum demersum under environmentally relevant conditions in soft and hard water including a German lake

    Energy Technology Data Exchange (ETDEWEB)

    Andresen, Elisa, E-mail: Elisa.Andresen@uni-konstanz.de [University of Konstanz, Department of Biology, D-78457 Konstanz (Germany); Opitz, Judith, E-mail: Daniela.Opitz@uni-konstanz.de [University of Konstanz, Department of Biology, D-78457 Konstanz (Germany); Thomas, George, E-mail: George.Thomas@uni-konstanz.de [University of Konstanz, Department of Biology, D-78457 Konstanz (Germany); Stärk, Hans-Joachim, E-mail: Ha-Jo.Staerk@ufz.de [UFZ – Helmholtz Centre for Environmental Research, Department of Analytical Chemistry, Permoserstr. 15, D-04318 Leipzig (Germany); Dienemann, Holger, E-mail: Holger.Dienemann@smul.sachsen.de [Saxon State Company for Environment and Agriculture, Business Domain 5 (Laboratory), Department 53, Bitterfelder Str. 25, D-04849 Bad Düben (Germany); Jenemann, Kerstin, E-mail: Kerstin.Jenemann@smul.sachsen.de [Sächsisches Landesamt für Umwelt, Landwirtschaft und Geologie, Abteilung Wasser, Boden, Wertstoffe, Zur Wetterwarte 11, D-01109 Dresden (Germany); Dickinson, Bryan C., E-mail: Bryan.Dickinson@gmail.com [Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138 (United States); Küpper, Hendrik, E-mail: Hendrik.Kuepper@uni-konstanz.de [University of Konstanz, Department of Biology, D-78457 Konstanz (Germany); University of South Bohemia, Faculty of Biological Sciences and Institute of Physical Biology, Branišovská 31, CZ-370 05 České Budejovice (Czech Republic)

    2013-10-15

    Highlights: •Hardly any macrophytic growth occurred in an oligotrophic hard water lake in Germany. •All parameters were optimal, besides elevated, nanomolar concentrations of Ni and Cd. •We cultivated submerged macrophytes in real and simulated hard and soft lake water. •Nanomolar Cd and Ni inhibited the plants’ photosynthetic light reactions in soft water. •The inhibition was synergistic, i.e. stronger than the addition of Cd and Ni effects. -- Abstract: Even essential trace elements are phytotoxic over a certain threshold. In this study, we investigated whether heavy metal concentrations were responsible for the nearly complete lack of submerged macrophytes in an oligotrophic lake in Germany. We cultivated the rootless aquatic model plant Ceratophyllum demersum under environmentally relevant conditions like sinusoidal light and temperature cycles and a low plant biomass to water volume ratio. Experiments lasted for six weeks and were analysed by detailed measurements of photosynthetic biophysics, pigment content and hydrogen peroxide production. We established that individually non-toxic cadmium (3 nM) and slightly toxic nickel (300 nM) concentrations became highly toxic when applied together in soft water, severely inhibiting photosynthetic light reactions. Toxicity was further enhanced by phosphate limitation (75 nM) in soft water as present in many freshwater habitats. In the investigated lake, however, high water hardness limited the toxicity of these metal concentrations, thus the inhibition of macrophytic growth in the lake must have additional reasons. The results showed that synergistic heavy metal toxicity may change ecosystems in many more cases than estimated so far.

  13. Effects of Cd and Ni toxicity to Ceratophyllum demersum under environmentally relevant conditions in soft and hard water including a German lake

    International Nuclear Information System (INIS)

    Andresen, Elisa; Opitz, Judith; Thomas, George; Stärk, Hans-Joachim; Dienemann, Holger; Jenemann, Kerstin; Dickinson, Bryan C.; Küpper, Hendrik

    2013-01-01

    Highlights: •Hardly any macrophytic growth occurred in an oligotrophic hard water lake in Germany. •All parameters were optimal, besides elevated, nanomolar concentrations of Ni and Cd. •We cultivated submerged macrophytes in real and simulated hard and soft lake water. •Nanomolar Cd and Ni inhibited the plants’ photosynthetic light reactions in soft water. •The inhibition was synergistic, i.e. stronger than the addition of Cd and Ni effects. -- Abstract: Even essential trace elements are phytotoxic over a certain threshold. In this study, we investigated whether heavy metal concentrations were responsible for the nearly complete lack of submerged macrophytes in an oligotrophic lake in Germany. We cultivated the rootless aquatic model plant Ceratophyllum demersum under environmentally relevant conditions like sinusoidal light and temperature cycles and a low plant biomass to water volume ratio. Experiments lasted for six weeks and were analysed by detailed measurements of photosynthetic biophysics, pigment content and hydrogen peroxide production. We established that individually non-toxic cadmium (3 nM) and slightly toxic nickel (300 nM) concentrations became highly toxic when applied together in soft water, severely inhibiting photosynthetic light reactions. Toxicity was further enhanced by phosphate limitation (75 nM) in soft water as present in many freshwater habitats. In the investigated lake, however, high water hardness limited the toxicity of these metal concentrations, thus the inhibition of macrophytic growth in the lake must have additional reasons. The results showed that synergistic heavy metal toxicity may change ecosystems in many more cases than estimated so far

  14. Role of Artificial Intelligence Techniques (Automatic Classifiers) in Molecular Imaging Modalities in Neurodegenerative Diseases.

    Science.gov (United States)

    Cascianelli, Silvia; Scialpi, Michele; Amici, Serena; Forini, Nevio; Minestrini, Matteo; Fravolini, Mario Luca; Sinzinger, Helmut; Schillaci, Orazio; Palumbo, Barbara

    2017-01-01

    Artificial Intelligence (AI) is a very active Computer Science research field aiming to develop systems that mimic human intelligence and is helpful in many human activities, including Medicine. In this review we presented some examples of the exploiting of AI techniques, in particular automatic classifiers such as Artificial Neural Network (ANN), Support Vector Machine (SVM), Classification Tree (ClT) and ensemble methods like Random Forest (RF), able to analyze findings obtained by positron emission tomography (PET) or single-photon emission tomography (SPECT) scans of patients with Neurodegenerative Diseases, in particular Alzheimer's Disease. We also focused our attention on techniques applied in order to preprocess data and reduce their dimensionality via feature selection or projection in a more representative domain (Principal Component Analysis - PCA - or Partial Least Squares - PLS - are examples of such methods); this is a crucial step while dealing with medical data, since it is necessary to compress patient information and retain only the most useful in order to discriminate subjects into normal and pathological classes. Main literature papers on the application of these techniques to classify patients with neurodegenerative disease extracting data from molecular imaging modalities are reported, showing that the increasing development of computer aided diagnosis systems is very promising to contribute to the diagnostic process.

  15. Glaucoma and Alzheimer Disease: A Single Age-Related Neurodegenerative Disease of the Brain.

    Science.gov (United States)

    Mancino, Raffaele; Martucci, Alessio; Cesareo, Massimo; Giannini, Clarissa; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Nucci, Carlo

    2017-12-06

    Open Angle Glaucoma is one of the leading causes of irreversible blindness worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma, however a subset of patients experience disease progression even in presence of normal intraocular pressure values. This implies that risk factors other than intraocular pressure are involved in the pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases such as Alzheimer Disease has been suggested. In this regard, we have recently described a high prevalence of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3 (HRT-3), in a group of patients with Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of dementia associated with progressive deterioration of memory and cognition. Complaints related to vision are common among Alzheimer Disease patients. Features common to both diseases, including risk factors and pathophysiological mechanisms, gleaned from the recent literature do suggest that Alzheimer Disease and glaucoma can be considered age-related neurodegenerative diseases that may co-exist in the elderly. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism

    Directory of Open Access Journals (Sweden)

    Natalia Fernández-Borges

    2013-01-01

    Full Text Available Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term “prion-like” is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection. In vitro and in vivo experiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's diseases (PD, and amyotrophic lateral sclerosis (ALS have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term “infection” that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as “seeding” or “de novo induction” are being used to describe the in vivo propagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of “disease-causing agents” to include those already accepted as well as other misfolded proteins. In this new scenario, “seeding” would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole “infection” process.

  17. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?

    Directory of Open Access Journals (Sweden)

    Pamela eMaher

    2015-12-01

    Full Text Available Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors and a class of G-protein coupled receptors (metabotropic glutamate receptors. Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

  18. Maximizing the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective

    Directory of Open Access Journals (Sweden)

    Catherine J. Moody

    2017-08-01

    Full Text Available Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND, and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND recently developed a novel funding mechanism to rapidly mobilize scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape [Alzheimer's, Parkinson's, frontotemporal degeneration, amyotrophic lateral sclerosis (ALS, Lewy-body and vascular dementia] were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.

  19. Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

    International Nuclear Information System (INIS)

    Kamei, Hidekazu

    1989-01-01

    The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author)

  20. Correlation of auditory brain stem response and the MRI measurements in neuro-degenerative disorders

    Energy Technology Data Exchange (ETDEWEB)

    Kamei, Hidekazu (Tokyo Women' s Medical Coll. (Japan))

    1989-06-01

    The purpose of this study is to elucidate correlations of several MRI measurements of the cranium and brain, functioning as a volume conductor, to the auditory brain stem response (ABR) in neuro-degenerative disorders. The subjects included forty-seven patients with spinocerebellar degeneration (SCD) and sixteen of amyotrophic lateral sclerosis (ALS). Statistically significant positive correlations were found between I-V and III-V interpeak latencies (IPLs) and the area of cranium and brain in the longitudinal section of SCD patients, and between I-III and III-V IPLs and the area in the longitudinal section of those with ALS. And, also there were statistically significant correlations between the amplitude of the V wave and the area of brain stem as well as that of the cranium in the longitudinal section of SCD patients, and between the amplitude of the V wave and the area of the cerebrum in the longitudinal section of ALS. In conclusion, in the ABR, the IPLs were prolonged and the amplitude of the V wave was decreased while the MRI size of the cranium and brain increased. When the ABR is applied to neuro-degenerative disorders, it might be important to consider not only the conduction of the auditory tracts in the brain stem, but also the correlations of the size of the cranium and brain which act as a volume conductor. (author).

  1. Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Ming Li

    2015-01-01

    Full Text Available In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip-PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders.

  2. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression.

    Science.gov (United States)

    Maes, Michael; Yirmyia, Raz; Noraberg, Jens; Brene, Stefan; Hibbeln, Joe; Perini, Giulia; Kubera, Marta; Bob, Petr; Lerer, Bernard; Maj, Mario

    2009-03-01

    Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo

  3. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Elizabeth A. LaMarca

    2018-04-01

    Full Text Available Human-induced pluripotent stem cells (hiPSCs have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional “mini-brains” and clustered, regularly interspersed short palindromic repeats (CRISPR-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson’s disease, and consider the future of this groundbreaking research.

  4. Support system and method for detecting neurodegenerative disorder

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to a system and a method for detection of abnormal motor activity during REM sleep, and further to systems and method for assisting in detecting neurodegenerative disorders such as Parkinson's. One embodiment relates to a method for detection of abnormal motor activity...... during REM sleep comprising the steps of: performing polysomnographic recordings of a sleeping subject, thereby obtaining one or more electromyography (EMG) derivations, preferably surface EMG recordings, and one or more EEG derivations, and/or one or more electrooculargraphy (EOG) derivations, detecting...... one or more REM sleep stages, preferably based on the one or more EEG and/or EOG derivations, determining the level of muscle activity during the one or more REM sleep stages based on the one or more EMG derivations, wherein a subject having an increased level of muscle activity during REM sleep...

  5. Role of agmatine in neurodegenerative diseases and epilepsy.

    Science.gov (United States)

    Moretti, Morgana; Matheus, Filipe C; de Oliveira, Paulo A; Neis, Vivian B; Ben, Juliana; Walz, Roger; Rodrigues, Ana Lucia S; Prediger, Rui Daniel

    2014-06-01

    Agmatine, a cationic polyamine synthesized after decarboxylation of L-arginine by the enzyme arginine decarboxylase, is an endogenous neuromodulator that emerges as a potential agent to manage diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, there is increasing number of preclinical studies demonstrating the beneficial effects of exogenous agmatine administration on depression, anxiety, hypoxic ischemia, nociception, morphine tolerance, memory, Parkinson`s disease, Alzheimer`s disease, traumatic brain injury related alterations/disorders and epilepsy. The aim of this review is to summarize the knowledge about the effects of agmatine in CNS and point out its potential as new pharmacological treatment for diverse neurological and neurodegenerative diseases. Moreover, some molecular mechanisms underlying the neuroprotective effects of agmatine will be discussed.

  6. Cyanobacteria, neurotoxins and water resources: are there implications for human neurodegenerative disease?

    Science.gov (United States)

    Metcalf, James S; Codd, Geoffrey A

    2009-01-01

    Cyanobacteria are cosmopolitan microbes that inhabit marine, freshwater and terrestrial environments. Under favourable conditions in waterbodies, they can form massive populations (blooms and scums), which present hazards to human and animal health. Such cyanobacteria often contain a variety of toxic substances (cyanotoxins) that can exist as both cell-associated and free forms in the surrounding water. Some cyanotoxins are highly neurotoxic and act through a variety of mechanisms. Recent findings of the production of the neurotoxin beta-N-methylamino-L-alanine (BMAA) by cyanobacteria in aquatic environments, and of BMAA in brain and cerebrospinal fluid samples of amyotrophic lateral sclerosis and Alzheimer's disease victims, raises the possibility that people may be exposed to waterborne BMAA of cyanobacterial origin and that this may contribute to human neurodegenerative disease. An understanding of the risks presented by waterborne BMAA and of available mitigation strategies to reduce this potential exposure is needed.

  7. Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases.

    Science.gov (United States)

    Costa, Silvia Lima; Silva, Victor Diogenes Amaral; Dos Santos Souza, Cleide; Santos, Cleonice Creusa; Paris, Irmgard; Muñoz, Patricia; Segura-Aguilar, Juan

    2016-07-01

    Neurodegenerative disorders have a common characteristic that is the involvement of different cell types, typically the reactivity of astrocytes and microglia, characterizing gliosis, which in turn contributes to the neuronal dysfunction and or death. Flavonoids are secondary metabolites of plant origin widely investigated at present and represent one of the most important and diversified among natural products phenolic groups. Several biological activities are attributed to this class of polyphenols, such as antitumor activity, antioxidant, antiviral, and anti-inflammatory, among others, which give significant pharmacological importance. Our group have observed that flavonoids derived from Brazilian plants Dimorphandra mollis Bent., Croton betulaster Müll. Arg., e Poincianella pyramidalis Tul., botanical synonymous Caesalpinia pyramidalis Tul. also elicit a broad spectrum of responses in astrocytes and neurons in culture as activation of astrocytes and microglia, astrocyte associated protection of neuronal progenitor cells, neuronal differentiation and neuritogenesis. It was observed the flavonoids also induced neuronal differentiation of mouse embryonic stem cells and human pluripotent stem cells. Moreover, with the objective of seeking preclinical pharmacological evidence of these molecules, in order to assess its future use in the treatment of neurodegenerative disorders, we have evaluated the effects of flavonoids in preclinical in vitro models of neuroinflammation associated with Parkinson's disease and glutamate toxicity associated with ischemia. In particular, our efforts have been directed to identify mechanisms involved in the changes in viability, morphology, and glial cell function induced by flavonoids in cultures of glial cells and neuronal cells alone or in interactions and clarify the relation with their neuroprotective and morphogetic effects.

  8. Translocator Protein-18 kDa (TSPO Positron Emission Tomography (PET Imaging and Its Clinical Impact in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Anne-Claire Dupont

    2017-04-01

    Full Text Available In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO. In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

  9. Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Panchanan Maiti

    2018-05-01

    Full Text Available Progressive accumulation of misfolded amyloid proteins in intracellular and extracellular spaces is one of the principal reasons for synaptic damage and impairment of neuronal communication in several neurodegenerative diseases. Effective treatments for these diseases are still lacking but remain the focus of much active investigation. Despite testing several synthesized compounds, small molecules, and drugs over the past few decades, very few of them can inhibit aggregation of amyloid proteins and lessen their neurotoxic effects. Recently, the natural polyphenol curcumin (Cur has been shown to be a promising anti-amyloid, anti-inflammatory and neuroprotective agent for several neurodegenerative diseases. Because of its pleotropic actions on the central nervous system, including preferential binding to amyloid proteins, Cur is being touted as a promising treatment for age-related brain diseases. Here, we focus on molecular targeting of Cur to reduce amyloid burden, rescue neuronal damage, and restore normal cognitive and sensory motor functions in different animal models of neurodegenerative diseases. We specifically highlight Cur as a potential treatment for Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases. In addition, we discuss the major issues and limitations of using Cur for treating these diseases, along with ways of circumventing those shortcomings. Finally, we provide specific recommendations for optimal dosing with Cur for treating neurological diseases.

  10. Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Ting Cao

    2018-05-01

    Full Text Available Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC inhibitor sodium butyrate (NaB has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG. We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.

  11. Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

    OpenAIRE

    Martin, Antonio; De Vivo, Giulia; Gentile, Vittorio

    2011-01-01

    Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Pa...

  12. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    Science.gov (United States)

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  13. The Emerging Role of Proteomics in Precision Medicine: Applications in Neurodegenerative Diseases and Neurotrauma.

    Science.gov (United States)

    Alaaeddine, Rana; Fayad, Mira; Nehme, Eliana; Bahmad, Hisham F; Kobeissy, Firas

    2017-01-01

    Inter-individual variability in response to pharmacotherapy has provoked a higher demand to personalize medical decisions. As the field of pharmacogenomics has served to translate personalized medicine from concept to practice, the contribution of the "omics" disciplines to the era of precision medicine seems to be vital in improving therapeutic outcomes. Although we have observed significant advances in the field of genomics towards personalized medicine , the field of proteomics-with all its capabilities- is still in its infancy towards the area of personalized precision medicine. Neurodegenerative diseases and neurotrauma are among the areas where the implementation of neuroproteomics approaches has enabled neuroscientists to broaden their understanding of neural disease mechanisms and characteristics. It has been shown that the influence of epigenetics, genetics and environmental factors were among the recognized factors contributing to the diverse presentation of a single disease as well as its treatment establishing the factor-disease interaction. Thus, management of these variable single disease presentation/outcome necessitated the need for factoring the influence of epigenetics, genetics, epigenetics, and other factors on disease progression to create a custom treatment plan unique to each individual. In fact, neuroproteomics with its high ability to decipher protein alterations along with their post translational modifications (PTMs) can be an ideal tool for personalized medicine goals including: discovery of molecular mechanisms underlying disease pathobiology, development of novel diagnostics, enhancement of pharmacological neurotherapeutic approaches and finally, providing a "proteome identity" for patients with certain disorders and diseases. So far, neuroproteomics approaches have excelled in the areas of biomarker discovery arena where several diagnostic, prognostic and injury markers have been identified with a direct impact on the

  14. Neurodegenerative Diseases: Might Citrus Flavonoids Play a Protective Role?

    Directory of Open Access Journals (Sweden)

    Santa Cirmi

    2016-09-01

    Full Text Available Neurodegenerative diseases (ND result from the gradual and progressive degeneration of the structure and function of the central nervous system or the peripheral nervous system or both. They are characterized by deterioration of neurons and/or myelin sheath, disruption of sensory information transmission and loss of movement control. There is no effective treatment for ND, and the drugs currently marketed are symptom-oriented, albeit with several side effects. Within the past decades, several natural remedies have gained attention as potential neuroprotective drugs. Moreover, an increasing number of studies have suggested that dietary intake of vegetables and fruits can prevent or delay the onset of ND. These properties are mainly due to the presence of polyphenols, an important group of phytochemicals that are abundantly present in fruits, vegetables, cereals and beverages. The main class of polyphenols is flavonoids, abundant in Citrus fruits. Our review is an overview on the scientific literature concerning the neuroprotective effects of the Citrus flavonoids in the prevention or treatment of ND. This review may be used as scientific basis for the development of nutraceuticals, food supplements or complementary and alternative drugs to maintain and improve the neurophysiological status.

  15. Recommendations for the Design of Serious Games in Neurodegenerative Diseases.

    Science.gov (United States)

    Ben-Sadoun, Grégory; Manera, Valeria; Alvarez, Julian; Sacco, Guillaume; Robert, Philippe

    2018-01-01

    The use of Serious Games (SG) in the health domain is expanding. In the field of Neurodegenerative Diseases (ND) such as Alzheimer's Disease, SG are currently employed to provide alternative solutions for patients' treatment, stimulation, and rehabilitation. The design of SG for people with ND implies collaborations between professionals in ND and professionals in SG design. As the field is quite young, professionals specialized in both ND and SG are still rare, and recommendations for the design of SG for people with ND are still missing. This perspective paper aims to provide recommendations in terms of ergonomic choices for the design of SG aiming at stimulating people with ND, starting from the existing SG already tested in this population: "MINWii", "Kitchen and Cooking", and "X-Torp". We propose to rely on nine ergonomic criteria: eight ergonomic criteria inspired by works in the domain of office automation: Compatibility, Guidance, Workload, Adaptability, Consistency, Significance of codes, Explicit control and Error management; and one ergonomic criterion related to videogame: the game rules. Perspectives derived from this proposal are also discussed.

  16. Improving drug delivery technology for treating neurodegenerative diseases.

    Science.gov (United States)

    Choonara, Yahya E; Kumar, Pradeep; Modi, Girish; Pillay, Viness

    2016-07-01

    Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

  17. Molecular origin of polyglutamine aggregation in neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Expansion of polyglutamine (polyQ tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel beta-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the beta-helices observed in simulations, all residues adopt beta-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 +/- 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel beta-hairpins in their ground state, in agreement with experiments. The lower stability of mutant beta-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.

  18. Recommendations for the Design of Serious Games in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Grégory Ben-Sadoun

    2018-02-01

    Full Text Available The use of Serious Games (SG in the health domain is expanding. In the field of Neurodegenerative Diseases (ND such as Alzheimer’s Disease, SG are currently employed to provide alternative solutions for patients’ treatment, stimulation, and rehabilitation. The design of SG for people with ND implies collaborations between professionals in ND and professionals in SG design. As the field is quite young, professionals specialized in both ND and SG are still rare, and recommendations for the design of SG for people with ND are still missing. This perspective paper aims to provide recommendations in terms of ergonomic choices for the design of SG aiming at stimulating people with ND, starting from the existing SG already tested in this population: “MINWii”, “Kitchen and Cooking”, and “X-Torp”. We propose to rely on nine ergonomic criteria: eight ergonomic criteria inspired by works in the domain of office automation: Compatibility, Guidance, Workload, Adaptability, Consistency, Significance of codes, Explicit control and Error management; and one ergonomic criterion related to videogame: the game rules. Perspectives derived from this proposal are also discussed.

