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Sample records for neurodegenerative disorder caused

  1. [Sleep in neurodegenerative disorders].

    Science.gov (United States)

    Happe, S; Mayer, G

    2006-10-01

    Neurodegenerative disorders are a group of heterogeneous, progressive disorders of varying etiology that affect one or more systems. They occur predominantly at older age, during which the structure and amount of sleep undergo changes. Neurodegenerative processes cause structural changes of the sleep/wake generators in the brainstem which result in disorders such as daytime sleepiness, insomnia, sleep-related movement and breathing disturbances, and disorders of the circadian rhythms. Some sleep disorders manifest years before the onset of neurodegenerative disorders and may serve as predictors. Polysomnography shows sleep fragmentation, tonic or phasic movements of the extremities, alteration of respiratory muscles, reduced slow wave sleep, REM sleep absence or without muscle atonia, increased arousal or wake activity, epileptiform EEG activity, and changes in sleep-related breathing. Very frequently, REM sleep behaviour disorder is associated with neurodegenerative disorders. In this overview we present symptoms, pathophysiology, and polysomnographic findings of sleep disorders in prevalent neurodegenerative disorders.

  2. Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23

    NARCIS (Netherlands)

    Watanabe, Hiroyuki; Mizoguchi, Hirokazu; Verbeek, Dineke S.; Kuzmin, Alexander; Nyberg, Fred; Krishtal, Oleg; Sakurada, Shinobu; Bakalkin, Georgy

    We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both

  3. Sleep disorders in neurodegenerative diseases.

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    Raggi, A; Ferri, R

    2010-11-01

    The aim of this review is to provide data on sleep disturbances in three categories of neurodegenerative disorders: synucleinopathies, tauopathies, and other diseases (this heterogeneous group includes also spinocerebellar degeneration and amyotrophic lateral sclerosis). Analysing and knowing sleep disorders in neurodegenerative diseases may offer important insights into the pathomechanism of some of these diseases and calls attention to the still insufficiently known 'sleep neurology'. The identification of sleep disorders in some neurodegenerative conditions may make their diagnosis easier and earlier; for example, rapid eye movements sleep behaviour disorder may precede any other clinical manifestation of synucleinopathies by more than 10 years. © 2010 The Author(s). Journal compilation © 2010 EFNS.

  4. Endocannabinoid system in neurodegenerative disorders.

    Science.gov (United States)

    Basavarajappa, Balapal S; Shivakumar, Madhu; Joshi, Vikram; Subbanna, Shivakumar

    2017-09-01

    Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs. © 2017 International Society for Neurochemistry.

  5. Neurobiology of sleep disturbances in neurodegenerative disorders.

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    Gagnon, J-F; Petit, D; Latreille, V; Montplaisir, J

    2008-01-01

    This review presents sleep disturbances and their underlying pathophysiology in three categories of neurodegenerative disorders namely tauopathies, synucleinopathies, and Huntington's disease (HD) and prion-related diseases. Sleep abnormalities are a major and early feature of neurodegenerative disorders, especially for synucleinopathies, HD and prion-related diseases, in which the sleep-related brainstem regions are severely altered and impaired sooner than in most of the tauopathies. In synucleinopathies, HD and prion-related diseases, specific sleep disturbances, different from those observed in tauopathies, are considered as core manifestations of the disease and in some cases, as preclinical signs. For this reason, the evaluation of sleep components in these neurodegenerative disorders may be useful to make a diagnosis and to assess the efficacy of pharmacotherapy. Since sleep disruption may occur early in the course of neurodegeneration, sleep disturbance may serve as groundwork to study the efficacy of neuroprotective agents to prevent or delay the development of a full-blown neurodegenerative disorder. The cause of sleep disturbances in neurodegenerative disorders may be attributed to several factors, including age-related modifications, symptoms of the disease, comorbid conditions and the neurodegenerative process itself.