  19. PENN neurodegenerative disease research - in the spirit of Benjamin Franklin.

    Science.gov (United States)

    Trojanowski, John Q

    2008-01-01

    Benjamin Franklin (1706-1790) was entrepreneur, statesman, supporter of the public good as well as inventor, and his most significant invention was the University of Pennsylvania (PENN). Franklin outlined his plans for a college providing practical and classical instruction to prepare youth for real-world pursuits in his 'Proposals Relating to the Education of Youth in Pensilvania' (1749), and Franklin's spirit of learning to serve society guides PENN to the present day. This is evidenced by the series of articles in this special issue of Neurosignals, describing research conducted by seasoned and newly recruited PENN faculty, addressing consequences of the longevity revolution which defines our epoch at the dawn of this millennium. While aging affects all organ systems, the nervous system is most critical to successful aging. Thus, the articles in this special issue of Neurosignals focus on research at PENN that is designed to prevent or ameliorate aging-related neurodegenerative disorders such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. This research could enhance our chances of aging successfully in the continuing longevity revolution, and the essay here provides context and background on this research.

  20. Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Ailton Melo

    2011-01-01

    Full Text Available The incidence and prevalence of neurodegenerative diseases (ND increase with life expectancy. This paper reviews the role of oxidative stress (OS in ND and pharmacological attempts to fight against reactive oxygen species (ROS-induced neurodegeneration. Several mechanisms involved in ROS generation in neurodegeneration have been proposed. Recent articles about molecular pathways involved in ROS generation were reviewed. The progress in the development of neuroprotective therapies has been hampered because it is difficult to define targets for treatment and determine what should be considered as neuroprotective. Therefore, the attention was focused on researches about pharmacological targets that could protect neurons against OS. Since it is necessary to look for genes as the ultimate controllers of all biological processes, this paper also tried to identify gerontogenes involved in OS and neurodegeneration. Since neurons depend on glial cells to survive, recent articles about the functioning of these cells in aging and ND were also reviewed. Finally, clinical trials testing potential neuroprotective agents were critically reviewed. Although several potential drugs have been screened in in vitro and in vivo models of ND, these results were not translated in benefit of patients, and disappointing results were obtained in the majority of clinical trials.

  1. Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine.

    Science.gov (United States)

    Kovacs, Gabor G

    2016-02-02

    Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

  2. The role of the motor system in action naming in patients with neurodegenerative extrapyramidal syndromes.

    Science.gov (United States)

    Cotelli, Maria; Manenti, Rosa; Brambilla, Michela; Borroni, Barbara

    2018-03-01

    Previous studies of patients with brain damage have suggested a close relationship between aphasia and movement disorders. Neurodegenerative extrapyramidal syndromes associated with cognitive impairment provide an interesting model for studying the neural substrates of cognitive and motor symptoms. In this review, we focused on studies investigating language production abilities in patients with Parkinson's disease (PD), Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP). According to some reports, these patients exhibit a reduction in performance in both action and object naming or verb production compared to healthy individuals. Furthermore, a disproportional impairment of action naming compared to object naming was systematically observed in patients with these disorders. The study of these clinical conditions offers the unique opportunity to examine the close link between linguistic features and motor characteristics of action. This particular pattern of language impairment may contribute to the debate on embodiment theory and on the involvement of the basal ganglia in language and in integrating language and movement. From a translational perspective, we suggest that language ability assessments are useful in the clinical work-up, along with neuropsychological and motor evaluations. Specific protocols should be developed in the near future to better characterize language deficits and to permit an early cognitive diagnosis. Moreover, the link between language deficits and motor impairment opens a new issue for treatment approaches. Treatment of one of these two symptoms may ameliorate the other, and treating both may produce a greater improvement in patients' global clinical conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Changes in Lecithin Concentration in the Human Brain Tissue in Some Neurodegenerative Conditions

    International Nuclear Information System (INIS)

    Ajanovic, A.; Mihaljevic, M.; Hasanbasic, D.; Rukavina, D.; Sofic, E.

    2011-01-01

    As a consequence of a possible increase in oxidative stress or deterioration of nerve cells during aging, in some states neurodegeneration was demonstrated by multiple biochemical deficiency, especially deficiency of cholesterol and lecithin in brain regions. The aim of this study was to determine the changes in the concentration of lecithin in different regions of brain tissue (MC - motor cortex, NC - nucleus caudates, GT - temporal gyrus) dissected postmortem from people with senile dementia of Alzheimer's type (SDAT), and persons with Parkinson's disease (PD) as compared to people who died without these diseases (C). Spectrophotometric determination of lecithin in 18 postmortem brain tissue regions collected from of 12 persons with SDAT, in 11 postmortem brain tissue regions of 8 persons with PD and in 18 postmortem brain tissue regions of 8 control persons, was performed by enzymatic method. The content of lecithin in MC: 14.4 mg/g fresh tissue (f.t.) and GT: 13.1 mg/g (f.t.) for SDAT was significantly reduced (p < 0.01) by about 30 %, compared to control where there was: 21.6 mg/g (f.t.) in MC and 18.3 mg/g (f.t.) in the GT estimated. In all regions of the brain of PD patients, the content of lecithin was decreased by about 12 % compared to control, but without statistical significance. These results suggest that changes in the content of lecithin in these regions of brain tissue might affect the changes in the membrane potential and cell degeneration. (author)

  4. ECO2M: A TOUGH2 Fluid Property Module for Mixtures of Water, NaCl, and CO2, Including Super- and Sub-Critical Conditions, and Phase Change Between Liquid and Gaseous CO2

    Energy Technology Data Exchange (ETDEWEB)

    Pruess, K.

    2011-04-01

    ECO2M is a fluid property module for the TOUGH2 simulator (Version 2.0) that was designed for applications to geologic storage of CO{sub 2} in saline aquifers. It includes a comprehensive description of the thermodynamics and thermophysical properties of H{sub 2}O - NaCl - CO{sub 2} mixtures, that reproduces fluid properties largely within experimental error for temperature, pressure and salinity conditions in the range of 10 C {le} T {le} 110 C, P {le} 600 bar, and salinity from zero up to full halite saturation. The fluid property correlations used in ECO2M are identical to the earlier ECO2N fluid property package, but whereas ECO2N could represent only a single CO{sub 2}-rich phase, ECO2M can describe all possible phase conditions for brine-CO{sub 2} mixtures, including transitions between super- and sub-critical conditions, and phase change between liquid and gaseous CO{sub 2}. This allows for seamless modeling of CO{sub 2} storage and leakage. Flow processes can be modeled isothermally or non-isothermally, and phase conditions represented may include a single (aqueous or CO{sub 2}-rich) phase, as well as two-and three-phase mixtures of aqueous, liquid CO{sub 2} and gaseous CO{sub 2} phases. Fluid phases may appear or disappear in the course of a simulation, and solid salt may precipitate or dissolve. TOUGH2/ECO2M is upwardly compatible with ECO2N and accepts ECO2N-style inputs. This report gives technical specifications of ECO2M and includes instructions for preparing input data. Code applications are illustrated by means of several sample problems, including problems that had been previously solved with TOUGH2/ECO2N.

  5. Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

    Science.gov (United States)

    Washington, Patricia M; Villapol, Sonia; Burns, Mark P

    2016-01-01

    Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases : A Template for Innovative Therapy

    NARCIS (Netherlands)

    de Haan, Peter; Klein, Hans C; 't Hart, Bert A

    2017-01-01

    Neurodegenerative and psychiatric diseases (NPDs) are today's most important group of diseases, surpassing both atherosclerotic cardiovascular disease and cancer in morbidity incidence. Although NPDs have a dramatic impact on our society because of their high incidence, mortality, and severe

  7. The role of DNA methylation and histone modifications in neurodegenerative diseases: A systematic review

    NARCIS (Netherlands)

    K.-X. Wen (Ke-Xin); J. Milic (Jelena); El-Khodor, B. (Bassem); K. Dhana (Klodian); J. Nano (Jana); Pulido, T. (Tammy); B. Kraja (Bledar); A. Zaciragic (Asija); W.M. Bramer (Wichor); J. Troup; R. Chowdhury (Rajiv); Arfam Ikram, M.; A. Dehghan (Abbas); T. Muka (Taulant); O.H. Franco (Oscar)

    2016-01-01

    textabstractImportance Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Objective To systematically review studies

  8. Combination Comprising Parthenolide For Use In The Treatment Of Alzheimer's Disease And Other Neurodegenerative Disorders

    KAUST Repository

    Bajic, Vladimir B.; Essack, Magbubah

    2015-01-01

    The present invention generally concerns particular methods and compositions for treatment of a neurodegenerative disease, such as Alzheimer's Disease. In particular embodiments, there is a composition comprising Parthenolide and a second agent

  9. 4 Tesla Whole Body MRI MRSI System for Investigation of Neurodegenerative Diseases

    National Research Council Canada - National Science Library

    Weiner, Michael W

    2004-01-01

    The overall long-term goal of imaging research to be performed with this 4 Tesla Siemens/Bruker MRI system is the development of improved diagnostic methods for accurate detection of neurodegenerative...

  10. Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders.

    Science.gov (United States)

    Fagherazzi, Elen V; Garcia, Vanessa A; Maurmann, Natasha; Bervanger, Thielly; Halmenschlager, Luis H; Busato, Stefano B; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Schröder, Nadja

    2012-02-01

    Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases. We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats. Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training. A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats. The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

  11. Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases

    OpenAIRE

    Melki, Ronald

    2015-01-01

    Abstract Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in humans. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. A plethora of reports suggest that distinct diseases have in common the ability of protein aggregates to spread and amplify within the central nervous system. This review summarizes briefly what is known about the nature of the protein ag...

  12. Self-awareness in neurodegenerative disease relies on neural structures mediating reward-driven attention.

    Science.gov (United States)

    Shany-Ur, Tal; Lin, Nancy; Rosen, Howard J; Sollberger, Marc; Miller, Bruce L; Rankin, Katherine P

    2014-08-01

    Accurate self-awareness is essential for adapting one's tasks and goals to one's actual abilities. Patients with neurodegenerative diseases, particularly those with right frontal involvement, often present with poor self-awareness of their functional limitations that may exacerbate their already jeopardized decision-making and behaviour. We studied the structural neuroanatomical basis for impaired self-awareness among patients with neurodegenerative disease and healthy older adults. One hundred and twenty-four participants (78 patients with neurodegenerative diseases including Alzheimer's disease, behavioural variant frontotemporal dementia, right-temporal frontotemporal dementia, semantic variant and non-fluent variant primary progressive aphasia, and 46 healthy controls) described themselves on the Patient Competency Rating Scale, rating observable functioning across four domains (daily living activities, cognitive, emotional control, interpersonal). All participants underwent structural magnetic resonance imaging. Informants also described subjects' functioning on the same scale. Self-awareness was measured by comparing self and informant ratings. Group differences in discrepancy scores were analysed using general linear models, controlling for age, sex and disease severity. Compared with controls, patients with behavioural variant frontotemporal dementia overestimated their functioning in all domains, patients with Alzheimer's disease overestimated cognitive and emotional functioning, patients with right-temporal frontotemporal dementia overestimated interpersonal functioning, and patients with non-fluent aphasia overestimated emotional and interpersonal functioning. Patients with semantic variant aphasia did not overestimate functioning on any domain. To examine the neuroanatomic correlates of impaired self-awareness, discrepancy scores were correlated with brain volume using voxel-based morphometry. To identify the unique neural correlates of overlooking

  13. On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Agnese Secondo

    2018-03-01

    Full Text Available In both excitable and non-excitable cells, calcium (Ca2+ signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE, namely the opening of plasma membrane (PM Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC prompting Ca2+ refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca2+ signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca2+ homeostasis or mediate Ca2+ overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson’s disease (PD models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer’s disease (AD pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington’s disease (HD transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up-regulation of

  14. TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

    Directory of Open Access Journals (Sweden)

    Suna Lahut

    2012-03-01

    Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies

  15. TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

    Directory of Open Access Journals (Sweden)

    Suna Lahut

    2012-03-01

    Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies.

  16. The glial response to intracerebrally delivered therapies for neurodegenerative disorders: Is this a critical issue?

    Directory of Open Access Journals (Sweden)

    Francesca eCicchetti

    2014-07-01

    Full Text Available The role of glial cells in the pathogenesis of many neurodegenerative conditions of the central nervous system (CNS is now well established (as is discussed in other reviews in this special issue of Frontiers in Neuropharmacology. What is less clear is whether there are changes in these same cells in terms of their behaviour and function in response to invasive experimental therapeutic interventions for these diseases. This has, and will continue to, become more of an issue as we enter a new era of novel treatments which require the agent to be directly placed/infused into the CNS such as deep brain stimulation, cell transplants, gene therapies and growth factor infusions. To date, all of these treatments have produced variable outcomes and the reasons for this have been widely debated but the host astrocytic and/or microglial response induced by such invasively delivered agents has not been discussed in any detail. In this review, we have attempted to summarise the limited published data on this, in particular we discuss the small number of human post-mortem studies reported in this field. By so doing, we hope to provide a better description and understanding of the extent and nature of both the astrocytic and microglial response, which in turn could lead to modifications in the way these therapeutic interventions are delivered.

  17. Cell based-gene delivery approaches for the treatment of spinal cord injury and neurodegenerative disorders.

    Science.gov (United States)

    Taha, Masoumeh Fakhr

    2010-03-01

    Cell based-gene delivery has provided an important therapeutic strategy for different disorders in the recent years. This strategy is based on the transplantation of genetically modified cells to express specific genes and to target the delivery of therapeutic factors, especially for the treatment of cancers and neurological, immunological, cardiovascular and heamatopoietic disorders. Although, preliminary reports are encouraging, and experimental studies indicate functionally and structurally improvements in the animal models of different disorders, universal application of this strategy for human diseases requires more evidence. There are a number of parameters that need to be evaluated, including the optimal cell source, the most effective gene/genes to be delivered, the optimal vector and method of gene delivery into the cells and the most efficient route for the delivery of genetically modified cells into the patient. Also, some obstacles have to be overcome, including the safety and usefulness of the approaches and the stability of the improvements. Here, recent studies concerning with the cell-based gene delivery for spinal cord injury and some neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are briefly reviewed, and their exciting consequences are discussed.

  18. Pomegranate seed oil nanoemulsions for the prevention and treatment of neurodegenerative diseases: the case of genetic CJD.

    Science.gov (United States)

    Mizrahi, Michal; Friedman-Levi, Yael; Larush, Liraz; Frid, Kati; Binyamin, Orli; Dori, Dvir; Fainstein, Nina; Ovadia, Haim; Ben-Hur, Tamir; Magdassi, Shlomo; Gabizon, Ruth

    2014-08-01

    Neurodegenerative diseases generate the accumulation of specific misfolded proteins, such as PrP(Sc) prions or A-beta in Alzheimer's diseases, and share common pathological features, like neuronal death and oxidative damage. To test whether reduced oxidation alters disease manifestation, we treated TgMHu2ME199K mice, modeling for genetic prion disease, with Nano-PSO, a nanodroplet formulation of pomegranate seed oil (PSO). PSO comprises large concentrations of a unique polyunsaturated fatty acid, Punicic acid, among the strongest natural antioxidants. Nano-PSO significantly delayed disease presentation when administered to asymptomatic TgMHu2ME199K mice and postponed disease aggravation in already sick mice. Analysis of brain samples revealed that Nano-PSO treatment did not decrease PrP(Sc) accumulation, but rather reduced lipid oxidation and neuronal loss, indicating a strong neuroprotective effect. We propose that Nano-PSO and alike formulations may be both beneficial and safe enough to be administered for long years to subjects at risk or to those already affected by neurodegenerative conditions. This team of authors report that a nanoformulation of pomegranade seed oil, containing high levels of a strong antioxidant, can delay disease onset in a mouse model of genetic prion diseases, and the formulation also indicates a direct neuroprotective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma.

    Science.gov (United States)

    Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim

    2017-01-01

    With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro . The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases.

  20. A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

    Science.gov (United States)

    Bush, W S; McCauley, J L; DeJager, P L; Dudek, S M; Hafler, D A; Gibson, R A; Matthews, P M; Kappos, L; Naegelin, Y; Polman, C H; Hauser, S L; Oksenberg, J; Haines, J L; Ritchie, M D

    2011-07-01

    Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-β isoforms, PLCβ1 and PLCβ4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS.

  1. Possible roles of transglutaminases in molecular mechanisms responsible for human neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Nicola Gaetano Gatta

    2016-11-01

    Full Text Available Transglutaminases are a family of Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/crosslinked adducts or –OH groups (to form ester linkages. In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases, Celiac Disease is just one of them. Interestingly, neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy, Huntington’s Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review describes the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

  2. Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases.

    Science.gov (United States)

    Brady, Scott T; Morfini, Gerardo A

    2017-09-01

    Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. The Influence of Adipose Tissue on Brain Development, Cognition, and Risk of Neurodegenerative Disorders.

    Science.gov (United States)

    Letra, Liliana; Santana, Isabel

    2017-01-01

    The brain is a highly metabolic organ and thus especially vulnerable to changes in peripheral metabolism, including those induced by obesity-associated adipose tissue dysfunction. In this context, it is likely that the development and maturation of neurocognitive circuits may also be affected and modulated by metabolic environmental factors, beginning in utero. It is currently recognized that maternal obesity, either pre-gestational or gestational, negatively influences fetal brain development and elevates the risk of cognitive impairment and neuropsychiatric disorders in the offspring. During infancy and adolescence, obesity remains a limiting factor for healthy neurodevelopment, especially affecting executive functions but also attention, visuospatial ability, and motor skills. In middle age, obesity seems to induce an accelerated brain aging and thus may increase the risk of age-related neurodegenerative diseases such as Alzheimer's disease. In this chapter we review and discuss experimental and clinical evidence focusing on the influence of adipose tissue dysfunction on neurodevelopment and cognition across lifespan, as well as some possible mechanistic links, namely the role of the most well studied adipokines.

  4. Gaussian processes with optimal kernel construction for neuro-degenerative clinical onset prediction

    Science.gov (United States)

    Canas, Liane S.; Yvernault, Benjamin; Cash, David M.; Molteni, Erika; Veale, Tom; Benzinger, Tammie; Ourselin, Sébastien; Mead, Simon; Modat, Marc

    2018-02-01

    Gaussian Processes (GP) are a powerful tool to capture the complex time-variations of a dataset. In the context of medical imaging analysis, they allow a robust modelling even in case of highly uncertain or incomplete datasets. Predictions from GP are dependent of the covariance kernel function selected to explain the data variance. To overcome this limitation, we propose a framework to identify the optimal covariance kernel function to model the data.The optimal kernel is defined as a composition of base kernel functions used to identify correlation patterns between data points. Our approach includes a modified version of the Compositional Kernel Learning (CKL) algorithm, in which we score the kernel families using a new energy function that depends both the Bayesian Information Criterion (BIC) and the explained variance score. We applied the proposed framework to model the progression of neurodegenerative diseases over time, in particular the progression of autosomal dominantly-inherited Alzheimer's disease, and use it to predict the time to clinical onset of subjects carrying genetic mutation.

  5. The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review.

    Directory of Open Access Journals (Sweden)

    Ke-Xin Wen

    Full Text Available Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND such as Alzheimer's disease (AD and Parkinson's disease (PD.To systematically review studies investigating epigenetic marks in AD or PD.Eleven bibliographic databases (Embase.com, Medline (Ovid, Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost, Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form.Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes. There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD.Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.

  6. Integration of technology-based outcome measures in clinical trials of Parkinson and other neurodegenerative diseases.

    Science.gov (United States)

    Artusi, Carlo Alberto; Mishra, Murli; Latimer, Patricia; Vizcarra, Joaquin A; Lopiano, Leonardo; Maetzler, Walter; Merola, Aristide; Espay, Alberto J

    2018-01-01

    We sought to review the landscape of past, present, and future use of technology-based outcome measures (TOMs) in clinical trials of neurodegenerative disorders. We systematically reviewed PubMed and ClinicalTrials.gov for published and ongoing clinical trials in neurodegenerative disorders employing TOMs. In addition, medical directors of selected pharmaceutical companies were surveyed on their companies' ongoing efforts and future plans to integrate TOMs in clinical trials as primary, secondary, or exploratory endpoints. We identified 164 published clinical trials indexed in PubMed that used TOMs as outcome measures in Parkinson disease (n = 132) or other neurodegenerative disorders (n = 32). The ClinicalTrials.gov search yielded 42 clinical trials using TOMs, representing 2.7% of ongoing trials. Sensor-based technology accounted for over 75% of TOMs applied. Gait and physical activity were the most common targeted domains. Within the next 5 years, 83% of surveyed pharmaceutical companies engaged in neurodegenerative disorders plan to deploy TOMs in clinical trials. Although promising, TOMs are underutilized in clinical trials of neurodegenerative disorders. Validating relevant endpoints, standardizing measures and procedures, establishing a single platform for integration of data and algorithms from different devices, and facilitating regulatory approvals should advance TOMs integration into clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.

    Science.gov (United States)

    Son, Mi-Young; Kwak, Jae Eun; Seol, Binna; Lee, Da Yong; Jeon, Hyejin; Cho, Yee Sook

    2015-09-01

    GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β-galactosidase (β-gal) gene. Insufficient β-gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective β-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1-NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  8. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    J. Thomas

    2015-01-01

    Full Text Available Alzheimer’s disease (AD is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia.

  9. Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders.

    Science.gov (United States)

    Ghosh, Arunava; Pahan, Kalipada

    2012-08-03

    Glial inflammation is an important feature of several neurodegenerative disorders. Suppressor of cytokine signaling (SOCS) proteins play a crucial role in inhibiting cytokine signaling and inflammatory gene expression in various cell types, including glial cells. However, mechanisms by which SOCS genes could be up-regulated are poorly understood. This study underlines the importance of gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, in up-regulating the expression of SOCS3 in glial cells. Gemfibrozil increased the expression of Socs3 mRNA and protein in mouse astroglia and microglia in both a time- and dose-dependent manner. Interestingly, gemfibrozil induced the activation of type IA phosphatidylinositol (PI) 3-kinase and AKT. Accordingly, inhibition of PI 3-kinase and AKT by chemical inhibitors abrogated gemfibrozil-mediated up-regulation of SOCS3. Furthermore, we demonstrated that gemfibrozil induced the activation of Krüppel-like factor 4 (KLF4) via the PI 3-kinase-AKT pathway and that siRNA knockdown of KLF4 abrogated gemfibrozil-mediated up-regulation of SOCS3. Gemfibrozil also induced the recruitment of KLF4 to the distal, but not proximal, KLF4-binding site of the Socs3 promoter. This study delineates a novel property of gemfibrozil in up-regulating SOCS3 in glial cells via PI 3-kinase-AKT-mediated activation of KLF4 and suggests that gemfibrozil may find therapeutic application in neuroinflammatory and neurodegenerative disorders.

  10. Modelling studies on neurodegenerative disease-causing triplet ...

    Indian Academy of Sciences (India)

    Unknown

    Abbreviations used: DM, dystrophia myotonica; FraX, fragile X syndrome; HD, Huntington disease; rms, root mean square. ... Further, at high salt condition, Greek key type quadruplex ..... tetrads at 30° twist and 3⋅4 Å rise (as observed in fiber.

  11. Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

    Science.gov (United States)

    Ita, Kevin

    2017-06-01

    With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

  12. Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Antonio Martin

    2011-01-01

    Full Text Available Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease, supranuclear palsy, Huntington's disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

  13. Intervention modalities for targeting cognitive-motor interference in individuals with neurodegenerative disease: a systematic review.

    Science.gov (United States)

    Wajda, Douglas A; Mirelman, Anat; Hausdorff, Jeffrey M; Sosnoff, Jacob J

    2017-03-01

    Individuals with neurodegenerative disease (NDD) commonly have elevated cognitive-motor interference, change in either cognitive or motor performance (or both) when tasks are performed simultaneously, compared to healthy controls. Given that cognitive-motor interference is related to reduced community ambulation and elevated fall risk, it is a target of rehabilitation interventions. Areas covered: This review details the collective findings of previous dual task interventions in individuals with NDD. A total of 21 investigations focusing on 4 different neurodegenerative diseases and one NDD precursor (Parkinson's disease, multiple sclerosis, Alzheimer's disease (AD), dementia other than AD, and mild cognitive impairment) consisting of 721 participants were reviewed. Expert commentary: Preliminary evidence from interventions targeting cognitive-motor interference, both directly and indirectly, show promising results for improving CMI in individuals with neurodegenerative diseases. Methodological limitations, common to pilot investigations preclude firm conclusions. Well-designed randomized control trials targeting cognitive motor interference are warranted.

  14. Research progress on the pathogenesis of rapid eye movement sleep behavior disorder and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Hai-yang JIANG

    2017-10-01

    Full Text Available Rapid eye movement sleep behavior disorder (RBD is a sleep disorder characterized by the disappearance of muscle relaxation and enacting one's dreams during rapid eye movement (REM, with most of the dreams being violent or aggressive. Prevalence of RBD, based on population, is 0.38%-2.01%, but it becomes much higher in patients with neurodegenerative diseases, especially α - synucleinopathies. RBD may herald the emergence of α-synucleinopathies by decades, thus it may be used as an effective early marker of neurodegenerative diseases. In this review, we summarized the progress on the pathogenesis of RBD and its relationship with neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2017.10.003

  15. The Role of Musk in Relieving the Neurodegenerative Changes Induced After Exposure to Chronic Stress.

    Science.gov (United States)

    Abd El Wahab, Manal Galal; Ali, Soad Shaker; Ayuob, Nasra Naeim

    2018-06-01

    This study aimed to evaluate the effect induced by musk on Alzheimer's disease-such as neurodegenerative changes in mice exposed to chronic unpredictable mild stress (CUMS). Forty male Swiss albino mice were divided into 4 groups (n = 10); control, CUMS, CUMS + fluoxetine, CUMS + musk. At the end of the experiment, behavior of the mice was assessed. Serum corticosterone level, hippocampal protein level of the glucocorticoid receptors, and brain-derived neurotropic factor were also assessed. Hippocampus was histopathologically examined. Musk improved depressive status induced after exposure to CUMS as evidenced by the forced swimming and open field tests and improved the short-term memory as evidenced by the elevated plus maze test. Musk reduced both corticosterone levels and the hippocampal neurodegenerative changes observed after exposure to CUMS. These improvements were comparable to those induced by fluoxetine. Musk alleviated the memory impairment and neurodegenerative changes induced after exposure to the chronic stress.

  16. Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease.

    Science.gov (United States)

    Wilke, Carlo; Gillardon, Frank; Deuschle, Christian; Dubois, Evelyn; Hobert, Markus A; Müller vom Hagen, Jennifer; Krüger, Stefanie; Biskup, Saskia; Blauwendraat, Cornelis; Hruscha, Michael; Kaeser, Stephan A; Heutink, Peter; Maetzler, Walter; Synofzik, Matthis

    2016-01-01

    Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.

  17. Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases.

    Science.gov (United States)

    Bickford, Paula C; Flowers, Antwoine; Grimmig, Bethany

    2017-08-01

    Aging is the primary risk factor for many neurodegenerative diseases. Thus, understanding the basic biological changes that take place with aging that lead to the brain being less resilient to disease progression of neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease or insults to the brain such as stroke or traumatic brain injuries. Clearly this will not cure the disease per se, yet increasing the ability of the brain to respond to injury could improve long term outcomes. The focus of this review is examining changes in microglia with age and possible therapeutic interventions involving the use of polyphenol rich dietary supplements. Published by Elsevier Inc.

  18. Neurodegenerative and Fatiguing Illnesses, Infections and Mitochondrial Dysfunction: Use of Natural Supplements to Improve Mitochondrial Function

    Directory of Open Access Journals (Sweden)

    Garth L. Nicolson

    2014-01-01

    Full Text Available Background: Many chronic diseases and illnesses are associated with one or more chronic infections, dysfunction of mitochondria and reduced production of ATP. This results in fatigue and other symptoms that occur in most if not all chronic conditions and diseases. Methods: This is a review of the published literature on chronic infections in neurodegenerative diseases and fatiguing illnesses that are also typified by mitochondrial dysfunction. This contribution also reviews the use of natural supplements to enhance mitochondrial function and reduce the effects of chronic infections to improve overall function in various chronic illnesses. Results: Mitochondrial function can be enhanced by the use of various natural supplements, notably Lipid Replacement Therapy (LRT using glyerolphospholipids and other mitochondrial supplements. In various chronic illnesses that are characterized by the presence of chronic infections, such as intracellular bacteria (Mycoplasma, Borrelia, Chlamydia and other infections and viruses, LRT has proven useful in multiple clinical trials. For example, in clinical studies on chronic fatigue syndrome, fibromyalgia syndrome and other chronic fatiguing illnesses where a large majority of patients have chronic infections, LRT significantly reduced fatigue by 35-43% in different clinical trials and increased mitochondrial function. In clinical trials on patients with multiple intracellular bacterial infections and intractable fatigue LRT plus other mitochondrial supplements significantly decreased fatigue and improved mood and cognition. Conclusions: LRT formulations designed to improve mitochondrial function appear to be useful as non-toxic dietary supplements for reducing fatigue and restoring mitochondrial and other cellular membrane functions in patients with chronic illnesses and multiple chronic infections.

  19. Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature.

    Science.gov (United States)

    Menezes, Rikitha; Pantelyat, Alexander; Izbudak, Izlem; Birnbaum, Julius

    2015-08-01

    Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjögren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury

  20. The influence of Na+,K+-ATPase on glutamate signaling in neurodegenerative diseases and senescence

    Directory of Open Access Journals (Sweden)

    Paula Fernanda Kinoshita

    2016-06-01

    Full Text Available Decreased Na+,K+-ATPase (NKA activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β and γ, with four distinct isoforms of the catalytic α subunit (α1-4. Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity. Within the central nervous system (CNS, the α2 isoform is expressed mostly in glial cells and the α3 isoform is neuron-specific. Mutations in ATP1A2 gene can result in familial hemiplegic migraine (FHM2, while mutations in the ATP1A3 gene can cause Rapid-onset dystonia-Parkinsonism (RDP and alternating hemiplegia of childhood (AHC, as well as the cerebellar ataxia, areflexia, pescavus, optic atrophy and sensorineural hearing loss (CAPOS syndrome. Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease. The age-related decline in brain α2/3 activity may arise from changes in the cyclic guanosine monophosphate (cGMP and cGMP‐dependent protein kinase (PKG pathway. Glutamate, through nitric oxide synthase (NOS, cGMP and PKG, stimulates brain α2/3 activity, with the glutamatergic N-methyl-D-aspartate (NMDA receptor cascade able to drive an adaptive, neuroprotective response to inflammatory and challenging stimuli, including amyloid‐β. Here we review the NKA, both as an ion pump as well as a receptor that interacts with NMDA, including the role of NKA subunits mutations. Failure of the NKA-associated adaptive response mechanisms may render neurons more susceptible to degeneration over the course of aging.

  1. Decision-making under Ambiguity in Neurodegenerative Disease

    OpenAIRE

    Rogers, Denise

    2011-01-01

    Decision-making is a complex skill that is essential for daily life. Yet the complexities of this process are often overlooked in favour of more obvious cognitive deficits during neuropsychological assessment, such as memory or attention impairments. Decision-making involves affective and motivational aspects of executive functions (Happaney, Zelazo & Stuss, 2004). Executive functions include a range of abilities that can be divided into three categories: 1) goal setting and planning, 2) acti...

  2. The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases

    NARCIS (Netherlands)

    Reijs, B.L.; Teunissen, C.E.; Goncharenko, N.; Betsou, F.; Blennow, K.; Baldeiras, I.; Brosseron, F.; Cavedo, E.; Fladby, T.; Froelich, L.; Gabryelewicz, T.; Gurvit, H.; Kapaki, E.; Koson, P.; Kulic, L.; Lehmann, S.; Lewczuk, P.; Lleo, A.; Maetzler, W.; Mendonca, A. de; Miller, A.M.; Molinuevo, J.L.; Mollenhauer, B.; Parnetti, L.; Rot, U.; Schneider, A.; Simonsen, A.H.; Tagliavini, F.; Tsolaki, M.; Verbeek, M.M.; Verhey, F.R.J.; Zboch, M.; Winblad, B.; Scheltens, P.; Zetterberg, H.; Visser, P.J.

    2015-01-01

    Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid

  3. Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Elżbieta Miller

    2014-01-01

    Full Text Available Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate that in vivo or postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs especially F4-neuroprotanes (F4-NPs are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.

  4. Percutaneous Endoscopic Gastrostomy Tube Insertion in Neurodegenerative Disease: A Retrospective Study and Literature Review

    Directory of Open Access Journals (Sweden)

    Pamela Sarkar

    2017-05-01

    Full Text Available Background/Aims With the notable exceptions of dementia, stroke, and motor neuron disease, relatively little is known about the safety and utility of percutaneous endoscopic gastrostomy (PEG tube insertion in patients with neurodegenerative disease. We aimed to determine the safety and utility of PEG feeding in the context of neurodegenerative disease and to complete a literature review in order to identify whether particular factors need to be considered to improve safety and outcome. Methods A retrospective case note review of patients referred for PEG insertion by neurologists in a single neuroscience center was conducted according to a pre-determined set of standards. For the literature review, we identified references from searches of PubMed, mainly with the search items “percutaneous endoscopic gastrostomy” and “neurology” or “neurodegenerative disease.” Results Short-term mortality and morbidity associated with PEG in patients with neurological disease were significant. Age greater than 75 years was associated with poor outcome, and a trend toward adverse outcome was observed in patients with low serum albumin. Conclusions This study highlights the relatively high risk of PEG in patients with neurodegenerative disease. We present points for consideration to improve outcome in this particularly vulnerable group of patients.

  5. Current therapeutic molecules and targets in neurodegenerative diseases based on in silico drug design.

    Science.gov (United States)

    Sehgal, Sheikh Arslan; Hammad, Mirza A; Tahir, Rana Adnan; Akram, Hafiza Nisha; Ahmad, Faheem

    2018-03-15

    As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases. Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS, and Huntington's disease. Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis, and Huntington's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: Clinical Assessments, Biomarkers, and Treatment

    Directory of Open Access Journals (Sweden)

    Min Li

    2018-01-01

    Conclusions: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated. There is a need for more treatment trials to determine the effectiveness of interventions of RBD on preventing the conversion to neurodegenerative diseases.

  7. Pig Models of Neurodegenerative Disorders: Utilization in Cell Replacement-Based Preclinical Safety and Efficacy Studies

    Czech Academy of Sciences Publication Activity Database

    Doležalová, D.; Hruška-Plocháň, M.; Bjarkam, C. R.; Sorensen, J. C. H.; Cunningham, M.; Weingarten, D.; Ciacci, J. D.; Juhás, Štefan; Juhásová, Jana; Motlík, Jan; Hefferan, M. P.; Hazel, T.; Johe, K.; Carromeu, C.; Muotri, A.; Bui, J. D.; Strnádel, J.; Marsala, M.

    2014-01-01

    Roč. 522, č. 12 (2014), s. 2784-2801 ISSN 0021-9967 R&D Projects: GA TA ČR(CZ) TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : pig * neurodegenerative models * stem cells Subject RIV: FH - Neurology Impact factor: 3.225, year: 2014

  8. The potential of microRNAs as biofluid markers of neurodegenerative diseases – a systematic review

    DEFF Research Database (Denmark)

    Danborg, Pia B; Simonsen, Anja H; Waldemar, Gunhild

    2014-01-01

    monitoring. This systematic review clarifies biomarker potential of miRNAs detected in biofluids of neurodegenerative disease patients. Thirty-three and ten miRNAs displayed significant expression between patients with multiple sclerosis and Alzheimer's disease, respectively, compared to healthy controls...

  9. Home video monitoring system for neurodegenerative diseases based on commercial HD cameras

    NARCIS (Netherlands)

    Abramiuc, B.; Zinger, S.; De With, P.H.N.; De Vries-Farrouh, N.; Van Gilst, M.M.; Bloem, B.; Overeem, S.

    2016-01-01

    Neurodegenerative disease (ND) is an umbrella term for chronic disorders that are characterized by severe joint cognitive-motor impairments, which are difficult to evaluate on a frequent basis. HD cameras in the home environment could extend and enhance the diagnosis process and could lead to better

  10. NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases

    NARCIS (Netherlands)

    Nalls, M.A.; Bras, J.; Hernandez, D.G.; Keller, M.F.; Majounie, E.; Renton, A.E.; Saad, M.; Jansen, I.E.; Guerreiro, R.; Lubbe, S.; Plagnol, V.; Gibbs, J.R.; Schulte, C.; Pankratz, N.; Sutherland, M.; Bertram, L.; Lill, C.M.; DeStefano, A.L.; Faroud, T.; Eriksson, N.; Tung, J.Y.; Edsall, C.; Nichols, N.; Brooks, J.; Arepalli, S.; Pliner, H.; Letson, C.; Heutink, P.; Martinez, M.; Gasser, T.; Traynor, B.J.; Wood, N.; Hardy, J.; Singleton, A.B.

    2015-01-01

    Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and

  11. Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury

    Directory of Open Access Journals (Sweden)

    Maja Vulovic

    2018-02-01

    Full Text Available The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer’s disease (AD. The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models.

  12. Enhancing attention in neurodegenerative diseases: current therapies and future directions

    Directory of Open Access Journals (Sweden)

    Sharma Kanchan

    2016-01-01

    Full Text Available We all experience at least occasional lapses in attention but in some neurological conditions, loss of attention is pervasive and debilitating. Treating deficits in attention first requires an understanding of the neurobiology of attention, which we now understand to be a set of different cognitive processes. Cholinesterase inhibitors are already established as effective attentional enhancers used in the treatment of certain dementias. Other stimulant agents such as modafanil, amphetamine and methylphenidate have demonstrated limited success in healthy individuals where attention is already optimal and clinical trials in patients with neurological disease are sparse. Dietary and lifestyle changes are gaining increasing prominence, as are experimental treatments such as deep brain stimulation and transcranial magnetic stimulation. As the therapeutic arsenal widens, clinicians will be able to match specific treatments to selective deficits in attention, giving patients a tailored management plan. Here we review common diseases that impair attention and emphasise how an understanding of attentional processing within the brain might lead to improved therapeutic strategies.

  13. The basics of preclinical drug development for neurodegenerative disease indications.

    Science.gov (United States)

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  14. The basics of preclinical drug development for neurodegenerative disease indications

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

  15. Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

    Directory of Open Access Journals (Sweden)

    Nicolas Delcourt

    2017-12-01

    Full Text Available The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes.

  16. Association between environmental exposure to pesticides and neurodegenerative diseases

    International Nuclear Information System (INIS)

    Parrón, Tesifón; Requena, Mar; Hernández, Antonio F.; Alarcón, Raquel

    2011-01-01

    Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: ► Environmental exposure to pesticides and neurodegenerative–psychiatric disorders. ► Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. ► Males from areas with high pesticide exposure had a higher risk of polyneuropathy.

  17. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Amin Mottahedin

    2017-07-01

    Full Text Available The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.

  18. New light on an old friend: targeting PUMA in radioprotection and therapy of cardiovascular and neurodegenerative diseases.

    Science.gov (United States)

    Tichy, Ales; Marek, Jan; Havelek, Radim; Pejchal, Jaroslav; Seifrtova, Martina; Zarybnicka, Lenka; Filipova, Alzbeta; Rezacova, Martina; Sinkorova, Zuzana

    2018-04-05

    This review summarizes recent progress in understanding the role of p53-upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA´s role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53-independent induction is described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with overview of other therapeutic applications. Finally, basic chemical structures for development of novel PUMA modulators such as pifithrine derivativeses, kinase inhibitors or modulators of Bcl-2 protein family are described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Trafficking and degradation pathways in pathogenic conversion of prions and prion-like proteins in neurodegenerative diseases.

    Science.gov (United States)

    Victoria, Guiliana Soraya; Zurzolo, Chiara

    2015-09-02

    Several neurodegenerative diseases such as transmissible spongiform encephalopathies, Alzheimer's and Parkinson's diseases are caused by the conversion of cellular proteins to a pathogenic conformer. Despite differences in the primary structure and subcellular localization of these proteins, which include the prion protein, α-synuclein and amyloid precursor protein (APP), striking similarity has been observed in their ability to seed and convert naïve protein molecules as well as transfer between cells. This review aims to cover what is known about the intracellular trafficking of these proteins as well as their degradation mechanisms and highlight similarities in their movement through the endocytic pathway that could contribute to the pathogenic conversion and seeding of these proteins which underlies the basis of these diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Lack of miRNA misregulation at early pathological stages in Drosophila neurodegenerative disease models

    Directory of Open Access Journals (Sweden)

    Anita eReinhardt

    2012-10-01

    Full Text Available Late onset neurodegenerative diseases represent a major public health concern as the population in many countries ages. Both frequent diseases such as Alzheimer disease (AD, 14% incidence for 80-84 year old Europeans or Parkinson disease (PD, 1.4% prevalence for > 55 years old share, with other low-incidence neurodegenerative pathologies such as spinocerebellar ataxias (SCAs, 0.01% prevalence and frontotemporal lobar degeneration (FTLD, 0.02% prevalence, a lack of efficient treatment in spite of important research efforts. Besides significant progress, studies with animal models have revealed unexpected complexities in the degenerative process, emphasizing a need to better understand the underlying pathological mechanisms. Recently, microRNAs, a class of small regulatory non-coding RNAs, have been implicated in some neurodegenerative diseases. The current data supporting a role of miRNAs in PD, tauopathies, dominant ataxias and FTLD will first be discussed to emphasize the different levels of the pathological processes which may be affected by miRNAs. To investigate a potential involvement of miRNA dysregulation in the early stages of these neurodegenerative diseases we have used Drosophila models for 7 diseases (PD, 3 FTLD, 3 dominant ataxias that recapitulate many features of the human diseases. We performed deep sequencing of head small RNAs after 3 days of pathological protein expression in the fly head neurons. We found no evidence for a statistically significant difference in miRNA expression in this early stage of the pathological process. In addition, we could not identify small non coding CAG repeat RNAs (sCAG in polyQ disease models. Thus our data suggest that transcriptional deregulation of miRNAs or sCAG is unlikely to play a significant role in the initial stages of neurodegenerative diseases.

  1. Building an integrated neurodegenerative disease database at an academic health center.

    Science.gov (United States)

    Xie, Sharon X; Baek, Young; Grossman, Murray; Arnold, Steven E; Karlawish, Jason; Siderowf, Andrew; Hurtig, Howard; Elman, Lauren; McCluskey, Leo; Van Deerlin, Vivianna; Lee, Virginia M-Y; Trojanowski, John Q

    2011-07-01

    It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. These comparative studies rely on powerful database tools to quickly generate data sets that match diverse and complementary criteria set by them. In this article, we present a novel integrated neurodegenerative disease (INDD) database, which was developed at the University of Pennsylvania (Penn) with the help of a consortium of Penn investigators. Because the work of these investigators are based on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, it allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used the Microsoft SQL server as a platform, with built-in "backwards" functionality to provide Access as a frontend client to interface with the database. We used PHP Hypertext Preprocessor to create the "frontend" web interface and then used a master lookup table to integrate individual neurodegenerative disease databases. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database. Using the INDD database, we compared the results of a biomarker study with those using an alternative approach by querying individual databases separately. We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies on several neurodegenerative diseases. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  2. Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Heeok Hong

    2016-05-01

    Full Text Available Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration.

  3. Prominent effects and neural correlates of visual crowding in a neurodegenerative disease population.

    Science.gov (United States)

    Yong, Keir X X; Shakespeare, Timothy J; Cash, Dave; Henley, Susie M D; Nicholas, Jennifer M; Ridgway, Gerard R; Golden, Hannah L; Warrington, Elizabeth K; Carton, Amelia M; Kaski, Diego; Schott, Jonathan M; Warren, Jason D; Crutch, Sebastian J

    2014-12-01

    Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n=26), typical Alzheimer's disease (n=17) and healthy control subjects (n=14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy

  4. Technologies enabling autologous neural stem cell-based therapies for neurodegenerative disease and injury

    Science.gov (United States)

    Bakhru, Sasha H.