  6. Genetically modified pig models for neurodegenerative disorders.

    Science.gov (United States)

    Holm, Ida E; Alstrup, Aage Kristian Olsen; Luo, Yonglun

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  7. 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.

  8. Using the WHOQOL-DIS to measure quality of life in persons with physical disabilities caused by neurodegenerative disorders.

    Science.gov (United States)

    Lucas-Carrasco, Ramona; Pascual-Sedano, Berta; Galán, Ingrid; Kulisevsky, Jaime; Sastre-Garriga, Jaume; Gómez-Benito, Juana

    2011-01-01

    Neurodegenerative disorders (ND) have a major impact on quality of life (QoL) and place a substantial burden on patients, their families and carers; they are the second leading cause of disability. The objective of this study was to examine QoL in persons with ND. A battery of subjective assessments was used, including the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the World Health Organization Quality of Life - Disability (WHOQOL-DIS). Psychometric properties of the WHOQOL-BREF and WHOQOL-DIS were investigated using classical psychometric methods. Participants (n = 149) were recruited and interviewed at two specialized centers to obtain information on health and disability perceptions, depressive symptoms (Hospital Anxiety and Depression Scale - Depression, HADS-D), Fatigue Assessment Scale (FAS), Satisfaction with Life (SWL), generic QoL (WHOQOL-BREF, WHOQOL-DIS), specific QoL (Multiple Sclerosis Impact Scale, MSIS-29; Parkinson's Disease Questionnaire, PDQ-39) and sociodemographics. Internal consistency was acceptable, except for the WHOQOL-BREF social (0.67). Associations, using Pearson's and Spearman's rho correlations, were confirmed between WHOQOL-BREF and WHOQOL-DIS with MSIS-29, PDQ-39, HADS-D, FAS and SWL. Regarding 'known group' differences, Student's t tests showed that WHOQOL-BREF and WHOQOL-DIS scores significantly discriminated between depressed and nondepressed and those perceiving a more severe impact of the disability on their lives. This study is the first to report on use of the WHOQOL-BREF and WHOQOL-DIS in Spanish persons with ND; they are promising useful tools in assessing persons with ND through the continuum of care, as they include important dimensions commonly omitted from other QoL measures. Copyright © 2010 S. Karger AG, Basel.

  9. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.

    NARCIS (Netherlands)

    Steinfeld, R.; Grapp, M.; Kraetzner, R.; Dreha-Kulaczewski, S.; Helms, G.; Dechent, P.; Wevers, R.A.; Grosso, S.; Gartner, J.

    2009-01-01

    Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited

  10. Sleep in Neurodevelopmental and Neurodegenerative Disorders.

    Science.gov (United States)

    Kotagal, Suresh

    2015-06-01

    There is a close relationship between sleep and childhood neurodevelopmental/neurodegenerative disorders. Understanding the sleep issues may provide greater insight into pathophysiology and treatment of these disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Sleep-disordered breathing in neurodegenerative diseases.

    Science.gov (United States)

    Gaig, Carles; Iranzo, Alex

    2012-04-01

    Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available.

  12. REM behaviour disorder and neurodegenerative diseases.

    Science.gov (United States)

    Zanigni, Stefano; Calandra-Buonaura, Giovanna; Grimaldi, Daniela; Cortelli, Pietro

    2011-12-01

    Rapid-eye movement (REM) sleep behaviour disorder (RBD) is an REM sleep parasomnia characterized by enactment of dream content during REM sleep associated with loss of muscle atonia. RBD can be either idiopathic or secondary to drugs or other diseases. The best recognized association is with neurodegenerative diseases, namely alpha-synucleinopathies. RBD may represent the first feature of neurodegeneration and can be considered an early marker of these disorders. This review describes the main clinical, pathogenetic, and therapeutic features of RBD, pointing to its association with neurodegenerative diseases and emphasizing the clinical and prognostic implications. Copyright © 2011 Elsevier B.V. All rights reserved.

  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. 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.

  15. 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.