    The intrinsic abilities of mammalian neural stem cells (NSCs) to self-renew, migrate over large distances, and give rise to all primary neural cell types of the brain offer unprecedented opportunity for cell-based treatment of neurodegenerative diseases and injuries. This thesis discusses development of technologies in support of autologous NSC-based therapies, encompassing harvest of brain tissue biopsies from living human patients; isolation of NSCs from harvested tissue; efficient culture and expansion of NSCs in 3D polymeric microcapsule culture systems; optimization of microcapsules as carriers for efficient in vivo delivery of NSCs; genetic engineering of NSCs for drug-induced, enzymatic release of transplanted NSCs from microcapsules; genetic engineering for drug-induced differentiation of NSCs into specific therapeutic cell types; and synthesis of chitosan/iron-oxide nanoparticles for labeling of NSCs and in vivo tracking by cellular MRI. Sub-millimeter scale tissue samples were harvested endoscopically from subventricular zone regions of living patient brains, secondary to neurosurgical procedures including endoscopic third ventriculostomy and ventriculoperitoneal shunt placement. On average, 12,000 +/- 3,000 NSCs were isolated per mm 3 of subventricular zone tissue, successfully demonstrated in 26 of 28 patients, ranging in age from one month to 68 years. In order to achieve efficient expansion of isolated NSCs to clinically relevant numbers (e.g. hundreds of thousands of cells in Parkinson's disease and tens of millions of cells in multiple sclerosis), an extracellular matrix-inspired, microcapsule-based culture platform was developed. Initial culture experiments with murine NSCs yielded unprecedented expansion folds of 30x in 5 days, from initially minute NSC populations (154 +/- 15 NSCs per 450 mum diameter capsule). Within 7 days, NSCs expanded as almost perfectly homogenous populations, with 94.9% +/- 4.1% of cultured cells staining positive for

  5. Humoral activity of cord blood-derived stem/progenitor cells: implications for stem cell-based adjuvant therapy of neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Edyta Paczkowska

    Full Text Available BACKGROUND: Stem/progenitor cells (SPCs demonstrate neuro-regenerative potential that is dependent upon their humoral activity by producing various trophic factors regulating cell migration, growth, and differentiation. Herein, we compared the expression of neurotrophins (NTs and their receptors in specific umbilical cord blood (UCB SPC populations, including lineage-negative, CD34(+, and CD133(+ cells, with that in unsorted, nucleated cells (NCs. METHODS AND RESULTS: The expression of NTs and their receptors was detected by QRT-PCR, western blotting, and immunofluorescent staining in UCB-derived SPC populations (i.e., NCs vs. lineage-negative, CD34(+, and CD133(+ cells. To better characterize, global gene expression profiles of SPCs were determined using genome-wide RNA microarray technology. Furthermore, the intracellular production of crucial neuro-regenerative NTs (i.e., BDNF and NT-3 was assessed in NCs and lineage-negative cells after incubation for 24, 48, and 72 h in both serum and serum-free conditions. We discovered significantly higher expression of NTs and NT receptors at both the mRNA and protein level in lineage-negative, CD34(+, and CD133(+ cells than in NCs. Global gene expression analysis revealed considerably higher expression of genes associated with the production and secretion of proteins, migration, proliferation, and differentiation in lineage-negative cells than in CD34(+ or CD133(+ cell populations. Notably, after short-term incubation under serum-free conditions, lineage-negative cells and NCs produced significantly higher amounts of BDNF and NT-3 than under steady-state conditions. Finally, conditioned medium (CM from lineage-negative SPCs exerted a beneficial impact on neural cell survival and proliferation. CONCLUSIONS: Collectively, our findings demonstrate that UCB-derived SPCs highly express NTs and their relevant receptors under steady-state conditions, NT expression is greater under stress-related conditions and

  6. Tremor in neurodegenerative ataxias, Huntington disease and tic disorder.

    Science.gov (United States)

    Rudzińska, M; Krawczyk, M; Wójcik-Pędziwiatr, M; Szczudlik, A; Tomaszewski, T

    2013-01-01

    Tremor is the most prevalent movement disorder, defined as rhythmic oscillations of a body part, caused by alternating or synchronic contractions of agonistic or antagonistic muscles. The aim of the study was to assess prevalence and to characterize parameters of tremor accompanying de-generative ataxias, Huntington disease (HD) and tic disorders in comparison with a control group. Forty-three patients with degenerative ataxias, 28 with HD and 26 with tic disorders together with 51 healthy controls were included in the study. For each participant, clinical and instrumental assessment (accelerometer, electromyography [EMG], graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor), with hands extended (postural tremor), during the 'finger-to-nose' test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, the type of tremor was determined as essential tremor type or enhanced physiological tremor type. The incidence of tremor in the accelerometry in patients with degenerative ataxia (50%) significantly differs from controls (10%) (p = 0.001). The dominant tremor was postural, low-intense, with 7-Hz frequency, essential tremor (23%) or other tremor type (23%), while enhanced physiological tremor was the least frequent (2%). Tremor in patients with HD and tic disorders was found in 10% and 20% of patients, respectively, similarly to the control group. Tremor was mild, postural and of essential tremor type, less frequently of enhanced physiological tremor type. No correlation between severity of tremor and severity of disease was found. The prevalence of tremor is considerably higher among patients with degenerative ataxias compared with HD, tic disorder and the control group. The most common type of tremor accompanying ataxias, HD and tic disorders is essential tremor type.

  7. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

    Directory of Open Access Journals (Sweden)

    Kaisa Kyöstilä

    2015-04-01

    Full Text Available Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136 in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

  8. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Larissa Takser

    Full Text Available Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN, microcystin-LR (MC-LR, and anatoxin-a (ATX-a, individually as well as their mixture. In addition, we studied the neurotoxins β-N-methylamino-l-alanine (BMAA and its isomer 2,4-diaminobutyric acid (DAB, as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food. Keywords: Cyanotoxins, Low doses, Apoptosis, Inflammation, Brain cells, Neurodegenerative diseases

  9. The Minister Council decree about conditions for to bring into the Polish customs area, to take away from the Polish customs area, and to transit through this area nuclear materials, radioactive sources and device including such sources

    International Nuclear Information System (INIS)

    Miller, L.

    2002-01-01

    The decree refers to conditions for to bring into the Polish customs area, to take away from the Polish customs area, and to transit through this area nuclear materials, radioactive sources and devices containing such sources

  10. Physical Exercise-Induced Adult Neurogenesis: A Good Strategy to Prevent Cognitive Decline in Neurodegenerative Diseases?

    Directory of Open Access Journals (Sweden)

    Suk-yu Yau

    2014-01-01

    Full Text Available Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.

  11. Decrease in Hurst exponent of human gait with aging and neurodegenerative diseases

    International Nuclear Information System (INIS)

    Zhauang Jianjun; Ning Xinbao; Yang Xiaodong; Huo Chengyu; Hou Fengzhen

    2008-01-01

    In this paper the decrease in the Hurst exponent of human gait with aging and neurodegenerative diseases was observed by using an improved rescaled range (R/S) analysis method. It indicates that the long-range correlations of gait rhythm from young healthy people are stronger than those from the healthy elderly and the diseased. The result further implies that fractal dynamics in human gait will be altered due to weakening or impairment of neural control on locomotion resulting from aging and neurodegenerative diseases. Due to analysing short-term data sequences rather than long datasets required by most nonlinear methods, the algorithm has the characteristics of simplicity and sensitivity, most importantly, fast calculation as well as powerful anti-noise capacities. These findings have implications for modelling locomotor control and also for quantifying gait dynamics in varying physiologic and pathologic states

  12. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases.

    Science.gov (United States)

    González, Hugo; Elgueta, Daniela; Montoya, Andro; Pacheco, Rodrigo

    2014-09-15

    Neuroinflammation constitutes a fundamental process involved in the progression of several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. Microglial cells play a central role in neuroinflammation, promoting neuroprotective or neurotoxic microenvironments, thus controlling neuronal fate. Acquisition of different microglial functions is regulated by intercellular interactions with neurons, astrocytes, the blood-brain barrier, and T-cells infiltrating the central nervous system. In this study, an overview of the regulation of microglial function mediated by different intercellular communications is summarised and discussed. Afterward, we focus in T-cell-mediated regulation of neuroinflammation involved in neurodegenerative disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Theory of mind, empathy and emotion perception in cortical and subcortical neurodegenerative diseases.

    Science.gov (United States)

    Fortier, J; Besnard, J; Allain, P

    2018-04-01

    Although the impact of neurodegenerative diseases on everyday interactions is well known in the literature, their impact on social cognitive processes remains unclear. The concept of social cognition refers to a set of skills, all of which are essential for living in a community. It involves social knowledge, perception and processing of social cues, and representation of mental states. This report is a review of recent findings on the impact of cortical and subcortical neurodegenerative diseases on three social cognitive processes, namely, the theory of mind, empathy and processing emotions. The focus here is on a conceptual approach to each of these skills and their cerebral underpinnings. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  14. Conformation-Specific IR and UV Spectroscopy of the Amino Acid Glutamine: Amide-Stacking and Hydrogen Bonding in AN Important Residue in Neurodegenerative Diseases

    Science.gov (United States)

    Walsh, Patrick S.; Dean, Jacob C.; Zwier, Timothy S.

    2014-06-01

    Glutamine plays an important role in several neurodegenerative diseases including Huntington's disease (HD) and Alzheimer's disease (AD). An intriguing aspect of the structure of glutamine is its incorporation of an amide group in its side chain, thereby opening up the possibility of forming amide-amide H-bonds between the peptide backbone and side chain. In this study the conformational preferences of two capped gluatamines Z(carboxybenzyl)-Glutamine-X (X=OH, NHMe) are studied under jet-cooled conditions in the gas phase in order to unlock the intrinsic structural motifs that are favored by this flexible sidechain. Conformational assignments are made by comparing the hydride stretch ( 3100-3700 cm-1) and amide I and II ( 1400-1800 cm-1) resonant ion-dip infrared spectra with predictions from harmonic frequency calculations. Assigned structures will be compared to previously published results on both natural and unnatural residues. Particular emphasis will be placed on the comparison between glutamine and unconstrained γ-peptides due to the similar three-carbon spacing between backbone and side chain in glutamine to the backbone spacing in γ-peptides. The ability of the glutamine side-chain to form amide stacked conformations will be a main focus, along with the prevalence of extended backbone type structures. W. H. James, III, C W. Müller, E. G. Buchanan, M. G. D. Nix, L. Guo, L. Roskop, M. S. Gordon, L. V. Slipchenko, S. H. Gellman, and T. S. Zwier, J. Am. Chem. Soc., 2009, 131(40), 14243-14245.

  15. Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases

    OpenAIRE

    Rydbirk, Rasmus; Folke, Jonas; Winge, Kristian; Aznar, Susana; Pakkenberg, Bente; Brudek, Tomasz

    2016-01-01

    Evaluation of gene expression levels by reverse transcription quantitative real-time PCR (RT-qPCR) has for many years been the favourite approach for discovering disease-associated alterations. Normalization of results to stably expressed reference genes (RGs) is pivotal to obtain reliable results. This is especially important in relation to neurodegenerative diseases where disease-related structural changes may affect the most commonly used RGs. We analysed 15 candidate RGs in 98 brain sampl...

  16. Bioinformatics Mining and Modeling Methods for the Identification of Disease Mechanisms in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Martin Hofmann-Apitius

    2015-12-01

    Full Text Available Since the decoding of the Human Genome, techniques from bioinformatics, statistics, and machine learning have been instrumental in uncovering patterns in increasing amounts and types of different data produced by technical profiling technologies applied to clinical samples, animal models, and cellular systems. Yet, progress on unravelling biological mechanisms, causally driving diseases, has been limited, in part due to the inherent complexity of biological systems. Whereas we have witnessed progress in the areas of cancer, cardiovascular and metabolic diseases, the area of neurodegenerative diseases has proved to be very challenging. This is in part because the aetiology of neurodegenerative diseases such as Alzheimer´s disease or Parkinson´s disease is unknown, rendering it very difficult to discern early causal events. Here we describe a panel of bioinformatics and modeling approaches that have recently been developed to identify candidate mechanisms of neurodegenerative diseases based on publicly available data and knowledge. We identify two complementary strategies—data mining techniques using genetic data as a starting point to be further enriched using other data-types, or alternatively to encode prior knowledge about disease mechanisms in a model based framework supporting reasoning and enrichment analysis. Our review illustrates the challenges entailed in integrating heterogeneous, multiscale and multimodal information in the area of neurology in general and neurodegeneration in particular. We conclude, that progress would be accelerated by increasing efforts on performing systematic collection of multiple data-types over time from each individual suffering from neurodegenerative disease. The work presented here has been driven by project AETIONOMY; a project funded in the course of the Innovative Medicines Initiative (IMI; which is a public-private partnership of the European Federation of Pharmaceutical Industry Associations

  17. Targeting Microglial KATP Channels to Treat Neurodegenerative Diseases: A Mitochondrial Issue

    Directory of Open Access Journals (Sweden)

    Manuel J. Rodríguez

    2013-01-01

    Full Text Available Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATP channel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.

  18. Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases.

    Science.gov (United States)

    Gibson, Gary E; Huang, Hsueh-Meei

    2004-08-01

    Considerable evidence indicates that oxidative stress accompanies age-related neurodegenerative diseases. Specific mechanisms by which oxidative stress leads to neurodegeneration are unknown. Two targets of oxidative stress that are known to change in neurodegenerative diseases are the mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (KGDHC) and endoplasmic reticulum calcium stores. KGDHC activities are diminished in all common neurodegenerative diseases and the changes are particularly well documented in Alzheimer's disease (AD). A second change that occurs in cells from AD patients is an exaggerated endoplasmic reticulum calcium store [i.e., bombesin-releasable calcium stores (BRCS)]. H(2)O(2), a general oxidant, changes both variables in the same direction as occurs in disease. Other oxidants selectively alter these variables. Various antioxidants were used to help define the critical oxidant species that modifies these responses. All of the antioxidants diminish the oxidant-induced carboxy-dichlorofluorescein (cDCF) detectable reactive oxygen species (ROS), but have diverse actions on these cellular processes. For example, alpha-keto-beta-methyl-n-valeric acid (KMV) diminishes the H(2)O(2) effects on BRCS, while trolox and DMSO exaggerate the response. Acute trolox treatment does not alter H(2)O(2)-induced changes in KGDHC, whereas chronic treatment with trolox increases KGDHC almost threefold. The results suggest that KGDHC and BRCS provide targets by which oxidative stress may induce neurodegeneration and a useful tool for selecting antioxidants for reversing age-related neurodegeneration.

  19. Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

    Science.gov (United States)

    Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta

    2017-01-01

    Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression. PMID:29249935

  20. Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

    Directory of Open Access Journals (Sweden)

    Luisa Benussi

    2017-12-01

    Full Text Available Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD, Frontotemporal dementia (FTD and Lewy body dementia (LBD. We will report evidences that the Brain Derived Neurotrophic Factor (BDNF, the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression.

  1. Brain Aggregates: An Effective In Vitro Cell Culture System Modeling Neurodegenerative Diseases.

    Science.gov (United States)

    Ahn, Misol; Kalume, Franck; Pitstick, Rose; Oehler, Abby; Carlson, George; DeArmond, Stephen J

    2016-03-01

    Drug discovery for neurodegenerative diseases is particularly challenging because of the discrepancies in drug effects between in vitro and in vivo studies. These discrepancies occur in part because current cell culture systems used for drug screening have many limitations. First, few cell culture systems accurately model human aging or neurodegenerative diseases. Second, drug efficacy may differ between dividing and stationary cells, the latter resembling nondividing neurons in the CNS. Brain aggregates (BrnAggs) derived from embryonic day 15 gestation mouse embryos may represent neuropathogenic processes in prion disease and reflect in vivo drug efficacy. Here, we report a new method for the production of BrnAggs suitable for drug screening and suggest that BrnAggs can model additional neurological diseases such as tauopathies. We also report a functional assay with BrnAggs by measuring electrophysiological activities. Our data suggest that BrnAggs could serve as an effective in vitro cell culture system for drug discovery for neurodegenerative diseases. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  2. Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

    Directory of Open Access Journals (Sweden)

    Mahmood Rasool

    2014-01-01

    Full Text Available Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS. Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer’s disease, Parkinson’s disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.

  3. Neurodegenerative diseases in the era of targeted therapeutics: how to handle a tangled issue.

    Science.gov (United States)

    Tofaris, George K; Schapira, Anthony H V

    2015-05-01

    Neurodegenerative diseases are age-related and relentlessly progressive with increasing prevalence and no cure or lasting symptomatic therapy. The well-recognized prodromal phase in many forms of neurodegeneration suggests a prolonged period of neuronal compensated dysfunction prior to cell loss that may be amenable to therapeutic intervention. Although most efforts to date have been focused on misfolded toxic proteins, it is now clear that widespread changes in protein homeostasis occur early in these diseases and understanding this fundamental biology is key to the design of targeted therapies. What has emerged from molecular genetics and animal studies is a previously less appreciated association of neurodegenerative diseases with defects in the molecular regulation of protein trafficking between cellular organelles, especially the intricate network of endosomes, lysosomes, autophagosomes and mitochondria. Here we summarized the broader concepts that stemmed from this Special Issue on "Protein Clearance in Neurodegenerative diseases: from mechanisms to therapies". This article is part of a Special Issue entitled 'Neuronal Protein'. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. A neural network underlying intentional emotional facial expression in neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Kelly A. Gola

    2017-01-01

    Full Text Available Intentional facial expression of emotion is critical to healthy social interactions. Patients with neurodegenerative disease, particularly those with right temporal or prefrontal atrophy, show dramatic socioemotional impairment. This was an exploratory study examining the neural and behavioral correlates of intentional facial expression of emotion in neurodegenerative disease patients and healthy controls. One hundred and thirty three participants (45 Alzheimer's disease, 16 behavioral variant frontotemporal dementia, 8 non-fluent primary progressive aphasia, 10 progressive supranuclear palsy, 11 right-temporal frontotemporal dementia, 9 semantic variant primary progressive aphasia patients and 34 healthy controls were video recorded while imitating static images of emotional faces and producing emotional expressions based on verbal command; the accuracy of their expression was rated by blinded raters. Participants also underwent face-to-face socioemotional testing and informants described participants' typical socioemotional behavior. Patients' performance on emotion expression tasks was correlated with gray matter volume using voxel-based morphometry (VBM across the entire sample. We found that intentional emotional imitation scores were related to fundamental socioemotional deficits; patients with known socioemotional deficits performed worse than controls on intentional emotion imitation; and intentional emotional expression predicted caregiver ratings of empathy and interpersonal warmth. Whole brain VBMs revealed a rightward cortical atrophy pattern homologous to the left lateralized speech production network was associated with intentional emotional imitation deficits. Results point to a possible neural mechanisms underlying complex socioemotional communication deficits in neurodegenerative disease patients.

  5. Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Androutsopoulos, Vasilis P. [Center of Toxicology Science and Research, University of Crete, Heraklion, Crete (Greece); Kanavouras, Konstantinos [Laboratory of Neurological Sciences, University of Crete, Heraklion, Crete (Greece); Tsatsakis, Aristidis M., E-mail: aris@med.uoc.gr [Center of Toxicology Science and Research, University of Crete, Heraklion, Crete (Greece)

    2011-11-15

    Organophosphate pesticides are a class of compounds that are widely used in agricultural and rural areas. Paraoxonase 1 (PON1) is a phase-I enzyme that is involved in the hydrolysis of organophosphate esters. Environmental poisoning by organophosphate compounds has been the main driving force of previous research on PON1 enzymes. Recent discoveries in animal models have revealed the important role of the enzyme in lipid metabolism. However although PON1 function is well established in experimental models, the contribution of PON1 in neurodegenerative diseases remains unclear. In this minireview we summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. A brief overview of latest epidemiological studies, regarding the two most important PON1 coding region polymorphisms PON1-L55M and PON1-Q192R is presented. Positive and negative associations of PON1 with disease occurrence are reported. Notably the MM and RR alleles contribute a risk enhancing effect for the development of some neurodegenerative diseases, which may be explained by the reduced lipoprotein free radical scavenging activity that may give rise to neuronal damage, through distinct mechanism. Conflicting findings that fail to support this postulate may represent the human population ethnic heterogeneity, different sample size and environmental parameters affecting PON1 status. We conclude that further epidemiological studies are required in order to address the exact contribution of PON1 genome in combination with organophosphate exposure in populations with neurodegenerative diseases.

  6. [Retinal imaging of the macula and optic disc in neurodegenerative diseases].

    Science.gov (United States)

    Turski, G N; Schmitz-Valckenberg, S; Holz, F G; Finger, R P

    2017-02-01

    Due to current demographic trends, the prevalence of mild cognitive impairment and dementia is expected to increase considerably. For potential new therapies it is important to identify patients at risk as early as possible. Currently, there is no population-based screening. Therefore, identification of biomarkers that will help screen the population at risk is urgently needed. Thus, a literature review on retinal pathology in neurodegenerative diseases was performed. PubMed was searched for studies published up to August 2016 using the following keywords: "mild cognitive impairment", "dementia", "eye", "ocular biomarkers", "OCT" and "OCT angiography". Relevant publications were selected and summarized qualitatively. Multiple studies using noninvasive in vivo optical coherence tomography (OCT) imaging showed nonspecific retinal pathological changes in patients with neurodegenerative diseases such as mild cognitive impairment, Alzheimer's and Parkinson's disease. Pathological changes in macular volume, optic nerve fiber layer thickness and the ganglion cell complex were observed. However, based on available evidence, no ocular biomarkers for neurodegeneration which could be integrated in routine clinical diagnostics have been identified. The potential use of OCT in the early diagnostic workup and monitoring of progression of neurodegenerative diseases needs to be further explored in longitudinal studies with large cohorts.

  7. Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Laura Foucault-Fruchard

    2017-01-01

    Full Text Available Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all characterized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

  8. Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Androutsopoulos, Vasilis P.; Kanavouras, Konstantinos; Tsatsakis, Aristidis M.

    2011-01-01

    Organophosphate pesticides are a class of compounds that are widely used in agricultural and rural areas. Paraoxonase 1 (PON1) is a phase-I enzyme that is involved in the hydrolysis of organophosphate esters. Environmental poisoning by organophosphate compounds has been the main driving force of previous research on PON1 enzymes. Recent discoveries in animal models have revealed the important role of the enzyme in lipid metabolism. However although PON1 function is well established in experimental models, the contribution of PON1 in neurodegenerative diseases remains unclear. In this minireview we summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. A brief overview of latest epidemiological studies, regarding the two most important PON1 coding region polymorphisms PON1-L55M and PON1-Q192R is presented. Positive and negative associations of PON1 with disease occurrence are reported. Notably the MM and RR alleles contribute a risk enhancing effect for the development of some neurodegenerative diseases, which may be explained by the reduced lipoprotein free radical scavenging activity that may give rise to neuronal damage, through distinct mechanism. Conflicting findings that fail to support this postulate may represent the human population ethnic heterogeneity, different sample size and environmental parameters affecting PON1 status. We conclude that further epidemiological studies are required in order to address the exact contribution of PON1 genome in combination with organophosphate exposure in populations with neurodegenerative diseases.

  9. Cerebral Blood Flow and A beta-Amyloid Estimates by WARAM Analysis of [C-11]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

    DEFF Research Database (Denmark)

    Rodell, Anders B.; O'Keefe, Graeme; Rowe, Christopher C.

    2017-01-01

    Alzheimer’s disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute...... metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer’s disease. Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer’s Disease (AD), eight subjects with dementia...

  10. Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease?

    NARCIS (Netherlands)

    de Vries, H.E.; Witte, M.; Hondius, D.; Rozemuller, A.J.M.; Drukarch, B.; Hoozemans, J.J.M.; van Horssen, J.

    2008-01-01

    Neurodegenerative diseases share various pathological features, such as accumulation of aberrant protein aggregates, microglial activation, and mitochondrial dysfunction. These pathological processes are associated with generation of reactive oxygen species (ROS), which cause oxidative stress and

  11. A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans

    Science.gov (United States)

    Chernoff, Neil; Hill, D. J.; Diggs, D. L.; Faison, B. D.; Francis, B. M.; Lang, J. R.; Larue, M. M.; Le, T.-T.; Loftin, Keith A.; Lugo, J. N.; Schmid, J. E.; Winnik, W. W.

    2017-01-01

    The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer’s disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

  12. EEG Radiotelemetry in Small Laboratory Rodents: A Powerful State-of-the Art Approach in Neuropsychiatric, Neurodegenerative, and Epilepsy Research

    Directory of Open Access Journals (Sweden)

    Andreas Lundt

    2016-01-01

    Full Text Available EEG radiotelemetry plays an important role in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies providing valuable insights into underlying pathophysiological mechanisms and thereby facilitating the development of new translational approaches. We elaborate on the major advantages of nonrestraining EEG radiotelemetry in contrast to restraining procedures such as tethered systems or jacket systems containing recorders. Whereas a main disadvantage of the latter is their unphysiological, restraining character, telemetric EEG recording overcomes these disadvantages. It allows precise and highly sensitive measurement under various physiological and pathophysiological conditions. Here we present a detailed description of a straightforward successful, quick, and efficient technique for intraperitoneal as well as subcutaneous pouch implantation of a standard radiofrequency transmitter in mice and rats. We further present computerized 3D-stereotaxic placement of both epidural and deep intracerebral electrodes. Preoperative preparation of mice and rats, suitable anaesthesia, and postoperative treatment and pain management are described in detail. A special focus is on fields of application, technical and experimental pitfalls, and technical connections of commercially available radiotelemetry systems with other electrophysiological setups.

  13. Targeting Specific HATs for Neurodegenerative Disease Treatment: Translating Basic Biology to Therapeutic Possibilities

    Directory of Open Access Journals (Sweden)

    Sheila K. Pirooznia

    2013-03-01

    Full Text Available Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HATs activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and

  14. Contribution of glucocorticoids and glucocorticoid receptors to the regulation of neurodegenerative processes.

    Science.gov (United States)

    Vyas, Sheela; Maatouk, Layal

    2013-12-01

    Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer's or Parkinson's or Huntington's disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

  15. Comprehension of insincere communication in neurodegenerative disease: lies, sarcasm, and theory of mind.

    Science.gov (United States)

    Shany-Ur, Tal; Poorzand, Pardis; Grossman, Scott N; Growdon, Matthew E; Jang, Jung Y; Ketelle, Robin S; Miller, Bruce L; Rankin, Katherine P

    2012-01-01

    Comprehension of insincere communication is an important aspect of social cognition requiring visual perspective taking, emotion reading, and understanding others' thoughts, opinions, and intentions. Someone who is lying intends to hide their insincerity from the listener, while a sarcastic speaker wants the listener to recognize they are speaking insincerely. We investigated whether face-to-face testing of comprehending insincere communication would effectively discriminate among neurodegenerative disease patients with different patterns of real-life social deficits. We examined ability to comprehend lies and sarcasm from a third-person perspective, using contextual cues, in 102 patients with one of four neurodegenerative diseases (behavioral variant frontotemporal dementia [bvFTD], Alzheimer's disease [AD], progressive supranuclear palsy [PSP], and vascular cognitive impairment) and 77 healthy older adults (normal controls--NCs). Participants answered questions about videos depicting social interactions involving deceptive, sarcastic, or sincere speech using The Awareness of Social Inference Test. All subjects equally understood sincere remarks, but bvFTD patients displayed impaired comprehension of lies and sarcasm compared with NCs. In other groups, impairment was not disease-specific but was proportionate to general cognitive impairment. Analysis of the task components revealed that only bvFTD patients were impaired on perspective taking and emotion reading elements and that both bvFTD and PSP patients had impaired ability to represent others' opinions and intentions (i.e., theory of mind). Test performance correlated with informants' ratings of subjects' empathy, perspective taking and neuropsychiatric symptoms in everyday life. Comprehending insincere communication is complex and requires multiple cognitive and emotional processes vulnerable across neurodegenerative diseases. However, bvFTD patients show uniquely focal and severe impairments at every level

  16. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases.

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2013-12-01

    Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.

  17. Worsening Cognitive Impairment and Neurodegenerative Pathology Progressively Increase Risk for Delirium

    Science.gov (United States)

    Davis, Daniel H.J.; Skelly, Donal T.; Murray, Carol; Hennessy, Edel; Bowen, Jordan; Norton, Samuel; Brayne, Carol; Rahkonen, Terhi; Sulkava, Raimo; Sanderson, David J.; Rawlins, J. Nicholas; Bannerman, David M.; MacLullich, Alasdair M.J.; Cunningham, Colm

    2015-01-01

    Background Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. Methods Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. Results In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. Conclusion A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology. PMID:25239680

  18. Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Silvia Vanni

    2018-01-01

    Full Text Available Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively and in different genetic forms of prion diseases (gPrD in comparison to Alzheimer's disease (AD subjects and age-matched controls.Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20, iCJD (n = 11, sCJD (n = 23, gPrD (n = 30, and AD (n = 14 patients and age-matched controls (n = 30. RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis.Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level.Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue—together with specific molecular and conformational features of the pathological agent of the disease—seem to dictate the peculiar

  19. [Epigenetic regulations and cerebral plasticity: towards new therapeutic options in neurodegenerative diseases?

    Science.gov (United States)

    Merienne, Karine; Boutillier, Anne-Laurence

    2016-01-01

    Although revealed in the 1950's, epigenetics is still a fast-growing field. Its delineations continuously evolve and become clarified. In particular, "neuroepigenetics", a notion that encompasses epigenetic regulations associated with neuronal processes, appears very promising. Indeed, the challenge to be undertaken in this sub-field is double. On the one hand, it should bring molecular comprehension of specific neuronal processes, some of them falling within the long term regulations, such as learning and memory. On the other hand, it could bring therapeutic options for brain diseases, e.g. neurodegenerative diseases such as Alzheimer's or Huntington's diseases. © Société de Biologie, 2017.

  20. Role of the nucleolus in neurodegenerative diseases with particular reference to the retina: a review.

    Science.gov (United States)

    Sia, Paul I; Wood, John Pm; Chidlow, Glyn; Sharma, Shiwani; Craig, Jamie; Casson, Robert J

    2016-04-01

    The nucleolus has emerged as a key regulator of cellular growth and the response to stress, in addition to its traditionally understood function in ribosome biogenesis. The association between nucleolar function and neurodegenerative disease is increasingly being explored. There is also recent evidence indicating that the nucleolus may well be crucial in the development of the eye. In this present review, the role of the nucleolus in retinal development as well as in neurodegeneration with an emphasis on the retina is discussed. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

  1. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

    DEFF Research Database (Denmark)

    Tingaud-Sequeira, Angèle; Raldúa, Demetrio; Lavie, Julie

    2017-01-01

    ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid...... and motor skill impairment. A disruption of retina architecture and retinotectal projections was observed, together with an inhibition of lens clarification and a low number of mechanosensory hair cells in the inner ear and lateral line system. The severe phenotypes in abhd12 knockdown morphants were...

  2. Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases.

    Science.gov (United States)

    Vanni, Silvia; Zattoni, Marco; Moda, Fabio; Giaccone, Giorgio; Tagliavini, Fabrizio; Haïk, Stéphane; Deslys, Jean-Philippe; Zanusso, Gianluigi; Ironside, James W; Carmona, Margarita; Ferrer, Isidre; Kovacs, Gabor G; Legname, Giuseppe

    2018-01-01

    Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls. Methods: Total RNA was obtained from the frontal cortex of vCJD ( n = 20), iCJD ( n = 11), sCJD ( n = 23), gPrD ( n = 30), and AD ( n = 14) patients and age-matched controls ( n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis. Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level. Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)-together with specific molecular and conformational features of the pathological agent of the disease-seem to dictate the peculiar hemoglobin

  3. Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders.

    Science.gov (United States)

    Di Domenico, Fabio; Tramutola, Antonella; Butterfield, D Allan

    2017-10-01

    Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Induced tauopathy in a novel 3D-culture model mediates neurodegenerative processes: a real-time study on biochips.

    Directory of Open Access Journals (Sweden)

    Diana Seidel

    Full Text Available Tauopathies including Alzheimer's disease represent one of the major health problems of aging population worldwide. Therefore, a better understanding of tau-dependent pathologies and consequently, tau-related intervention strategies is highly demanded. In recent years, several tau-focused therapies have been proposed with the aim to stop disease progression. However, to develop efficient active pharmaceutical ingredients for the broad treatment of Alzheimer's disease patients, further improvements are necessary for understanding the detailed neurodegenerative processes as well as the mechanism and side effects of potential active pharmaceutical ingredients (API in the neuronal system. In this context, there is a lack of suitable complex in vitro cell culture models recapitulating major aspects of taupathological degenerative processes in sufficient time and reproducible manner.Herewith, we describe a novel 3D SH-SY5Y cell-based, tauopathy model that shows advanced characteristics of matured neurons in comparison to monolayer cultures without the need of artificial differentiation promoting agents. Moreover, the recombinant expression of a novel highly pathologic fourfold mutated human tau variant lead to a fast and emphasized degeneration of neuritic processes. The neurodegenerative effects could be analyzed in real time and with high sensitivity using our unique microcavity array-based impedance spectroscopy measurement system. We were able to quantify a time- and concentration-dependent relative impedance decrease when Alzheimer's disease-like tau pathology was induced in the neuronal 3D cell culture model. In combination with the collected optical information, the degenerative processes within each 3D-culture could be monitored and analyzed. More strikingly, tau-specific regenerative effects caused by tau-focused active pharmaceutical ingredients could be quantitatively monitored by impedance spectroscopy.Bringing together our novel complex 3

  5. Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

    Directory of Open Access Journals (Sweden)

    Katerina Markopoulou

    Full Text Available Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L, which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may

  6. Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

    Science.gov (United States)

    Markopoulou, Katerina; Chase, Bruce A; Robowski, Piotr; Strongosky, Audrey; Narożańska, Ewa; Sitek, Emilia J; Berdynski, Mariusz; Barcikowska, Maria; Baker, Matt C; Rademakers, Rosa; Sławek, Jarosław; Klein, Christine; Hückelheim, Katja; Kasten, Meike; Wszolek, Zbigniew K

    2016-01-01

    Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the

  7. Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.

    Science.gov (United States)

    Wexler, Eric M; Rosen, Ezra; Lu, Daning; Osborn, Gregory E; Martin, Elizabeth; Raybould, Helen; Geschwind, Daniel H

    2011-10-04

    Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.

  8. The central biobank and virtual biobank of BIOMARKAPD: a resource for studies on neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Babette eReijs

    2015-10-01

    Full Text Available AbstractBiobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's Disease (BIOMARKAPD is a European multicenter study, funded by the EU Joint Programme - Neurodegenerative Disease Research (JPND, that aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer’s disease (AD and Parkinson’s disease (PD. The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF and blood samples were collected according to the BIOMARKAPD standardized preanalytical procedures (SOP and stored at Integrated BioBank of Luxembourg (IBBL. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI, AD, frontotemporal dementia (FTD, vascular dementia (VaD, multiple system atrophy (MSA, progressive supranuclear palsy (PSP, PD, PD with dementia, and dementia with Lewy bodies (DLB. The virtual biobank contains information on over 8600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.

  9. MicroRNA Biomarkers in Neurodegenerative Diseases and Emerging Nano-Sensors Technology

    Directory of Open Access Journals (Sweden)

    Pratik Shah

    2017-01-01

    Full Text Available MicroRNAs (miRNAs are essential small RNA molecules (20–24 nt that negatively regulate the expression of target genes at the post-transcriptional level. Due to their roles in a variety of biological processes, the aberrant expression profiles of miRNAs have been identified as biomarkers for many diseases, such as cancer, diabetes, cardiovascular disease and neurodegenerative diseases. In order to precisely, rapidly and economically monitor the expression of miRNAs, many cutting-edge nanotechnologies have been developed. One of the nanotechnologies, based on DNA encapsulated silver nanoclusters (DNA/AgNCs, has increasingly been adopted to create nanoscale bio-sensing systems due to its attractive optical properties, such as brightness, tuneable emission wavelengths and photostability. Using the DNA/AgNCs sensor methods, the presence of miRNAs can be detected simply by monitoring the fluorescence alteration of DNA/AgNCs sensors. We introduce these DNA/ AgNCs sensor methods and discuss their possible applications for detecting miRNA biomarkers in neurodegenerative diseases.

  10. Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

    Science.gov (United States)

    Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

    2018-01-01

    Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

  11. Beer and bread to brains and beyond: can yeast cells teach us about neurodegenerative disease?

    Science.gov (United States)

    Gitler, Aaron D

    2008-01-01

    For millennia, humans have harnessed the astonishing power of yeast, producing such culinary masterpieces as bread, beer and wine. Therefore, in this new millennium, is it very farfetched to ask if we can also use yeast to unlock some of the modern day mysteries of human disease? Remarkably, these seemingly simple cells possess most of the same basic cellular machinery as the neurons in the brain. We and others have been using the baker's yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms of devastating neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's and amyotrophic lateral sclerosis. While very different in their pathophysiology, they are collectively referred to as protein-misfolding disorders because of the presence of misfolded and aggregated forms of various proteins in the brains of affected individuals. Using yeast genetics and the latest high-throughput screening technologies, we have identified some of the potential causes underpinning these disorders and discovered conserved genes that have proven effective in preventing neuron loss in animal models. Thus, these genes represent new potential drug targets. In this review, I highlight recent work investigating mechanisms of cellular toxicity in a yeast Parkinson's disease model and discuss how similar approaches are being applied to additional neurodegenerative diseases.

  12. Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease.

    Science.gov (United States)

    Ruiz-Riquelme, Alejandro; Sánchez-Iglesias, Sofía; Rábano, Alberto; Guillén-Navarro, Encarna; Domingo-Jiménez, Rosario; Ramos, Adriana; Rosa, Isaac; Senra, Ana; Nilsson, Peter; García, Ángel; Araújo-Vilar, David; Requena, Jesús R

    2015-11-01

    Celia's Encephalopathy (MIM #615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2 mutation (c.985C>T) that results in an aberrant isoform of seipin (Celia seipin). This mutation is lethal in both homozygosity and compounded heterozygosity with a lipodystrophic BSCL2 mutation, resulting in a progressive encephalopathy with fatal outcomes at ages 6-8. Strikingly, heterozygous carriers are asymptomatic, conflicting with the gain of toxic function attributed to this mutation. Here we report new key insights about the molecular pathogenic mechanism of this new syndrome. Intranuclear inclusions containing mutant seipin were found in brain tissue from a homozygous patient suggesting a pathogenic mechanism similar to other neurodegenerative diseases featuring brain accumulation of aggregated, misfolded proteins. Sucrose gradient distribution showed that mutant seipin forms much larger aggregates as compared with wild type (wt) seipin, indicating an impaired oligomerization. On the other hand, the interaction between wt and Celia seipin confirmed by coimmunoprecipitation (CoIP) assays, together with the identification of mixed oligomers in sucrose gradient fractionation experiments can explain the lack of symptoms in heterozygous carriers. We propose that the increased aggregation and subsequent impaired oligomerization of Celia seipin leads to cell death. In heterozygous carriers, wt seipin might prevent the damage caused by mutant seipin through its sequestration into harmless mixed oligomers. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Raman Spectroscopy: An Emerging Tool in Neurodegenerative Disease Research and Diagnosis.

    Science.gov (United States)

    Devitt, George; Howard, Kelly; Mudher, Amrit; Mahajan, Sumeet

    2018-03-21

    The pathogenesis underlining many neurodegenerative diseases remains incompletely understood. The lack of effective biomarkers and disease preventative medicine demands the development of new techniques to efficiently probe the mechanisms of disease and to detect early biomarkers predictive of disease onset. Raman spectroscopy is an established technique that allows the label-free fingerprinting and imaging of molecules based on their chemical constitution and structure. While analysis of isolated biological molecules has been widespread in the chemical community, applications of Raman spectroscopy to study clinically relevant biological species, disease pathogenesis, and diagnosis have been rapidly increasing since the past decade. The growing number of biomedical applications has shown the potential of Raman spectroscopy for detection of novel biomarkers that could enable the rapid and accurate screening of disease susceptibility and onset. Here we provide an overview of Raman spectroscopy and related techniques and their application to neurodegenerative diseases. We further discuss their potential utility in research, biomarker detection, and diagnosis. Challenges to routine use of Raman spectroscopy in the context of neuroscience research are also presented.

  14. FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders.

    Science.gov (United States)

    Fanjul-Vélez, Félix; Salas-García, Irene; Ortega-Quijano, Noé; Arce-Diego, José Luis

    2015-01-01

    Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Glucose 6 phosphatase dehydrogenase (G6PD and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Manju Tiwari

    2017-12-01

    Full Text Available Glucose 6 phosphate dehydrogenase (G6PD is a key and rate limiting enzyme in the pentose phosphate pathway (PPP. The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH. There are preponderance research findings that demonstrate the enzyme (G6PD role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.

  16. Modeling cognitive deficits following neurodegenerative diseases and traumatic brain injuries with deep convolutional neural networks.

    Science.gov (United States)

    Lusch, Bethany; Weholt, Jake; Maia, Pedro D; Kutz, J Nathan

    2018-06-01

    The accurate diagnosis and assessment of neurodegenerative disease and traumatic brain injuries (TBI) remain open challenges. Both cause cognitive and functional deficits due to focal axonal swellings (FAS), but it is difficult to deliver a prognosis due to our limited ability to assess damaged neurons at a cellular level in vivo. We simulate the effects of neurodegenerative disease and TBI using convolutional neural networks (CNNs) as our model of cognition. We utilize biophysically relevant statistical data on FAS to damage the connections in CNNs in a functionally relevant way. We incorporate energy constraints on the brain by pruning the CNNs to be less over-engineered. Qualitatively, we demonstrate that damage leads to human-like mistakes. Our experiments also provide quantitative assessments of how accuracy is affected by various types and levels of damage. The deficit resulting from a fixed amount of damage greatly depends on which connections are randomly injured, providing intuition for why it is difficult to predict impairments. There is a large degree of subjectivity when it comes to interpreting cognitive deficits from complex systems such as the human brain. However, we provide important insight and a quantitative framework for disorders in which FAS are implicated. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Chanshuai Han

    2018-02-01

    Full Text Available Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

  18. Brain rust: recent discoveries on the role of oxidative stress in neurodegenerative diseases.

    Science.gov (United States)

    de Oliveira, Diêgo Madureira; Ferreira Lima, Rute Maria; El-Bachá, Ramon Santos

    2012-05-01

    Oxidative stress (OS) and damages due to excessive reactive oxygen species (ROS) are common causes of injuries to cells and organisms. The prevalence of neurodegenerative diseases (ND) increases with aging and much of the research involving ROS and OS has emerged from works in this field. This text reviews some recent published articles about the role of OS in ND. Since there are many reviews in this field, the focus was centered in articles published recently. The Scientific Journals Directory supported by the Brazilian Ministry of Education Office for the Coordination of Higher Educational Personnel Improvement (CAPES) was used to search, download, and review articles. The search engine looked for the terms 'oxidative stress AND neurodegenerative diseases AND nutrition' in 10 different scientific collections. Biochemical markers for ND lack sensitivity or specificity for diagnosis or for tracking response to therapy today. OS has an intimate connection with ND, albeit low levels of ROS seem to protect the brain. Deleterious changes in mitochondria, OS, calcium, glucocorticoids, inflammation, trace metals, insulin, cell cycle, protein aggregation, and hundreds to thousands of genes occur in ND. The interaction of genes with their environment, may explain ND. Although OS has received much attention over the years, which increased the number of scientific works on antioxidant interventions, no one knows how to stop or delay ND at present. Interventions in vitro, in vivo, and in humans will continue to contribute for a better understanding of these pathologies.

  19. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Science.gov (United States)

    Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

    2014-11-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  20. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.

    Science.gov (United States)

    Kao, Aimee W; Eisenhut, Robin J; Martens, Lauren Herl; Nakamura, Ayumi; Huang, Anne; Bagley, Josh A; Zhou, Ping; de Luis, Alberto; Neukomm, Lukas J; Cabello, Juan; Farese, Robert V; Kenyon, Cynthia

    2011-03-15

    Frontotemporal lobar degeneration is a progressive neurodegenerative syndrome that is the second most common cause of early-onset dementia. Mutations in the progranulin gene are a major cause of familial frontotemporal lobar degeneration [Baker M, et al. (2006) Nature 442:916-919 and Cruts M, et al. (2006) Nature 442:920-924]. Although progranulin is involved in wound healing, inflammation, and tumor growth, its role in the nervous system and the mechanism by which insufficient levels result in neurodegeneration are poorly understood [Eriksen and Mackenzie (2008) J Neurochem 104:287-297]. We have characterized the normal function of progranulin in the nematode Caenorhabditis elegans. We found that mutants lacking pgrn-1 appear grossly normal, but exhibit fewer apoptotic cell corpses during development. This reduction in corpse number is not caused by reduced apoptosis, but instead by more rapid clearance of dying cells. Likewise, we found that macrophages cultured from progranulin KO mice displayed enhanced rates of apoptotic-cell phagocytosis. Although most neurodegenerative diseases are thought to be caused by the toxic effects of aggregated proteins, our findings suggest that susceptibility to neurodegeneration may be increased by a change in the kinetics of programmed cell death. We propose that cells that might otherwise recover from damage or injury are destroyed in progranulin mutants, which in turn facilitates disease progression.

  1. Effect of meditation on cognitive functions in context of aging and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Rafał eMarciniak

    2014-01-01

    Full Text Available Effect of different meditation practices on various aspects of mental and physical health is receiving growing attention. The present paper reviews evidence about effects of several mediation practices on cognitive functions in the context of aging and neurodegenerative diseases. The effect of meditation in this area is still poorly explored. Seven studies were detected through the databases search which explores the effect of meditation on attention, memory, executive functions and other miscellaneous measures of cognition in a sample of older people and people suffering from neurodegenerative diseases. Overall, reviewed studies suggested a positive effect of meditation techniques, particularly in the area of attention, as well as memory, verbal fluency and cognitive flexibility. These findings are discussed in the context of MRI studies suggesting structural correlates of the effects. Meditation can be a potentially suitable non-pharmacological intervention aimed at the prevention of cognitive decline in the elderly. However, the conclusions of these studies are limited by their methodological flaws and differences of various types of meditation techniques. Further research in this direction could help to verify the validity of the findings and clarify the problematic aspects.

  2. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Yasser Iturria-Medina

    2014-11-01

    Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  3. Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Ian James Martins

    2015-12-01

    Full Text Available Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

  4. Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders.