  16. Potential future neuroprotective therapies for neurodegenerative disorders and stroke.

    Science.gov (United States)

    Tarawneh, Rawan; Galvin, James E

    2010-02-01

    The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease each have distinct clinical symptoms and pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, inflammation, apoptosis, and mitochondrial injury that contribute to neuronal loss. Although cerebrovascular disease has different causes from the neurodegenerative disorders, many of the same common disease mechanisms come into play following a stroke. Novel therapies that target each of these mechanisms may be effective in decreasing the risk of disease, abating symptoms, or slowing down their progression. Although most of these therapies are experimental, and require further investigation, a few seem to offer promise.

  17. Circadian clock disruption in neurodegenerative diseases: Cause and effect?

    Directory of Open Access Journals (Sweden)

    Erik Steven Musiek

    2015-02-01

    Full Text Available Disturbance of the circadian system, manifested as disrupted daily rhythms of physiologic parameters such as sleep, activity, and hormone secretion, has long been observed as a symptom of several neurodegenerative diseases, including Alzheimer Disease. Circadian abnormalities have generally been considered consequences of the neurodegeneration. Recent evidence suggests, however, that circadian disruption might actually contribute to the neurodegenerative process, and thus might be a modifiable cause of neural injury. Herein we will review the evidence implicating circadian rhythms disturbances and clock gene dysfunction in neurodegeneration, with an emphasis on future research directions and potential therapeutic implications for neurodegenerative diseases.

  18. 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

  19. Idiopathic REM sleep behavior disorder as a long-term predictor of neurodegenerative disorders.

    Science.gov (United States)

    Fulda, Stephany

    2011-12-01

    REM sleep behavior disorder (RBD) is a parasomnia characterized by dream-enacting behavior and loss of muscle atonia during REM sleep. Idiopathic RBD occurs in the absence of any neurological disease or other possible cause, is male-predominant and its clinical course is generally chronic progressive. Secondary RBD may be related to neurodegenerative disorders such as multiple system atrophy, Parkinson's disease and Lewy body dementia. Recent long-term prospective studies have shown that 30% to 65% of patients with idiopathic RBD will eventually develop a neurodegenerative disorder with the rate of emergence depending on the length of the follow-up period. RBD may therefore be one of the earliest signs of and/or a long-term predictor for neurodegenerative disorders. Because RBD antecedes the development of these disorders by several years or decades, its recognition may enable the delay or prevention of neurodegenerative disorders through the early application of neuroprotective or disease-modifying therapies in the future.

  20. Transmission of Neurodegenerative Disorders Through Blood Transfusion

    DEFF Research Database (Denmark)

    Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus

    2016-01-01

    : Multivariable Cox regression models were used to estimate hazard ratios for dementia of any type, Alzheimer disease, and Parkinson disease in patients receiving blood transfusions from donors who were later diagnosed with any of these diseases versus patients who received blood from healthy donors. Whether...... excess occurrence of neurodegenerative disease occurred among recipients of blood from a subset of donors was also investigated. As a positive control, transmission of chronic hepatitis before and after implementation of hepatitis C virus screening was assessed. RESULTS: Among included patients, 2.......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...

  1. Recent Patent Advances For Neurodegenerative Disorders And Its Treatment.

    Science.gov (United States)

    Kumar, Bhavna; Sharma, Deepika

    2017-10-10

    Neurodegenerative disorders are one of the common diseases that affect our society with tremendous medical and financial burdens. As a whole, neurodegeneration affects individuals of all ages, but becomes increasingly frequent with age, coming to affect a very large share of our elderly population which is severely affecting the patient, caregivers, and enormously increasing the financial burden of the nation. These diseases share a very complex nature, which often result from combined genetic, environment and pathogenic factors. Various challenges are faced by the scientific community that researches on the pathogenesis and the therapy of neurodegenerative disorder. The review has been analysed for recent patent documents and treatment approaches for neurodegenerative disorders. The study design is based on updating the international and national literatures and an exhaustive patent search and compiling of various patented documents for the treatment of neurodegenerative disorders (EP2282779 A1, US20110229555 A1) to provide information in the state of technological innovation in terms of research and development. In the present review, the authors described various neurodegenerative diseases, there treatment strategies and emphasized on various patented approaches for age-related neurodegenerative disorders such as New therapeutic approaches for treating Alzheimer disease and related disorders through a modulation of cell stress response EP2282779 A1, through combined therapies that modulate angiogenesis US20120058992 A1. The review will attract the interest of academics, researchers, students and pharmaceutical companies in the recent on-going activities in neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. 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:

  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. 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.