    Science.gov (United States)

    Saniotis, Arthur; Henneberg, Maciej; Sawalma, Abdul-Rahman

    2018-01-01

    Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

  5. Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support.

    Science.gov (United States)

    Marsh, Samuel E; Blurton-Jones, Mathew

    2017-06-01

    Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease currently affect tens of millions of people worldwide. Unfortunately, as the world's population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. In this mini-review we will discuss recent work that examines the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. We will then also discuss some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Arthur Saniotis

    2018-03-01

    Full Text Available Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an “Endomyccorhizae like interface” (ELI nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

  7. New seismograph includes filters

    Energy Technology Data Exchange (ETDEWEB)

    1979-11-02

    The new Nimbus ES-1210 multichannel signal enhancement seismograph from EG and G geometrics has recently been redesigned to include multimode signal fillers on each amplifier. The ES-1210F is a shallow exploration seismograph for near subsurface exploration such as in depth-to-bedrock, geological hazard location, mineral exploration, and landslide investigations.

  8. Levels of potential bioactive compounds including carotenoids, vitamin C and phenolic compounds, and expression of their cognate biosynthetic genes vary significantly in different varieties of potato (Solanum tuberosum L.) grown under uniform cultural conditions.

    Science.gov (United States)

    Valcarcel, Jesus; Reilly, Kim; Gaffney, Michael; O'Brien, Nora M

    2016-02-01

    In addition to their high carbohydrate content, potatoes are also an important dietary source of vitamin C and bioactive secondary metabolites, including phenolic compounds and carotenoids, which have been suggested to play a role in human health. The expression of genes encoding key enzymes involved in the synthesis of these compounds was assessed by reverse transcription-quantitative polymerase chain reaction and compared to the accumulation of the corresponding product in seven potato varieties showing contrasting levels of metabolite accumulation. Strong positive correlations were found between phenolic content in the flesh of tubers and transcript levels of phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes. The expression of PAL and CHS was also related to that of AN1, a transcription factor involved in the synthesis of anthocyanins, suggesting that these genes are regulated in a coordinated manner. No clear relationship was found between transcript levels of phytoene synthase (PSY) or L-galactono-1,4-lactone dehydrogenase (GLDH) genes and total carotenoid or vitamin C accumulation, respectively. Data indicate that levels of total phenolic and flavonoid compounds in potato are controlled primarily by PAL and CHS gene expression. Transcript levels of PSY and GLDH did not control accumulation of carotenoids or vitamin C. © 2015 Society of Chemical Industry.

  9. Synopsis on Managment Strategies for Neurodegenerative Disorders: Challenges from Bench to Bedside in Successful Drug Discovery and Development.

    Science.gov (United States)

    Bhat, Sheraz Ahmad; Kamal, Mohammad Amjad; Yarla, Nagendra Sastry; Ashraf, Ghulam Md

    2017-01-01

    The maintenance of health requires successful cell functioning, which in turn depends upon the proper and active conformation of proteins besides other biomolecules. However, occasionally these proteins may misfold and lead to the appearance and progression of protein conformational diseases. These diseases apart from others include several neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other lesser known diseases. Although much knowledge has been gained, these NDDs still warrant advance research in the elucidation of their mechanisms as well as effective therapeutic interventions and proper management. There is an ever-growing and urgent need to improve the diagnosis and management of NDDs due to their devastating nature, serious social impact and neuropsychiatric symptoms. It is also envisioned that we may be able to encourage, develop, and strengthen the cell defenses against amyloid toxicity and prevent neuronal destruction and consequently neurodegeneration. In this review, the implications of protein misfolding and aggregation in NDDs are discussed along with some of the most recent findings on the curative and beneficial effects of natural molecules such as polyphenols. This paper also reviews the anti-aggregation and protective effects of some organic and peptidic compounds duly supported experimentally, as prospective future therapeutics for NDDs. The synopses presented in this review shall prove helpful in further understanding of the causes, cures and management of lethal NDDs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Potential Therapeutic Effects of Curcumin, the Anti-inflammatory Agent, Against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases

    Science.gov (United States)

    Aggarwal, Bharat B.; Harikumar, Kuzhuvelil B.

    2009-01-01

    Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that the this activity of turmeric is due to curcumin, a diferuloylmethane. This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various pro-inflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further. PMID:18662800

  11. Alzheimer’s Disease and HLA-A2: Linking Neurodegenerative to Immune Processes through an In Silico Approach

    Directory of Open Access Journals (Sweden)

    Ricardo A. Cifuentes

    2014-01-01

    Full Text Available There is a controversial relationship between HLA-A2 and Alzheimer’s disease (AD. It has been suggested a modifier effect on the risk that depends on genetic loadings. Thus, the aims of this study were to evaluate this relationship and to reveal genes associated with both concepts the HLA-A gene and AD. Consequently, we did first a classical systematic review and a meta-analysis of case-control studies. Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining. The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians, in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1. In contrast, the in silico approach retrieved nonrandomly shared genes by both concepts (P = 0.02, which additionally encode truly interacting proteins. The network of proteins encoded by APP, ICAM-1, ITGB2, ITGAL, SELP, SELL, IL2, IL1B, CD4, and CD8A linked immune to neurodegenerative processes and highlighted the potential roles in AD pathogenesis of endothelial regulation, infectious diseases, specific antigen presentation, and HLA-A2 in maintaining synapses.

  12. Dysregulation of the HPA axis as a core pathophysiology mediating co-morbid depression in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Xin eDu

    2015-03-01

    Full Text Available There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.

  13. Essential oil from lemon peels inhibit key enzymes linked to neurodegenerative conditions and pro-oxidant induced lipid peroxidation.

    Science.gov (United States)

    Oboh, Ganiyu; Olasehinde, Tosin A; Ademosun, Ayokunle O

    2014-01-01

    This study sought to investigate the effects of essential oil from lemon (Citrus limoni) peels on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities in vitro. The essential oil was extracted by hydrodistillation, dried with anhydrous Na2SO4 and characterized using gas chromatography. Antioxidant properties of the oil and inhibition of pro-oxidant-induced lipid peroxidation in rats brain homogenate were also assessed. The essential oil inhibited AChE and BChE activities in a concentration-dependent manner. GC analysis revealed the presence of sabinene, limonene, α-pinene, β-pinene, neral, geranial, 1,8-cineole, linalool, borneol, α-terpineol, terpinen-4-ol, linalyl acetate and β-caryophyllene. Furthermore, the essential oil exhibited antioxidant activities as typified by ferric reducing property, Fe(2+)-chelation and radicals [DPPH, ABTS, OH, NO] scavenging abilities. The inhibition of AChE and BChE activities, inhibition of pro-oxidant induced lipid peroxidation and antioxidant activities could be possible mechanisms for the use of the essential oil in the management and prevention of oxidative stress-induced neurodegeneration.

  14. Analytic device including nanostructures

    KAUST Repository

    Di Fabrizio, Enzo M.; Fratalocchi, Andrea; Totero Gongora, Juan Sebastian; Coluccio, Maria Laura; Candeloro, Patrizio; Cuda, Gianni

    2015-01-01

    A device for detecting an analyte in a sample comprising: an array including a plurality of pixels, each pixel including a nanochain comprising: a first nanostructure, a second nanostructure, and a third nanostructure, wherein size of the first nanostructure is larger than that of the second nanostructure, and size of the second nanostructure is larger than that of the third nanostructure, and wherein the first nanostructure, the second nanostructure, and the third nanostructure are positioned on a substrate such that when the nanochain is excited by an energy, an optical field between the second nanostructure and the third nanostructure is stronger than an optical field between the first nanostructure and the second nanostructure, wherein the array is configured to receive a sample; and a detector arranged to collect spectral data from a plurality of pixels of the array.

  15. Saskatchewan resources. [including uranium

    Energy Technology Data Exchange (ETDEWEB)

    1979-09-01

    The production of chemicals and minerals for the chemical industry in Saskatchewan are featured, with some discussion of resource taxation. The commodities mentioned include potash, fatty amines, uranium, heavy oil, sodium sulfate, chlorine, sodium hydroxide, sodium chlorate and bentonite. Following the successful outcome of the Cluff Lake inquiry, the uranium industry is booming. Some developments and production figures for Gulf Minerals, Amok, Cenex and Eldorado are mentioned.

  16. REM Sleep Behavior Disorder: Updated Review of the Core Features, the RBD-Neurodegenerative Disease Association, Evolving Concepts, Controversies, and Future Directions

    Science.gov (United States)

    Boeve, Bradley F.

    2010-01-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. Patients appear to “act out their dreams,” in which the exhibited behaviors mirror the content of the dreams, and the dream content often involves a chasing or attacking theme. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straight-forward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail. PMID:20146689

  17. Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminum in neurodegenerative diseases, including Alzheimer's disease.

    Science.gov (United States)

    Exley, Christopher

    2014-01-01

    In the aluminum age, it is clearly unpalatable for aluminum, the globe's most successful metal, to be implicated in human disease. It is unpalatable because for approximately 100 years human beings have reaped the rewards of the most abundant metal of the Earth's crust without seriously considering the potential consequences for human health. The aluminum industry is a pillar of the developed and developing world and irrespective of the tyranny of human exposure to aluminum it cannot be challenged without significant consequences for businesses, economies, and governments. However, no matter how deep the dependency or unthinkable the withdrawal, science continues to document, if not too slowly, a burgeoning body burden of aluminum in human beings. Herein, I will make the case that it is inevitable both today and in the future that an individual's exposure to aluminum is impacting upon their health and is already contributing to, if not causing, chronic diseases such as Alzheimer's disease. This is the logical, if uncomfortable, consequence of living in the aluminum age.

  18. Being Included and Excluded

    DEFF Research Database (Denmark)

    Korzenevica, Marina

    2016-01-01

    Following the civil war of 1996–2006, there was a dramatic increase in the labor mobility of young men and the inclusion of young women in formal education, which led to the transformation of the political landscape of rural Nepal. Mobility and schooling represent a level of prestige that rural...... politics. It analyzes how formal education and mobility either challenge or reinforce traditional gendered norms which dictate a lowly position for young married women in the household and their absence from community politics. The article concludes that women are simultaneously excluded and included from...... community politics. On the one hand, their mobility and decision-making powers decrease with the increase in the labor mobility of men and their newly gained education is politically devalued when compared to the informal education that men gain through mobility, but on the other hand, schooling strengthens...

  19. Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72.

    Science.gov (United States)

    Budini, Mauricio; Buratti, Emanuele; Morselli, Eugenia; Criollo, Alfredo

    2017-01-01

    Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Additionally, recent studies have identified a role for these proteins in the control of autophagy. In this manuscript, we review what is known regarding the autophagic mechanism and discuss the involvement of TDP-43 and C9orf72 in autophagy and their impact on neurodegenerative diseases.

  20. Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders.

    Science.gov (United States)

    Meldrum, B

    1993-01-01

    The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man. Various unusual amino acids of plant origin can produce acute excitotoxic syndromes. In man domoate (consumed in mussels that have fed on (Nitschia pungens) can produce an acute syndrome associated with limbic system lesions and anterograde amnesia. Kainate and domoate produce similar syndromes in rodents; acromelate produces spinal pathology. The mechanisms and manifestations of chronic excitotoxicity are less clearly established. A combination of impaired energy metabolism or impaired buffering of calcium and free radicals and endogenous or exogenous excitotoxins may contribute to neuronal loss in human neurodegenerative disorders.

  1. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

    Directory of Open Access Journals (Sweden)

    Alisia Carnemolla

    Full Text Available The heat shock response (HSR is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.

  2. Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain.

    Science.gov (United States)

    Jiang, Chunyang; Zhang, Shun; Liu, Hongliang; Guan, Zhizhong; Zeng, Qiang; Zhang, Cheng; Lei, Rongrong; Xia, Tao; Wang, Zhenglun; Yang, Lu; Chen, Yihu; Wu, Xue; Zhang, Xiaofei; Cui, Yushan; Yu, Linyu; Wang, Aiguo

    2014-03-01

    Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.

  3. Potential importance of B cells in aging and aging-associated neurodegenerative diseases.

    Science.gov (United States)

    Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny

    2017-04-01

    Our understanding of B cells as merely antibody producers is slowly changing. Alone or in concert with antibody, they control outcomes of seemingly different diseases such as cancer, rheumatoid arthritis, diabetes, and multiple sclerosis. While their role in activation of effector immune cells is beneficial in cancer but bad in autoimmune diseases, their immunosuppressive and regulatory subsets (Bregs) inhibit autoimmune and anticancer responses. These pathogenic and suppressive functions are not static and appear to be regulated by the nature and strength of inflammation. Although aging increases inflammation and changes the composition and function of B cells, surprisingly, little is known whether the change affects aging-associated neurodegenerative disease, such as Alzheimer's disease (AD). Here, by analyzing B cells in cancer and autoimmune and neuroinflammatory diseases, we elucidate their potential importance in AD and other aging-associated neuroinflammatory diseases.

  4. Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis

    Directory of Open Access Journals (Sweden)

    Afroza Khanam Irin

    2015-01-01

    Full Text Available Neurodegenerative as well as autoimmune diseases have unclear aetiologies, but an increasing number of evidences report for a combination of genetic and epigenetic alterations that predispose for the development of disease. This review examines the major milestones in epigenetics research in the context of diseases and various computational approaches developed in the last decades to unravel new epigenetic modifications. However, there are limited studies that systematically link genetic and epigenetic alterations of DNA to the aetiology of diseases. In this work, we demonstrate how disease-related epigenetic knowledge can be systematically captured and integrated with heterogeneous information into a functional context using Biological Expression Language (BEL. This novel methodology, based on BEL, enables us to integrate epigenetic modifications such as DNA methylation or acetylation of histones into a specific disease network. As an example, we depict the integration of epigenetic and genetic factors in a functional context specific to Parkinson’s disease (PD and Multiple Sclerosis (MS.

  5. [Organ donation after active euthanasia in a patient with a neurodegenerative disease].

    Science.gov (United States)

    van Dijk, Gert; Giezeman, Ariane; Ultee, Fred; Hamers, Raoul

    2013-01-01

    In countries where active euthanasia by a physician is allowed under law - Belgium and the Netherlands - physicians are sometimes confronted with patients who want to donate organs after active euthanasia has been performed. This combination of procedures has been reported in Belgium, and this article is the first description of such a case in the Netherlands. It concerns a patient with a neurodegenerative disease who donated organs after euthanasia. The combination of two complex and controversial procedures - active euthanasia and organ donation - raises important ethical, legal and practical issues. It is suggested that with a thorough preparation and a strict separation of both procedures, organ donation after active euthanasia can strengthen patient autonomy and increase the number of donated organs.

  6. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

    Science.gov (United States)

    Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

    2013-06-01

    Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds.

  7. Circadian Rhythm Neuropeptides in Drosophila: Signals for Normal Circadian Function and Circadian Neurodegenerative Disease.

    Science.gov (United States)

    He, Qiankun; Wu, Binbin; Price, Jeffrey L; Zhao, Zhangwu

    2017-04-21

    Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state.

  8. The Progress of Mitophagy and Related Pathogenic Mechanisms of the Neurodegenerative Diseases and Tumor

    Directory of Open Access Journals (Sweden)

    Ying Song

    2015-01-01

    Full Text Available Mitochondrion, an organelle with two layers of membrane, is extremely vital to eukaryotic cell. Its major functions are energy center and apoptosis censor inside cell. The intactness of mitochondrial membrane is important to maintain its structure and function. Mitophagy is one kind of autophagy. In recent years, studies of mitochondria have shown that mitophagy is regulated by various factors and is an important regulation mechanism for organisms to maintain their normal state. In addition, abnormal mitophagy is closely related to several neurodegenerative diseases and tumor. However, the related signal pathway and its regulation mechanism still remain unclear. As a result, summarizing the progress of mitophagy and its related pathogenic mechanism not only helps to reveal the complicated molecular mechanism, but also helps to find a new target to treat the related diseases.

  9. The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases.

    Science.gov (United States)

    Victoria, Guiliana Soraya; Zurzolo, Chiara

    2017-09-04

    Progression of pathology in neurodegenerative diseases is hypothesized to be a non-cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a "donor cell" that is the source of misfolded aggregates to an "acceptor cell" in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer's, Huntington's, and Parkinson's diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies. © 2017 Victoria and Zurzolo.

  10. Poor caregiver mental health predicts mortality of patients with neurodegenerative disease.

    Science.gov (United States)

    Lwi, Sandy J; Ford, Brett Q; Casey, James J; Miller, Bruce L; Levenson, Robert W

    2017-07-11

    Dementia and other neurodegenerative diseases cause profound declines in functioning; thus, many patients require caregivers for assistance with daily living. Patients differ greatly in how long they live after disease onset, with the nature and severity of the disease playing an important role. Caregiving can also be extremely stressful, and many caregivers experience declines in mental health. In this study, we investigated the role that caregiver mental health plays in patient mortality. In 176 patient-caregiver dyads, we found that worse caregiver mental health predicted greater patient mortality even when accounting for key risk factors in patients (i.e., diagnosis, age, sex, dementia severity, and patient mental health). These findings highlight the importance of caring for caregivers as well as patients when attempting to improve patients' lives.

  11. Five-class differential diagnostics of neurodegenerative diseases using random undersampling boosting

    DEFF Research Database (Denmark)

    Tong, Tong; Ledig, Christian; Guerrero, Ricardo

    2017-01-01

    Differentiating between different types of neurodegenerative diseases is not only crucial in clinical practice when treatment decisions have to be made, but also has a significant potential for the enrichment of clinical trials. The purpose of this study is to develop a classification framework......-wise grading features) and non-imaging features (CSF measures) were extracted for each subject. In clinical practice, the prevalence of different dementia types is imbalanced, posing challenges for learning an effective classification model. Therefore, we propose the use of the RUSBoost algorithm in order...... to train classifiers and to handle the class imbalance training problem. Furthermore, a multi-class feature selection method based on sparsity is integrated into the proposed framework to improve the classification performance. It also provides a way for investigating the importance of different features...

  12. Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Pauline Gaignard

    2017-12-01

    Full Text Available The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress and brain steroid levels in both young (3-month-old and aged (20-month-old male and female mice.

  13. Development of PET tracers for neuro inflammation imaging in neuro degenerative diseases; Developpement de radiotraceurs de la neuroinflammation pour l'imagerie des pathologies neurodegeneratives

    Energy Technology Data Exchange (ETDEWEB)

    Chauveau, F

    2007-10-15

    Inflammatory processes such as micro-glial or endothelial activation are involved in many neuro-degenerative conditions. Neuro-inflammation imaging is considered an attractive tool for fundamental research, diagnosis and therapeutic evaluation in neuro-pathologies. First, an aptamer was selected against a recombinant fragment of the endothelial target VCAM-1, but proved unable to bind the target protein in native conformation, as expressed by a cell line. Second, five radioligands of the peripheral benzodiazepine receptor (PBR), a marker of micro-glial activation, were evaluated in vivo using PET (Positron Emission Tomography) imaging in a rat model of neuro-inflammation, and were compared to [11C]PK11195. Four radiotracers displayed a better contrast than [11C]PK11195. In a competitive field of research, this work demonstrates the efficiency of in vivo screening of radiotracers for fast selection of clinically relevant molecules. (author)

  14. Development of PET tracers for neuro inflammation imaging in neuro degenerative diseases; Developpement de radiotraceurs de la neuroinflammation pour l'imagerie des pathologies neurodegeneratives

    Energy Technology Data Exchange (ETDEWEB)

    Chauveau, F

    2007-10-15

    Inflammatory processes such as micro-glial or endothelial activation are involved in many neuro-degenerative conditions. Neuro-inflammation imaging is considered an attractive tool for fundamental research, diagnosis and therapeutic evaluation in neuro-pathologies. First, an aptamer was selected against a recombinant fragment of the endothelial target VCAM-1, but proved unable to bind the target protein in native conformation, as expressed by a cell line. Second, five radioligands of the peripheral benzodiazepine receptor (PBR), a marker of micro-glial activation, were evaluated in vivo using PET (Positron Emission Tomography) imaging in a rat model of neuro-inflammation, and were compared to [11C]PK11195. Four radiotracers displayed a better contrast than [11C]PK11195. In a competitive field of research, this work demonstrates the efficiency of in vivo screening of radiotracers for fast selection of clinically relevant molecules. (author)

  15. The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.

    Science.gov (United States)

    Penke, Botond; Fulop, Livia; Szucs, Maria; Frecska, Ede

    2018-01-01

    Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. Research articles on Sigma-1 receptor were reviewed. ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

    Science.gov (United States)

    Goemaere, Julie; Knoops, Bernard

    2012-02-01

    Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

  17. Brain imaging for oxidative stress and mitochondrial dysfunction in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Okazawa, H.; Tsujikawa, T.; Kiyono, Y.; Ikawa, M.; Yoneda, M.

    2014-01-01

    Oxidative stress, one of the most probable molecular mechanisms for neuronal impairment, is reported to occur in the affected brain regions of various neurodegenerative diseases. Recently, many studies showed evidence of a link between oxidative stress or mitochondrial damage and neuronal degeneration. Basic in vitro experiments and postmortem studies demonstrated that biomarkers for oxidative damage can be observed in the pathogenic regions of the brain and the affected neurons. Model animal studies also showed oxidative damage associated with neuronal degeneration. The molecular imaging method with positron emission tomography (PET) is expected to delineate oxidatively stressed microenvironments to elucidate pathophysiological changes of the in vivo brain; however, only a few studies have successfully demonstrated enhanced stress in patients. Radioisotope copper labeled diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) may be the most promising candidate for this oxidative stress imaging. The tracer is usually known as a hypoxic tissue imaging PET probe, but the accumulation mechanism is based on the electron rich environment induced by mitochondrial impairment and/or microsomal over-reduction, and thus it is considered to represent the oxidative stress state correlated with the degree of disease severity. In this review, Cu-ATSM PET is introduced in detail from the basics to practical methods in clinical studies, as well as recent clinical studies on cerebrovascular diseases and neurodegenerative diseases. Several other PET probes are also introduced from the point of view of neuronal oxidative stress imaging. These molecular imaging methods should be promising tools to reveal oxidative injuries in various brain diseases

  18. Context-dependent neural activation: internally and externally guided rhythmic lower limb movement in individuals with and without neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Madeleine Eve Hackney

    2015-12-01

    Full Text Available Parkinson’s Disease (PD is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients’ quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, tai chi have shown improvements to motor symptoms, lower limb control and postural stability in people with PD (Amano, Nocera, Vallabhajosula, Juncos, Gregor, Waddell et al., 2013; Earhart, 2009; M. E. Hackney & Earhart, 2008; Kadivar, Corcos, Foto, & Hondzinski, 2011; Morris, Iansek, & Kirkwood, 2009; Ridgel, Vitek, & Alberts, 2009. However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG and externally guided (EG movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG versus EG designs. Because of the potential task specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging (fMRI and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training and highlight research gaps. We believe better understanding of lower limb neural

  19. Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke.

    Science.gov (United States)

    Wang, Yuechun; Reis, Cesar; Applegate, Richard; Stier, Gary; Martin, Robert; Zhang, John H

    2015-10-01

    In the area of brain injury and neurodegenerative diseases, a plethora of experimental and clinical evidence strongly indicates the promise of therapeutically exploiting the endogenous adaptive system at various levels like triggers, mediators and the end-effectors to stimulate and mobilize intrinsic protective capacities against brain injuries. It is believed that ischemic pre-conditioning and post-conditioning are actually the strongest known interventions to stimulate the innate neuroprotective mechanism to prevent or reverse neurodegenerative diseases including stroke and traumatic brain injury. Recently, studies showed the effectiveness of ischemic per-conditioning in some organs. Therefore the term ischemic conditioning, including all interventions applied pre-, per- and post-ischemia, which spans therapeutic windows in 3 time periods, has recently been broadly accepted by scientific communities. In addition, it is extensively acknowledged that ischemia-mediated protection not only affects the neurons but also all the components of the neurovascular network (consisting of neurons, glial cells, vascular endothelial cells, pericytes, smooth muscle cells, and venule/veins). The concept of cerebroprotection has been widely used in place of neuroprotection. Intensive studies on the cellular signaling pathways involved in ischemic conditioning have improved the mechanistic understanding of tolerance to cerebral ischemia. This has added impetus to exploration for potential pharmacologic mimetics, which could possibly induce and maximize inherent protective capacities. However, most of these studies were performed in rodents, and the efficacy of these mimetics remains to be evaluated in human patients. Several classical signaling pathways involving apoptosis, inflammation, or oxidation have been elaborated in the past decades. Newly characterized mechanisms are emerging with the advances in biotechnology and conceptual renewal. In this review we are going to focus on

  20. Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias?

    Science.gov (United States)

    2014-01-01

    Introduction Two methods of non-invasive brain stimulation, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrable positive effects on cognition and can ameliorate neuropsychiatric symptoms such as depression. Less is known about the efficacy of these approaches in common neurodegenerative diseases. In this review, we evaluate the effects of TMS and tDCS upon cognitive and neuropsychiatric symptoms in the major dementias, including Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and frontotemporal dementia (FTD), as well as the potential pre-dementia states of Mild Cognitive Impairment (MCI) and Parkinson’s disease (PD). Methods PubMed (until 7 February 2014) and PsycINFO (from 1967 to January Week 3 2014) databases were searched in a semi-systematic manner in order to identify relevant treatment studies. A total of 762 studies were identified and 32 studies (18 in the dementias and 14 in PD populations) were included. Results No studies were identified in patients with PDD, FTD or VaD. Of the dementias, 13 studies were conducted in patients with AD, one in DLB, and four in MCI. A total of 16 of the 18 studies showed improvements in at least one cognitive or neuropsychiatric outcome measure. Cognitive or neuropsychiatric improvements were observed in 12 of the 14 studies conducted in patients with PD. Conclusions Both TMS and tDCS may have potential as interventions for the treatment of symptoms associated with dementia and PD. These results are promising; however, available data were limited, particularly within VaD, PDD and FTD, and major challenges exist in order to maximise the efficacy and clinical utility of both techniques. In particular, stimulation parameters vary considerably between studies and are likely to subsequently impact upon treatment efficacy. PMID:25478032

  1. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    International Nuclear Information System (INIS)

    So, Young; Kim, Hahn Young; Roh, Hong Gee; Han, Seol Heui

    2007-01-01

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr ∼ 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1∼9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI

  2. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    Energy Technology Data Exchange (ETDEWEB)

    So, Young; Kim, Hahn Young; Roh, Hong Gee; Han, Seol Heui [Konkuk University School of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr {approx} 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1{approx}9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI.

  3. The central biobank and virtual biobank of BiOMarKaPD: a resource for studies on neurodegenerative diseases

    NARCIS (Netherlands)

    Reijs, B.L.R.; Teunissen, C.E.; Goncharenko, N.; Betsou, F.; Blennow, K.; Baldeiras, I.; Brosseron, F.; Cavedo, E.; Fladby, T.; Froelich, L.; Gabryelewicz, T.; Gurvit, H.; Kapaki, E.; Koson, P.; Kulic, L.; Lehmann, S.; Lewczuk, P.; Lleo, A.; Maetzler, W.; de Mendonca, A.; Miller, A.M.; Molinuevo, J.L.; Mollenhauer, B.; Parnetti, L.; Rot, U.; Schneider, A.; Simonsen, A.H.; Tagliavini, F.; Tsolaki, M.; Verbeek, M.M.; Verhey, F. R. J.; Zboch, M.; Winblad, B.; Scheltens, P.; Zetterberg, H.; Visser, P.J.

    2015-01-01

    Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid

  4. Transgenic Rat Model of Huntington's Disease: A Histopathological Study and Correlations with Neurodegenerative Process in the Brain of HD Patients.

    Czech Academy of Sciences Publication Activity Database

    Mazurová, Y.; Anděrová, Miroslava; Němečková, I.; Bezrouk, A.

    2014-01-01

    Roč. 2014, Aug 03 (2014), s. 291531 ISSN 2314-6133 R&D Projects: GA ČR(CZ) GBP304/12/G069 Grant - others:GA MŠk(CZ) Prvouk P37 Institutional support: RVO:68378041 Keywords : Huntington's Disease * neurodegenerative process in the brain Subject RIV: FH - Neurology Impact factor: 1.579, year: 2014

  5. Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Penkowa, M; Demestre, M

    2005-01-01

    -inflammatory, neuroprotective, antioxidant proteins expressed during EAE and MS, in which they might play a protective role. The present study aimed to describe the expression profile of a group of inflammatory, neurodegenerative and tissue repair markers as well as metallothioneins during proteolipid protein-induced EAE...

  6. Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?

    Science.gov (United States)

    Pellegrini, Carolina; Antonioli, Luca; Colucci, Rocchina; Blandizzi, Corrado; Fornai, Matteo

    2018-05-24

    Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.

  7. Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco, Mexico

    Science.gov (United States)

    Navarro-Meza, Mónica; Gabriel-Ortiz, Genaro; Pacheco-Moisés, Fermín P.; Cruz-Ramos, José A.; López-Espinoza, Antonio

    2014-01-01

    Objective To evaluate and compare the intake of lipids and (A, E, and C) vitamins in patients with and without possible neurodegenerative diseases. Methods Twenty adults with possible Alzheimer's disease or Parkinson's disease and 41 control subjects (50–89 years old) from a rural region were studied. Dietary intake was evaluated with the analysis of macronutrients and micronutrients conducted by a food frequency questionnaire and 24 hours dietary record. Analyses were adjusted for age, sex, body mass index, and energy intake. Through interrogation and use of medical record form of health secretary we obtained information about the sociodemographic characteristics. Multivariate analysis of variance to allow for covariated adjustment was used. Results Patients had a lower energy intake, vitamin C (P = 0.016), fruits (P < 0.001), vegetables (P = 0.037), and oils and fat (P = 0.002), than the controls. Interestingly, the C vitamin intake in patients was still higher than the recommended. Patients had a higher consumption of cereals (P = 0.017), high-animal fat diet (P = 0.024), and whole milk (P < 0.001); 2.4% of the controls smoke and 5% are alcohol consumers. Eighty-five percent of patients and 78% of the controls do not have physical activity. Family history of subjects in this study indicated chronic diseases. Conclusion The subjects included in this study had a high intake of C vitamin, this is due to the consumption of fruits and vegetables. However, patients with possible Alzheimer's or Parkinson's disease had a lower intake of fruits and vegetables, which could be due to type of food to which they have access. PMID:24257159

  8. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases.

    Science.gov (United States)

    Takser, Larissa; Benachour, Nora; Husk, Barry; Cabana, Hubert; Gris, Denis

    2016-01-01

    Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN), microcystin-LR (MC-LR), and anatoxin-a (ATX-a), individually as well as their mixture. In addition, we studied the neurotoxins β- N -methylamino-l-alanine (BMAA) and its isomer 2,4-diaminobutyric acid (DAB), as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3-15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food.

  9. Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future.

    Science.gov (United States)

    Moos, Walter H; Faller, Douglas V; Glavas, Ioannis P; Harpp, David N; Irwin, Michael H; Kanara, Iphigenia; Pinkert, Carl A; Powers, Whitney R; Steliou, Kosta; Vavvas, Demetrios G; Kodukula, Krishna

    2017-01-01

    Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.

  10. 18F-Labelled catecholamine type radiopharmaceuticals in the diagnosis of neurodegenerative diseases and neuroendocrine tumours: approaches to synthesis and development prospects

    Science.gov (United States)

    Vatsadze, S. Z.; Eremina, O. E.; Veselova, I. A.; Kalmykov, S. N.; Nenajdenko, V. G.

    2018-04-01

    The pathogenesis of many socially significant diseases such as neurodegenerative dementias and neuroendocrine tumours involves imbalance of neurotransmitters. Among the known neuroimaging methods, positron emission tomography (PET) is the most perfect and informative technique for diagnosing these diseases. The potential of PET is largely determined by the inventory of available radiopharmaceuticals, that is, biologically active molecules containing short-lived nuclides with positron decay. This review gives a systematic account of the application of fluorine-18-labelled catecholamine type radiopharmaceuticals in clinical investigations of the sympathetic and central nervous systems. The methods for the synthesis of these agents and existing problems are considered. The material is arranged according to the mechanisms of reactions that underlie the synthetic approaches: electrophilic, nucleophilic and metal-catalyzed reactions. The bibliography includes 198 references.

  11. Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection.

    Science.gov (United States)

    Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali

    2017-04-15

    Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression. Copyright © 2016. Published by Elsevier B.V.

  12. The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis.

    Science.gov (United States)

    Leveugle, B; Spik, G; Perl, D P; Bouras, C; Fillit, H M; Hof, P R

    1994-07-04

    Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these

  13. The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Erica L. Gorenberg

    2017-05-01

    Full Text Available Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs: Cysteine String Protein alpha (CSPα; DNAJC5, auxilin (DNAJC6, and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13. These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70, enhancing the chaperone's ATPase activity. CSPα is a synaptic vesicle protein known to chaperone the t-SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110, which interacts with Hsc70, DNAJAs, and

  14. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  15. Classified directory of the field of refrigeration and air conditioning technology 2006. Register of the expert companies in the field of refrigeration and air conditioning plants craft including a supply and service list - register of the suppliers in the field of refrigeration and air conditioning technology including the complete ranges of material groups offered - register of expert schools, technical experts, technical expert information and norms; Branchenbuch der Kaelte- und Klimatechnik 2006. Verzeichnis der Fachbetriebe des Kaelte- und Klimaanlagenbauerhandwerks mit Liefer- und Leistungsangebot - Verzeichnis der Lieferanten von Kaelte- und Klimatechnik mit vollstaendigem Warengruppenangebot - Verzeichnis von Fachschulen, Sachverstaendigen u.v.a. - Technische Fachinformationen und Normen

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-07-01

    The present edition of the ''Classified directory of the field of refrigeration and air conditioning technology'' 2006 contains useful addresses, data and facts of the field: (a) approximately 1.500 addresses of expert companies in the field of refrigeration and air conditioning technology; (b) a register of suppliers and material groups in the field of refrigeration and air conditioning technology; (c) a technical part containing the most important norms of the field, laws and regulations in order to inform the reader for his daily work. The reference book is supposed to provide a good overview for the work in the field of technical building equipment. (orig./AKF)

  16. Krabbe Disease: Report of a Rare Lipid Storage and Neurodegenerative Disorder.

    Science.gov (United States)

    Pavuluri, Pratyusha; Vadakedath, Sabitha; Gundu, Rajkumar; Uppulety, Sushmitha; Kandi, Venkataramana

    2017-01-01

    Krabbe disease is a rare (one in 100,000 births) autosomal recessive condition, usually noticed among children. It causes sphingolipidosis (dysfunctional metabolism of sphingolipids) and leads to fatal degenerative changes affecting the myelin sheath of the nervous system. We report a case of a six-year-old male child who presented with symptoms of muscle spasticity and irritability. Diagnosis of this disease can only be made with clinical suspicion. Laboratory diagnosis includes brain magnetic resonance imaging (MRI), magnetic resonance (MR) spectroscopy, biochemical analysis of cerebrospinal fluid, and genetic analysis for detecting mutation in genes coding for galactosyl cerebroside (GALC). We report a case of late infantile Krabbe disease.

  17. Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Marta Pajares

    2017-04-01

    Full Text Available Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2-like 2. NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.

  18. A Single Neonatal Exposure to BMAA in a Rat Model Produces Neuropathology Consistent with Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Laura Louise Scott

    2017-12-01

    Full Text Available Although cyanobacterial β-N-methylamino-l-alanine (BMAA has been implicated in the development of Alzheimer’s Disease (AD, Parkinson’s Disease (PD and Amyotrophic Lateral Sclerosis (ALS, no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present here a neonatal BMAA model that causes β-amyloid deposition, neurofibrillary tangles of hyper-phosphorylated tau, TDP-43 inclusions, Lewy bodies, microbleeds and microgliosis as well as severe neuronal loss in the hippocampus, striatum, substantia nigra pars compacta, and ventral horn of the spinal cord in rats following a single BMAA exposure. We also report here that BMAA exposure on particularly PND3, but also PND4 and 5, the critical period of neurogenesis in the rodent brain, is substantially more toxic than exposure to BMAA on G14, PND6, 7 and 10 which suggests that BMAA could potentially interfere with neonatal neurogenesis in rats. The observed selective toxicity of BMAA during neurogenesis and, in particular, the observed pattern of neuronal loss observed in BMAA-exposed rats suggest that BMAA elicits its effect by altering dopamine and/or serotonin signaling in rats.

  19. SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling.

    Science.gov (United States)

    Shahid, Mohammad; Shahzad Cheema, Muhammad; Klenner, Alexander; Younesi, Erfan; Hofmann-Apitius, Martin

    2013-03-01

    Systems pharmacological modeling of drug mode of action for the next generation of multitarget drugs may open new routes for drug design and discovery. Computational methods are widely used in this context amongst which support vector machines (SVM) have proven successful in addressing the challenge of classifying drugs with similar features. We have applied a variety of such SVM-based approaches, namely SVM-based recursive feature elimination (SVM-RFE). We use the approach to predict the pharmacological properties of drugs widely used against complex neurodegenerative disorders (NDD) and to build an in-silico computational model for the binary classification of NDD drugs from other drugs. Application of an SVM-RFE model to a set of drugs successfully classified NDD drugs from non-NDD drugs and resulted in overall accuracy of ∼80 % with 10 fold cross validation using 40 top ranked molecular descriptors selected out of total 314 descriptors. Moreover, SVM-RFE method outperformed linear discriminant analysis (LDA) based feature selection and classification. The model reduced the multidimensional descriptors space of drugs dramatically and predicted NDD drugs with high accuracy, while avoiding over fitting. Based on these results, NDD-specific focused libraries of drug-like compounds can be designed and existing NDD-specific drugs can be characterized by a well-characterized set of molecular descriptors. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications

    Science.gov (United States)

    Santamaría-García, Hernando; Santangelo, Gabriella

    2018-01-01

    Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM), emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs), most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients' management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD), or may emerge during the disease course as critical aspects, such as for Parkinson's and Alzheimer's diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients' well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits. PMID:29854017

  1. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?

    Science.gov (United States)

    Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

    2009-12-01

    While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

  2. Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats

    Directory of Open Access Journals (Sweden)

    Jiro Kasahara

    2016-01-01

    Full Text Available Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine. The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

  3. Neurodegenerative properties of chronic pain: cognitive decline in patients with chronic pancreatitis.

    Directory of Open Access Journals (Sweden)

    Marijtje L A Jongsma

    Full Text Available Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance, use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains (psychomotor performance, memory, executive functions were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients.

  4. Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

    Science.gov (United States)

    Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

    2017-03-01

    Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

  5. The lysosomal storage disease continuum with ageing-related neurodegenerative disease.

    Science.gov (United States)

    Lloyd-Evans, Emyr; Haslett, Luke J

    2016-12-01

    Lysosomal storage diseases and diseases of ageing share many features both at the physiological level and with respect to the mechanisms that underlie disease pathogenesis. Although the exact pathophysiology is not exactly the same, it is astounding how many similar pathways are altered in all of these diseases. The aim of this review is to provide a summary of the shared disease mechanisms, outlining the similarities and differences and how genetics, insight into rare diseases and functional research has changed our perspective on the causes underlying common diseases of ageing. The lysosome should no longer be considered as just the stomach of the cell or as a suicide bag, it has an emerging role in cellular signalling, nutrient sensing and recycling. The lysosome is of fundamental importance in the pathophysiology of diseases of ageing and by comparing against the LSDs we not only identify common pathways but also therapeutic targets so that ultimately more effective treatments can be developed for all neurodegenerative diseases. Copyright © 2016. Published by Elsevier B.V.

  6. Non-Clinical Models for Neurodegenerative Diseases: Therapeutic Approach and Drug Validation in Animal Models

    Directory of Open Access Journals (Sweden)

    Caridad Ivette Fernandez

    2017-12-01

    Full Text Available In 2016, 19.8% of the Cuban population was aged 60 or over. As a result, age-associated degenerative diseases and other diseases have become priority targets from a prophylactic, diagnostic and therapeutic perspective. As a result, the Cuban biomedical scientific community has addressed its basic, preclinical and epidemiological research in order to rise up to the challenge. A firm step in this direction has been the international congress “State of the art in non-clinical models for neurodegenerative diseases” which has brought together preclinical and clinical researchers, technicians and regulatory staff members from different countries to review the state of the art in neurodegenerations, find unifying ideas, objectives and collaborations or partnership. The objective is to expose the perspectives of new biotechnological products from Cuba and other countries from the diagnostic, therapeutic and neuroprotective point of view. It is crucial, therefore, that the irreplaceable role of laboratory animals in achieving these objectives is understood but they must be used in rational, adequate and ethical manner. We expose the current development trends in this field, being of common interest to the work directed to the search for potential drugs, diagnostic tools and the promotion of changes in lifestyle as a preventive projection.

  7. Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Alexei Vazquez

    Full Text Available The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

  8. Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

    International Nuclear Information System (INIS)

    Yoshida, S.

    1999-01-01

    Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

  9. Quinoline Fluorescent Probes for Zinc - from Diagnostic to Therapeutic Molecules in Treating Neurodegenerative Diseases.

    Science.gov (United States)

    Czaplinska, Barbara; Spaczynska, Ewelina; Musiol, Robert

    2018-01-01

    Fluorescent compounds had gained strong attention due to their wide and appealing applications. Microscopic techniques and visualization are good examples among others. Introduction of fluorescent dyes into microbiology opens the possibility to observe tissues, organisms or organelle with exceptional sensitivity and resolution. Probes for detection of biologically relevant metals as zinc, iron or copper seems to be particularly important for drug design and pharmaceutical sciences. Quinoline derivatives are well known for their good metal affinity and wide spectrum of biological activity. In this regard, molecular sensors built on this scaffold may be useful not only as analytical but also as therapeutic agents. In the present review, application of quinoline moiety in designing of novel fluorescent probes for zinc is presented and discussed. Zinc cations are relevant for vast majority of processes and recently attract a great deal of attention for their role in neurodegenerative diseases. Compounds interacting with Zn2+ may be used for early diagnosis of such disorders, for example the Alzheimer disease. Quinoline-based zinc probes may exert some beneficial role in organism acting as theranostic agents. First preliminary drugs for Alzheimer therapy that are based on quinoline moiety are good example of this trend. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-12-01

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

  11. Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, S. [Department of Neurology, Wakayama Medical College, Wakayama (Japan)

    1999-07-01

    Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

  12. Chronic Neurodegenerative Illnesses and Epilepsy in Danish Adventists and Baptists: A Nationwide Cohort Study.

    Science.gov (United States)

    Thygesen, Lau Caspar; Gimsing, Louise NØrreslet; Bautz, Andrea; Hvidt, Niels Christian; Johansen, Christoffer

    2017-01-01

    Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exists. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco. We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer's disease, Parkinson's disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age. We compared hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence ratios (SIR) stratified by sex, age, and calendar time were calculated. SIR of dementia or Alzheimer's disease was significantly decreased for members of both communities (SDA, 0.78; 95% CI, 0.67-#x2013;0.90 and Baptists, 0.59; 0.47-#x2013;0.73). The SIRs of Parkinson's disease and epilepsy were not significantly different compared to the general population. We observe reduced incidence for dementia or Alzheimer's disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system.

  13. Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Matthew J Haney

    Full Text Available The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD. This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.

  14. An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders.

    Science.gov (United States)

    Yang, Yang; Jiang, Shuai; Yan, Juanjuan; Li, Yue; Xin, Zhenlong; Lin, Yan; Qu, Yan

    2015-02-01

    Recently, growing evidence has demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases.

    Science.gov (United States)

    Rydbirk, Rasmus; Folke, Jonas; Winge, Kristian; Aznar, Susana; Pakkenberg, Bente; Brudek, Tomasz

    2016-11-17

    Evaluation of gene expression levels by reverse transcription quantitative real-time PCR (RT-qPCR) has for many years been the favourite approach for discovering disease-associated alterations. Normalization of results to stably expressed reference genes (RGs) is pivotal to obtain reliable results. This is especially important in relation to neurodegenerative diseases where disease-related structural changes may affect the most commonly used RGs. We analysed 15 candidate RGs in 98 brain samples from two brain regions from Alzheimer's disease (AD), Parkinson's disease (PD), Multiple System Atrophy, and Progressive Supranuclear Palsy patients. Using RefFinder, a web-based tool for evaluating RG stability, we identified the most stable RGs to be UBE2D2, CYC1, and RPL13 which we recommend for future RT-qPCR studies on human brain tissue from these patients. None of the investigated genes were affected by experimental variables such as RIN, PMI, or age. Findings were further validated by expression analyses of a target gene GSK3B, known to be affected by AD and PD. We obtained high variations in GSK3B levels when contrasting the results using different sets of common RG underlining the importance of a priori validation of RGs for RT-qPCR studies.

  16. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

    Science.gov (United States)

    Felder, Christian C; Goldsmith, Paul J; Jackson, Kimberley; Sanger, Helen E; Evans, David A; Mogg, Adrian J; Broad, Lisa M

    2018-01-25

    The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. Copyright © 2018. Published by Elsevier Ltd.

  17. Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Adriana Covarrubias-Pinto

    2015-11-01

    Full Text Available Ascorbic acid is a key antioxidant of the Central Nervous System (CNS. Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders.