  5. Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases.

    Science.gov (United States)

    Trotti, Lynn Marie; Karroum, Elias G

    2016-07-01

    In patients with neurodegenerative diseases, sleep disorders are common; they impair the quality of life for patients and caregivers and are associated with poorer clinical outcomes. Melatonin has circadian, hypnotic, and free radical-scavenging effects, and preclinical data suggest benefits of melatonin on neurodegeneration. However, randomized, controlled trials of melatonin in patients with neurodegenerative diseases have not shown strong effects. Trials in Alzheimer's patients demonstrate a lack of benefit on sleep quantity. Subjective measures of sleep quality are mixed, with possible symptomatic improvements seen only on some measures or at some time points. Benefits on cognition have not been observed across several studies. In Parkinson's patients, there may be minimal benefit on objective sleep measures, but a suggestion of subjective benefit in few, small studies. Effective treatments for the sleep disorders associated with neurodegenerative diseases are urgently needed, but current data are insufficient to establish melatonin as such a treatment.

  6. DNA triplex structures in neurodegenerative disorder, Friedreich's ...

    Indian Academy of Sciences (India)

    2012-06-25

    Jun 25, 2012 ... 3. DNA triplet repeat expansions in human genome. In the beginning of the last decade, expanded DNA-trinucleotide repeats in genes were identified as unstable and responsible for a large number of neurological disorders like FRDA, fragile X syndrome, spinocerebellar ataxia and muscular dystrophy.

  7. Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction

    Science.gov (United States)

    2007-09-01

    TELEPHONE NUMBER (include area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Table of Contents 1 Narrative...neurodegenerative disorders including Wernicke -Korsakoff syndrome (reviewed in Martin et al., 2005). 2. Results At E15.5, Ts16 brains are slightly

  8. 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.

  9. Diabetic retinopathy is a neurodegenerative disorder.

    Science.gov (United States)

    Lynch, Stephanie K; Abràmoff, Michael D

    2017-10-01

    Since 1875, controversy has ensued over whether ocular diabetic complications are primarily vasculopathic or neuropathic in nature. Here, we discuss the historical context by which diabetic retinopathy (DR) came to be considered a primary vasculopathy, in contrast to more recent data suggesting the importance of diabetic retinal neurodegeneration (DRN) as the primary manifestation of ocular diabetic damage. Unsurprisingly, DRN parallels other diabetic complications related to neuropathy. In general, there are three possible relationships between microvascular DR and DRN: i) microvasculopathy causes neurodegeneration; ii) neurodegeneration causes microvasculopathy or iii) they are mutually independent. The authors' group has recently produced experimental data showing that DRN precedes even the earliest manifestations of DR microvasculopathy. In combination with earlier studies showing that focal implicit time delays predicted future development of DR microvasculopathy in the same location, relationships i) and iii) are unlikely. As such, ii) is the most likely relationship: DRN is a cause of DR. Granted, additional studies are needed to confirm this hypothesis and elucidate the mechanism of diabetes-induced neurodegeneration. We conclude this review by proposing experimental approaches to test the hypothesis that DRN causes DR. If confirmed, this new paradigm may lead to earlier detection of ocular diabetic damage and earlier treatment of early DR, thereby preventing visual loss in people with diabetes. Published by Elsevier Ltd.

  10. 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

  11. Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.

    Science.gov (United States)

    Velayudhan, Latha; Van Diepen, Erik; Marudkar, Mangesh; Hands, Oliver; Suribhatla, Srinivas; Prettyman, Richard; Murray, Jonathan; Baillon, Sarah; Bhattacharyya, Sagnik

    2014-01-01

    The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, Huntington's disease, Tourette's syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson's disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington's disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.

  12. Yeast buddies helping to unravel the complexity of neurodegenerative disorders.

    Science.gov (United States)

    Fruhmann, Gernot; Seynnaeve, David; Zheng, Ju; Ven, Karen; Molenberghs, Sofie; Wilms, Tobias; Liu, Beidong; Winderickx, Joris; Franssens, Vanessa

    2017-01-01

    Neurodegenerative disorders have a profound effect on the quality of life of patients and their environment. However, the development of adequate therapies requires accurate understanding of the underlying disease pathogenesis. On that account, yeast models can play an important role, as they enable the elucidation of the mechanisms leading to neurodegenerative disorders. Furthermore, by using so-called humanized yeast systems, the findings in yeast can be interpolated to humans. In this review, we will give an overview of the current body of knowledge on the use of yeast models with regard to Huntington's, Parkinson's and Alzheimer's disease. In addition to the results, obtained with the baker's yeast Saccharomyces cerevisiae, we also consider the existing literature on the less common but promising fission yeast Schizosaccharomyces pombe. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Localization of Axonal Motor Molecules Machinery in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Fulvio Florenzano

    2012-04-01

    Full Text Available Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of the cell body. All these actions are executed through cytoskeleton, transport and regulatory elements that appear to be disrupted in neurodegenerative diseases. Motor-driven transport both supplies and clears distal cellular portions with proteins and organelles. This transport is especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings. Thus, any disturbance of axonal transport may have severe consequences for neuronal function and survival. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylation, but also in their subcellular distribution within populations of neurons, which are selectively affected in the course of neurodegenerative diseases. The implications of this altered subcellular localization and how this affects axon survival and neuronal death still remain poorly understood, although several hypotheses have been suggested. Furthermore, cytoskeleton and transport element localization can be selectively disrupted in some disorders suggesting that specific loss of the axonal functionality could be a primary hallmark of the disorder. This can lead to axon degeneration and neuronal death either directly, through the functional absence of essential axonal proteins, or indirectly, through failures in communication among different cellular domains. This review compares the localization of cytoskeleton and transport elements in some neurodegenerative disorders to ask what aspects may be essential for axon survival and neuronal death.

  14. 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.

  15. Need to improve clinical trials in rare neurodegenerative disorders.

    Science.gov (United States)

    Puopolo, Maria; Pocchiari, Maurizio

    2011-01-01

    Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.

  16. Need to improve clinical trials in rare neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Maria Puopolo

    2011-01-01

    Full Text Available Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.

  17. Connected Speech in Neurodegenerative Language Disorders: A Review.

    Science.gov (United States)

    Boschi, Veronica; Catricalà, Eleonora; Consonni, Monica; Chesi, Cristiano; Moro, Andrea; Cappa, Stefano F

    2017-01-01

    Language assessment has a crucial role in the clinical diagnosis of several neurodegenerative diseases. The analysis of extended speech production is a precious source of information encompassing the phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic levels of language organization. The knowledge about the distinctive linguistic variables identifying language deficits associated to different neurodegenerative diseases has progressively improved in the last years. However, the heterogeneity of such variables and of the way they are measured and classified limits any generalization and makes the comparison among studies difficult. Here we present an exhaustive review of the studies focusing on the linguistic variables derived from the analysis of connected speech samples, with the aim of characterizing the language disorders of the most prevalent neurodegenerative diseases, including primary progressive aphasia, Alzheimer's disease, movement disorders, and amyotrophic lateral sclerosis. A total of 61 studies have been included, considering only those reporting group analysis and comparisons with a group of healthy persons. This review first analyzes the differences in the tasks used to elicit connected speech, namely picture description, story narration, and interview, considering the possible different contributions to the assessment of different linguistic domains. This is followed by an analysis of the terminologies and of the methods of measurements of the variables, indicating the need for harmonization and standardization. The final section reviews the linguistic domains affected by each different neurodegenerative disease, indicating the variables most consistently impaired at each level and suggesting the key variables helping in the differential diagnosis among diseases. While a large amount of valuable information is already available, the review highlights the need of further work, including the development of automated methods, to

  18. Vestibular Deficits in Neurodegenerative Disorders: Balance, Dizziness, and Spatial Disorientation.

    Science.gov (United States)

    Cronin, Thomas; Arshad, Qadeer; Seemungal, Barry M

    2017-01-01

    The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated extensive central nervous system projections-from the cerebellum and brainstem to the thalamic relays to cortical projections. This system is important for spatial orientation and balance, both of critical ecological importance, particularly for successful navigation in our environment. Balance disorders and spatial disorientation are common presenting features of neurodegenerative diseases; however, little is known regarding central vestibular processing in these diseases. A ubiquitous aspect of central vestibular processing is its promiscuity given that vestibular signals are commonly found in combination with other sensory signals. This review discusses how impaired central processing of vestibular signals-typically in combination with other sensory and motor systems-may account for the impaired balance and spatial disorientation in common neurodegenerative conditions. Such an understanding may provide for new diagnostic tests, potentially useful in detecting early disease while a mechanistic understanding of imbalance and spatial disorientation in these patients may enable a vestibular-targeted therapy for such problems in neurodegenerative diseases. Studies with state of the art central vestibular testing are now much needed to tackle this important topic.

  19. Vestibular Deficits in Neurodegenerative Disorders: Balance, Dizziness, and Spatial Disorientation

    Directory of Open Access Journals (Sweden)

    Thomas Cronin

    2017-10-01

    Full Text Available The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated extensive central nervous system projections—from the cerebellum and brainstem to the thalamic relays to cortical projections. This system is important for spatial orientation and balance, both of critical ecological importance, particularly for successful navigation in our environment. Balance disorders and spatial disorientation are common presenting features of neurodegenerative diseases; however, little is known regarding central vestibular processing in these diseases. A ubiquitous aspect of central vestibular processing is its promiscuity given that vestibular signals are commonly found in combination with other sensory signals. This review discusses how impaired central processing of vestibular signals—typically in combination with other sensory and motor systems—may account for the impaired balance and spatial disorientation in common neurodegenerative conditions. Such an understanding may provide for new diagnostic tests, potentially useful in detecting early disease while a mechanistic understanding of imbalance and spatial disorientation in these patients may enable a vestibular-targeted therapy for such problems in neurodegenerative diseases. Studies with state of the art central vestibular testing are now much needed to tackle this important topic.

  20. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank.

    Science.gov (United States)

    Bieniek, Kevin F; Ross, Owen A; Cormier, Kerry A; Walton, Ronald L; Soto-Ortolaza, Alexandra; Johnston, Amelia E; DeSaro, Pamela; Boylan, Kevin B; Graff-Radford, Neill R; Wszolek, Zbigniew K; Rademakers, Rosa; Boeve, Bradley F; McKee, Ann C; Dickson, Dennis W

    2015-12-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future

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

    Science.gov (United States)

    Stoyanova, I I

    2014-12-01

    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: 1) neuronal loss in motor, sensory or cognitive systems, leading to cognitive and motor decline; and 2) a strong correlation between metabolic changes and neurodegeneration. In order to treat them, a better understanding of their complexity is required: it is necessary to interpret the neuronal damage in light of the metabolic changes, and to find the disrupted link between the peripheral organs governing energy metabolism and the CNS. This review is an attempt to present ghrelin as part of molecular regulatory interface between energy metabolism, neuroendocrine and neurodegenerative processes. Ghrelin takes part in lipid and glucose metabolism, in higher brain functions such as sleep-wake state, learning and memory consolidation; it influences mitochondrial respiration and shows neuroprotective effect. All these make ghrelin an attractive target for development of biomarkers or therapeutics for prevention or treatment of disorders, in which cell protection and recruitment of new neurons or synapses are needed. Copyright © 2014. Published by Elsevier Inc.

  2. 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...

  3. Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes?

    Directory of Open Access Journals (Sweden)

    Rosanna Parlato

    2015-05-01

    Full Text Available Within the cell nucleus the nucleolus is the site of rRNA transcription and ribosome biogenesis and its activity is clearly essential for a correct cell function, however its specific role in neuronal homeostasis remains mainly unknown. Here we review recent evidence that impaired nucleolar activity is a common mechanism in different neurodegenerative disorders. We focus on the specific causes and consequences of impaired nucleolar activity to better understand the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD. In particular, we discuss the genetic and epigenetic factors that might regulate nucleolar function in these diseases. In addition, we describe novel animal models enabling the dissection of the context-specific series of events triggered by nucleolar disruption, also known as nucleolar stress. Finally, we suggest how this novel mechanism could help to identify strategies to treat these still incurable disorders.

  4. Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Disease.

    Science.gov (United States)

    Howell, Michael Joseph; Schenck, Carlos Hugh

    2015-06-01

    The dream enactment of rapid eye movement sleep behavior disorder (RBD) is often the first indication of an impending α-synuclein disorder, such as Parkinson disease, multiple-system atrophy, or dementia with Lewy bodies. To provide an overview of RBD from the onset of dream enactment through the emergence of a parkinsonian disorder. Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized trials, and basic science investigations, were identified in a PubMed search of articles on RBD from January 1, 1986, through July 31, 2014. Under normal conditions, vivid dream mentation combined with skeletal muscle paralysis characterizes rapid eye movement sleep. In RBD, α-synuclein abnormalities in the brainstem disinhibit rapid eye movement sleep motor activity, leading to dream enactment. The behaviors of RBD are often theatrical, with complexity, aggression, and violence; fighting and fleeing actions can be injurious to patients as well as bed partners. Rapid eye movement sleep behavior disorder is distinguished from other parasomnias by clinical features and the demonstration of rapid eye movement sleep without atonia on polysomnography. Consistent with early neurodegeneration, patients with RBD demonstrate subtle motor, cognitive, and autonomic impairments. Approximately 50% of patients with spontaneous RBD will convert to a parkinsonian disorder within a decade. Ultimately, nearly all (81%-90%) patients with RBD develop a neurodegenerative disorder. Among patients with Parkinson disease, RBD predicts a non-tremor-predominant subtype, gait freezing, and an aggressive clinical course. The most commonly cited RBD treatments include low-dose clonazepam or high-dose melatonin taken orally at bedtime. Treatment of RBD can prevent injury to patients and bed partners. Because RBD is a prodromal syndrome of Parkinson disease (or related disorder), it represents a unique opportunity for developing and testing disease

  5. Environmental Pollutants as Risk Factors for Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Miguel eChin-Chan

    2015-04-01

    Full Text Available Neurodegenerative diseases including Alzheimer (AD and Parkinson (PD have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ peptide and the phosphorylation of Tau protein (P-Tau, causing senile/amyloid plaques and neurofibrillary tangles characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn, which is a key constituent of Lewy bodies, a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzymes such as neprilysin or insulin degrading enzyme. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.

  6. 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...

  7. Melatonin in Alzheimer's disease and other neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Poeggeler B

    2006-05-01

    Full Text Available Abstract Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's disease (PD and Huntington's disease (HD. As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin

  8. Few patients with neurodegenerative disorders require spinal surgery

    Science.gov (United States)

    Epstein, Nancy E.; Gottesman, Malcolm

    2014-01-01

    Background: Few patients with neurodegenerative disorders (ND) (e.g., Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Postpolio Syndrome (PPS)) require spinal surgery. Typically, their neurological symptoms and signs reflect their underlying neurologic disorders rather than structural spinal pathology reported on magnetic resonance images (MR) or computed tomographic scans (CT). Methods: The first author, a neurosurgeon, reviewed 437 spinal consultations performed over a 20-month period. Of 254 patients seen in first opinion (e.g., had not been seen by a spinal surgeon), 9 had MS, while 2 had ALS. Of 183 patients seen in second opinion (e.g., prior spinal surgeons recommended surgery), 4 had MS, 2 had ALS, and 1 had PPS. We performed this study to establish how often patients with ND, seen in first or second opinion, require spinal surgery. We focused on whether second opinions from spinal surgeons would limit the number of operations offered to these patients. Results: Two of 11 patients with ND seen in first opinion required surgery. The first patient required a C5-7 laminectomy/C2-T2 fusion, followed by a L2-S1 laminectomy/L5S1 fusion. The second patient required a L2-L3 laminectomy/diskectomy/fusion. However, none of the seven patients seen in second opinion, who were previously told by outside surgeons they needed spinal surgery, required operations. Conclusions: Few patients with neurodegenerative syndromes (MS, ALS, PPS) and reported “significant” spondyloitic spinal disease interpreted on MR/CT studies required surgery. Great caution should be exercised in offering patients with ND spinal surgery, and second opinions should be encouraged to limit “unnecessary” procedures. PMID:24843817

  9. Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

    Science.gov (United States)

    Perluigi, Marzia; Reed, Tanea; Muharib, Tasneem; Hughes, Christopher P.; Robinson, Renã A.S.; Sultana, Rukhsana

    2012-01-01

    Abstract Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidative-stress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610–1655. PMID:22115501

  10. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases.

    Science.gov (United States)

    Irwin, Michael H; Moos, Walter H; Faller, Douglas V; Steliou, Kosta; Pinkert, Carl A

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2017-06-27

    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.

  12. Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders.

    Science.gov (United States)

    Sukoff Rizzo, Stacey J; Crawley, Jacqueline N

    2017-02-08

    Animal models offer heuristic research tools to understand the causes of human diseases and to identify potential treatments. With rapidly evolving genetic engineering technologies, mutations identified in a human disorder can be generated in the mouse genome. Phenotypic outcomes of the mutation are then explicated to confirm hypotheses about causes and to discover effective therapeutics. Most neurodevelopmental, neurodegenerative, and psychiatric disorders are diagnosed primarily by their prominent behavioral symptoms. Mouse behavioral assays analogous to the human symptoms have been developed to analyze the consequences of mutations and to evaluate proposed therapeutics preclinically. Here we describe the range of mouse behavioral tests available in the established behavioral neuroscience literature, along with examples of their translational applications. Concepts presented have been successfully used in other species, including flies, worms, fish, rats, pigs, and nonhuman primates. Identical strategies can be employed to test hypotheses about environmental causes and gene × environment interactions.

  13. Environmental Pollutants as Risk Factors for Neurodegenerative Disorders

    OpenAIRE

    Miguel eChin-Chan; Juliana eNavarro-Yepes; Betzabet eQuintanilla-Vega

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metal...

  14. Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders?

    Science.gov (United States)

    Jodeiri Farshbaf, Mohammad; Ghaedi, Kamran

    2017-02-01

    The prevalence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the research to establish novel therapeutic strategies. Iron as the one of most important cation not only play important role in the structure of electron transport chain proteins but also has pivotal duties in cellular activities. But disruption in iron hemostasis can make it toxin to neurons which causes lipid peroxidation, DNA damage and etc. In patients with Alzheimer and Parkinson misbalancing in iron homeostasis accelerate neurodegeneration and cause neuroinflmmation. mTOR as the common signaling pathway between cancer and neurodegenerative disorders controls iron uptake and it is in active form in both diseases. Anti-cancer drugs which target mTOR causes iron deficiency and dual effects of mTOR inhibitors can candidate them as a therapeutic strategy to alleviate neurodegeneration/inflammation because of iron overloading.