  18. Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Foteini Christidi

    2018-01-01

    Full Text Available Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM, emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs, most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients’ management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD, or may emerge during the disease course as critical aspects, such as for Parkinson’s and Alzheimer’s diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients’ well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits.

  19. [Cost of therapy for neurodegenerative diseases. Applying an activity-based costing system].

    Science.gov (United States)

    Sánchez-Rebull, María-Victoria; Terceño Gómez, Antonio; Travé Bautista, Angeles

    2013-01-01

    To apply the activity based costing (ABC) model to calculate the cost of therapy for neurodegenerative disorders in order to improve hospital management and allocate resources more efficiently. We used the case study method in the Francolí long-term care day center. We applied all phases of an ABC system to quantify the cost of the activities developed in the center. We identified 60 activities; the information was collected in June 2009. The ABC system allowed us to calculate the average cost per patient with respect to the therapies received. The most costly and commonly applied technique was psycho-stimulation therapy. Focusing on this therapy and on others related to the admissions process could lead to significant cost savings. ABC costing is a viable method for costing activities and therapies in long-term day care centers because it can be adapted to their structure and standard practice. This type of costing allows the costs of each activity and therapy, or combination of therapies, to be determined and aids measures to improve management. Copyright © 2012 SESPAS. Published by Elsevier Espana. All rights reserved.

  20. Deep Machine Learning Application to the Detection of Preclinical Neurodegenerative Diseases of Aging

    Directory of Open Access Journals (Sweden)

    Mathew J. Summers

    2017-12-01

    Full Text Available Artificial intelligence (AI deep learning protocols offer solutions to complex data processing and analysis. Increasingly these solutions are being applied in the healthcare field, most commonly in processing complex medical imaging data used for diagnosis. Current models apply AI to screening populations of patients for markers of disease and report detection accuracy rates exceeding those of human data screening. In this paper, we explore an alternate model for AI deployment, that of monitoring and analysing an individual’s level of function over time. In adopting this approach, we propose that AI may provide highly accurate and reliable detection of preclinical disease states associated with aging-related neurodegenerative diseases. One of the key challenges facing clinical detection of preclinical phases of diseases such as dementia is the high degree of inter-individual variability in aging-related changes to cognitive function. AI based monitoring of an individual over time offers the potential for the early detection of change in function for the individual, rather than relying on comparing the individual’s performance to population norms. We explore an approach to developing AI platforms for individual monitoring and preclinical disease detection and examine the potential benefits to the stakeholders in this technological development.

  1. Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders.

    Science.gov (United States)

    Kos, Claire; van Tol, Marie-José; Marsman, Jan-Bernard C; Knegtering, Henderikus; Aleman, André

    2016-10-01

    Apathy can be described as a loss of goal-directed purposeful behavior and is common in a variety of neurological and psychiatric disorders. Although previous studies investigated associations between abnormal brain functioning and apathy, it is unclear whether the neural basis of apathy is similar across different pathological conditions. The purpose of this systematic review was to provide an extensive overview of the neuroimaging literature on apathy including studies of various patient populations, and evaluate whether the current state of affairs suggest disorder specific or shared neural correlates of apathy. Results suggest that abnormalities within fronto-striatal circuits are most consistently associated with apathy across the different pathological conditions. Of note, abnormalities within the inferior parietal cortex were also linked to apathy, a region previously not included in neuroanatomical models of apathy. The variance in brain regions implicated in apathy may suggest that different routes towards apathy are possible. Future research should investigate possible alterations in different processes underlying goal-directed behavior, ranging from intention and goal-selection to action planning and execution. Copyright © 2016. Published by Elsevier Ltd.

  2. Tools for assessing mitochondrial dynamics in mouse tissues and neurodegenerative models

    Science.gov (United States)

    Pham, Anh H.

    Mitochondria are dynamic organelles that undergo membrane fusion and fission and transport. The dynamic properties of mitochondria are important for regulating mitochondrial function. Defects in mitochondrial dynamics are linked neurodegenerative diseases and affect the development of many tissues. To investigate the role of mitochondrial dynamics in diseases, versatile tools are needed to explore the physiology of these dynamic organelles in multiple tissues. Current tools for monitoring mitochondrial dynamics have been limited to studies in cell culture, which may be inadequate model systems for exploring the network of tissues. Here, we have generated mouse models for monitoring mitochondrial dynamics in a broad spectrum of tissues and cell types. The Photo-Activatable Mitochondrial (PhAM floxed) line enables Cre-inducible expression of a mitochondrial targeted photoconvertible protein, Dendra2 (mito-Dendra2). In the PhAMexcised line, mito-Dendra2 is ubiquitously expressed to facilitate broad analysis of mitochondria at various developmental processes. We have utilized these models to study mitochondrial dynamics in the nigrostriatal circuit of Parkinson's disease (PD) and in the development of skeletal muscles. Increasing evidences implicate aberrant regulation of mitochondrial fusion and fission in models of PD. To assess the function of mitochondrial dynamics in the nigrostriatal circuit, we utilized transgenic techniques to abrogate mitochondrial fusion. We show that deletion of the Mfn2 leads to the degeneration of dopaminergic neurons and Parkinson's-like features in mice. To elucidate the dynamic properties of mitochondria during muscle development, we established a platform for examining mitochondrial compartmentalization in skeletal muscles. This model system may yield clues to the role of mitochondrial dynamics in mitochondrial myopathies.

  3. Current status of treating neurodegenerative disease with induced pluripotent stem cells.

    Science.gov (United States)

    Pen, A E; Jensen, U B

    2017-01-01

    Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Neuro degenerative diseases: clinical concerns; Les maladies neuro-degeneratives: problemes cliniques

    Energy Technology Data Exchange (ETDEWEB)

    Ibanez, V. [Hopitaux Universitaires de Geneve (HUG), Unite de Neuroimagerie, Dept. de Psychiatrie (Switzerland)

    2005-04-15

    Idiopathic Parkinson's disease (PD) and Alzheimer's disease (AD) are the main neuro-degenerative diseases (NDDs) seen clinically. They share some common clinical symptoms and neuro-pathological findings. The increase of life expectancy in the developed countries will inevitably contribute to enhance the prevalence of these diseases. Behavioral disorders, common in NDDs, will produce major care management challenges. Idiopathic Parkinson's disease corresponds to a histopathological diagnosis, based on the observation of a de-pigmentation and a neuronal loss in the substantia nigra, as well as on the presence of intra-neuronal inclusion bodies. AD is insidious with slowly progressive dementia in which the decline in memory constitutes the main complaint. The diagnosis of definite AD requires the presence of clinical criteria as well as the histopathological confirmation of brain lesions. The two main lesions are the presence of senile plaques and neuro-fibrillary tangles. Positron emission tomography (PET) explores cerebral metabolism and neurotransmitter kinetics in NDDs using principally [{sup 18}F]-deoxyglucose and [{sup 18}F]-dopa. Nigrostriatal dopaminergic function is altered in PD, as evidenced by the low uptake of [{sup 18}F]-dopa in the posterior putamen as compared to anterior putamen and caudate nucleus. In contrast, [{sup 18}F]-dopa uptake is equally depressed in all striatal structures in progressive supra-nuclear palsy. Regional glucose metabolism at rest is preserved in elderly once cerebral atrophy is taken into account. On the contrary, glucose metabolism is globally reduced in AD, with marked decrease in the parietal and temporal regions. PET has proved to be useful to study in vivo neurochemical processes in patients suffering from NDDs. The potential of this approach is still largely unexploited, and depends on new ligand production to establish early diagnosis and treatment follow-up. (author)

  5. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

    Science.gov (United States)

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-02-04

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

  6. Stab injury and device implantation within the brain results in inversely multiphasic neuroinflammatory and neurodegenerative responses

    Science.gov (United States)

    Potter, Kelsey A.; Buck, Amy C.; Self, Wade K.; Capadona, Jeffrey R.

    2012-08-01

    An estimated 25 million people in the US alone rely on implanted medical devices, ˜2.5 million implanted within the nervous system. Even though many devices perform adequately for years, the host response to medical devices often severely limits tissue integration and long-term performance. This host response is believed to be particularly limiting in the case of intracortical microelectrodes, where it has been shown that glial cell encapsulation and localized neuronal cell loss accompany intracortical microelectrode implantation. Since neuronal ensembles must be within ˜50 µm of the electrode to obtain neuronal spikes and local field potentials, developing a better understanding of the molecular and cellular environment at the device-tissue interface has been the subject of significant research. Unfortunately, immunohistochemical studies of scar maturation in correlation to device function have been inconclusive. Therefore, here we present a detailed quantitative study of the cellular events and the stability of the blood-brain barrier (BBB) following intracortical microelectrode implantation and cortical stab injury in a chronic survival model. We found two distinctly inverse multiphasic profiles for neuronal survival in device-implanted tissue compared to stab-injured animals. For chronically implanted animals, we observed a biphasic paradigm between blood-derived/trauma-induced and CNS-derived inflammatory markers driving neurodegeneration at the interface. In contrast, stab injured animals demonstrated a CNS-mediated neurodegenerative environment. Collectively these data provide valuable insight to the possibility of multiple roles of chronic neuroinflammatory events on BBB disruption and localized neurodegeneration, while also suggesting the importance to consider multiphasic neuroinflammatory kinetics in the design of therapeutic strategies for stabilizing neural interfaces.

  7. Neuroimaging Studies of Essential Tremor: How Well Do These Studies Support/Refute the Neurodegenerative Hypothesis?

    Directory of Open Access Journals (Sweden)

    Elan D. Louis

    2014-05-01

    Full Text Available Background: Tissue‐based research has recently led to a new patho‐mechanistic model of essential tremor (ET—the cerebellar degenerative model. We are not aware of a study that has reviewed the current neuroimaging evidence, focusing on whether the studies support or refute the neurodegenerative hypothesis of ET. This was our aim.Methods: References for this review were identified by searches of PubMed (1966 to February 2014.Results: Several neuroimaging methods have been used to study ET, most of them based on magnetic resonance imaging (MRI. The methods most specific to address the question of neurodegeneration are MRI‐based volumetry, magnetic resonance spectroscopy, and diffusion‐weighted imaging. Studies using each of these methods provide support for the presence of cerebellar degeneration in ET, finding reduced cerebellar brain volumes, consistent decreases in cerebellar N‐acetylaspartate, and increased mean diffusivity. Other neuroimaging techniques, such as functional MRI and positron emission tomography (PET are less specific, but still sensitive to potential neurodegeneration. These techniques are used for measuring a variety of brain functions and their impairment. Studies using these modalities also largely support cerebellar neuronal impairment. In particular, changes in 11C‐flumazenil binding in PET studies and changes in iron deposition in an MRI study provide evidence along these lines. The composite data point to neuronal impairment and likely neuronal degeneration in ET.Discussion: Recent years have seen a marked increase in the number of imaging studies of ET. As a whole, the combined data provide support for the presence of cerebellar neuronal degeneration in this disease.

  8. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

    Directory of Open Access Journals (Sweden)

    Irene López González

    2016-02-01

    Full Text Available Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD and sporadic Parkinson’s disease (sPD. Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD subtypes MM1 and VV2, Pick’s disease (PiD, progressive supranuclear palsy (PSP and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau. The studies have disclosed variable gene regulation which is: (1 disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2 region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3 genotype-dependent as seen considering sCJD MM1 and VV2; and (4 stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

  9. The Human Tripeptide GHK-Cu in Prevention of Oxidative Stress and Degenerative Conditions of Aging: Implications for Cognitive Health

    Directory of Open Access Journals (Sweden)

    Loren Pickart

    2012-01-01

    Full Text Available Oxidative stress, disrupted copper homeostasis, and neuroinflammation due to overproduction of proinflammatory cytokines are considered leading causative factors in development of age-associated neurodegenerative conditions. Recently, a new mechanism of aging—detrimental epigenetic modifications—has emerged. Thus, compounds that possess antioxidant, anti-inflammatory activity as well as compounds capable of restoring copper balance and proper gene functioning may be able to prevent age-associated cognitive decline and ward off many common neurodegenerative conditions. The aim of this paper is to bring attention to a compound with a long history of safe use in wound healing and antiaging skin care. The human tripeptide GHK was discovered in 1973 as an activity in human albumin that caused old human liver tissue to synthesize proteins like younger tissue. It has high affinity for copper ions and easily forms a copper complex or GHK-Cu. In addition, GHK possesses a plethora of other regenerative and protective actions including antioxidant, anti-inflammatory, and wound healing properties. Recent studies revealed its ability to up- and downregulate a large number of human genes including those that are critical for neuronal development and maintenance. We propose GHK tripeptide as a possible therapeutic agent against age-associated neurodegeneration and cognitive decline.

  10. Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools

    OpenAIRE

    Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Fl?via; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andr?ia; Gon?alves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, M?rcia

    2015-01-01

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for...

  11. Aquatic conditions

    Science.gov (United States)

    Warren E. Heilman

    1999-01-01

    This publication provides citizens, private and public organizations, scientists, and others with information about the aquatic conditions in or near national forests in the Ozark-Ouachita Highlands: the Mark Twain in Missouri, the Ouachita in Arkansas and Oklahoma, and the Ozark-St. Francis National Forests in Arkansas. This report includes water quality analyses...

  12. Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

    Czech Academy of Sciences Publication Activity Database

    Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 9-10 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

  13. Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha.

    Science.gov (United States)

    Ven Murthy, M R; Ranjekar, Prabhakar K; Ramassamy, Charles; Deshpande, Manasi

    2010-09-01

    Ayurveda is a Sanskrit word, which means "the scripture for longevity". It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul [1]. Ayurveda dates back to the period of the Indus Valley civilization (about 3000 B.C) and has been passed on through generations of oral tradition, like the other four sacred texts (Rigveda, Yajurveda, Samaveda and Atharvanaveda) which were composed between 12(th) and 7(th) century B.C [2, 3]. References to the herbal medicines of Ayurveda are found in all of the other four Vedas, suggesting that Ayurveda predates the other Vedas by at least several centuries. It was already in full practice at the time of Buddha (6(th) century B.C) and had produced two of the greatest physicians of ancient India, Charaka and Shushrutha who composed the basic texts of their trade, the Samhitas. By this time, ayurveda had already developed eight different subspecialties of medical treatment, named Ashtanga, which included surgery, internal medicine, ENT, pediatrics, toxicology, health and longevity, and spiritual healing [4]. Ayurvedic medicine was mainly composed of herbal preparations which were occasionally combined with different levels of other compounds, as supplements [5]. In the Ayurvedic system, the herbs used for medicinal purposes are classed as brain tonics or rejuvenators. Among the plants most often used in Ayurveda are, in the descending order of importance: (a) Ashwagandha, (b) Brahmi, (c) Jatamansi, (d) Jyotishmati, (e) Mandukparni, (f) Shankhapushpi, and (g) Vacha. The general appearance of these seven plants is shown in Fig.1. Their corresponding Latin names, as employed in current scientific literature, the botanical families that each of them belongs to, their

  14. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

    Science.gov (United States)

    Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

    Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. The impact of patient and public involvement in the work of the Dementias & Neurodegenerative Diseases Research Network (DeNDRoN): case studies.

    Science.gov (United States)

    Iliffe, Steve; McGrath, Terry; Mitchell, Douglas

    2013-12-01

    (i) To describe patient and public involvement (PPI) in a network promoting research in dementia and neurodegenerative diseases, in terms of activity at the different stages of the research cycle and within the different levels of the research network. (ii) To use case studies to try and answer the question: what benefits (if any) does PPI in research bring to the research process? PPI in health research is a central part of government policy, but the evidence base underpinning it needs strengthening. PPI allows exploration of feasibility, acceptability and relevance of hypotheses, assists in the precise definition of research questions and increases accrual to studies. However, the measurement of outcomes is methodologically difficult, because the impact of lay researchers may occur through team interactions and be difficult to untangle from the efforts of professional researchers. Opportunities for PPI in rapidly progressive diseases may be limited, and involvement of people with marked cognitive impairment is particularly challenging. (i) Description of PPI within the DeNDRoN network. (ii) Case studies of three research projects which asked for extra help from centrally organized PPI. PPI in research projects on the DeNDRoN portfolio may function at different levels, occurring at project, local research network and national level. Case studies of three research projects show different roles for PPI in research and different functions for centrally organized PPI, including contribution to remedial action in studies that are not recruiting to target, solving problems because of the complexity and sensitivity of the research topic, and linking researchers to PPI resources. The case studies suggest that centrally organized PPI can have 'diagnostic' and remedial functions in studies that are struggling to recruit and serve as reinforcement for study-level PPI in the complex and sensitive research topics that are typical in neurodegenerative diseases research. PPI may

  16. p75 neurotrophin receptor positive dental pulp stem cells: new hope for patients with neurodegenerative disease and neural injury.

    Science.gov (United States)

    Dai, Jie-wen; Yuan, Hao; Shen, Shun-yao; Lu, Jing-ting; Zhu, Xiao-fang; Yang, Tong; Zhang, Jiang-fei; Shen, Guo-fang

    2013-08-01

    Neurodegenerative diseases and neural injury are 2 of the most feared disorders that afflict humankind by leading to permanent paralysis and loss of sensation. Cell based treatment for these diseases had gained special interest in recent years. Previous studies showed that dental pulp stem cells (DPSCs) could differentiate toward functionally active neurons both in vitro and in vivo, and could promote neuranagenesis through both cell-autonomous and paracrine neuroregenerative activities. Some of these neuroregenerative activities were unique to tooth-derived stem cells and superior to bone marrow stromal cells. However, DPSCs used in most of these studies were mixed and unfractionated dental pulp cells that contain several types of cells, and most were fibroblast cells while just contain a small portion of DPSCs. Thus, there might be weaker ability of neuranagenesis and more side effects from the fibroblast cells that cannot differentiate into neural cells. p75 neurotrophin receptor (p75NTR) positive DPSCs subpopulation was derived from migrating cranial neural crest cells and had been isolated from DPSCs, which had capacity of differentiation into neurons and repairing neural system. In this article, we hypothesize that p75NTR positive DPSCs simultaneously have greater propensity for neuronal differentiation and fewer side effects from fibroblast, and in vivo transptantation of autologous p75NTR positive DPSCs is a novel method for neuranagenesis. This will bring great hope to patients with neurodegenerative disease and neural injury.

  17. The Mircen project, neuro-degenerative disease: mechanisms, therapeutics and imaging research Unit URA Cea Cnrs 2210

    International Nuclear Information System (INIS)

    Hantraye, Ph.

    2006-01-01

    During the post-genomic era, significant advances in our understanding of the molecular basis of disease have been made. The power of functional and molecular imaging in translating this knowledge into effective therapy is now being more and more recognized. Thus, molecular imaging plays a vital role in the early identification of disease-related molecular markers, in the development of molecular-targeted therapies, and in monitoring phenotypic response to therapy both in experimental animals and in human patients. In this context, MIRCen (acronym for Molecular Imaging Research Center ) provides a comprehensive resource available to empower basic, translational, and clinical research through the application of imaging and drug, cell, and gene based technologies. The MIR center will be dedicated to the development of pre-clinical trials for the treatment of various seriously debilitating diseases such as neuro-degenerative diseases, cardiac and hepatic disorders, and infectious diseases (AIDS). Despite the fact that many of these pathologies are still incurable, recent advances in drug, cell and gene therapy point to the feasibility of new therapeutic approaches. The long term goals of MIRCen are therefore to develop and validate: - pertinent animal models for neuro-degenerative, hepatic, cardiac and infectious diseases in rodents as well as non-human primates, - novel technologies for in vivo sensing and imaging of disease-related molecular events,- drug, gene and cell based palliative and or curative therapeutic strategies aiming at protecting and /or restoring damaged or lost functions. (author)

  18. Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases

    International Nuclear Information System (INIS)

    Iacopino, A.M.; Christakos, S.

    1990-01-01

    The present studies establish that there are specific, significant decreases in the neuronal calcium-binding protein (28-kDa calbindin-D) gene expression in aging and in neurodegenerative diseases. The specificity of the changes observed in calbindin mRNA levels was tested by reprobing blots with calmodulin, cyclophilin, and B-actin cDNAs. Gross brain regions of the aging rat exhibited specific, significant decreases in calbindin·mRNA and protein levels in the cerebellum, corpus striatum, and brain-stem region but not in the cerebral cortex or hippocampus. Discrete areas of the aging human brain exhibited significant decreases in calbindin protein and mRNA in the cerebellum, corpus striatum, and nucleus basalis but not in the neocortex, hippocampus, amygdala, locus ceruleus, or nucleus raphe dorsalis. Comparison of diseased human brain tissue with age- and sex-matched controls yielded significant decreases calbindin protein and mRNA in the substantia nigra (Parkinson disease), in the corpus striatum (Huntington disease), in the nucleus basalis (Alzheimer disease), and in the hippocampus and nucleus raphe dorsalis (Parkinson, Huntington, and Alzheimer diseases) but not in the cerebellum, neocortex, amygdala, or locus ceruleus. These findings suggest that decreased calbindin gene expression may lead to a failure of calcium buffering or intraneuronal calcium homeostasis, which contributes to calcium-mediated cytotoxic events during aging and in the pathogenesis of neurodegenerative diseases

  19. The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells

    Directory of Open Access Journals (Sweden)

    Junjun Ni

    2017-01-01

    Full Text Available Oxidative stress and synapse dysfunction are the major neurodegenerative damage correlated to cognitive impairment in Alzheimer’s disease (AD. We have found that Brazilian green propolis (propolis improves the cognitive functions of mild cognitive impairment patients living at high altitude; however, mechanism underlying the effects of propolis is unknown. In the present study, we investigated the effects of propolis on oxidative stress, expression of brain-derived neurotrophic factor (BDNF, and activity-regulated cytoskeleton-associated protein (Arc, the critical factors of synapse efficacy, using human neuroblastoma SH-SY5Y cells. Pretreatment with propolis significantly ameliorated the hydrogen peroxide- (H2O2- induced cytotoxicity in SH-SY5Y cells. Furthermore, propolis significantly reduced the H2O2-generated reactive oxygen species (ROS derived from mitochondria and 8-oxo-2′-deoxyguanosine (8-oxo-dG, the DNA oxidative damage marker but significantly reversed the fibrillar β-amyloid and IL-1β-impaired BDNF-induced Arc expression in SH-SY5Y cells. Furthermore, propolis significantly upregulated BDNF mRNA expression in time- and dose-dependent manners. In addition, propolis induced Arc mRNA and protein expression via phosphoinositide-3 kinase (PI3K. These observations strongly suggest that propolis protects from the neurodegenerative damage in neurons through the properties of various antioxidants. The present study provides a potential molecular mechanism of Brazilian green propolis in prevention of cognitive impairment in AD as well as aging.

  20. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

    2016-12-20

    Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

  1. Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

    DEFF Research Database (Denmark)

    Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina

    2014-01-01

    cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND.......6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans......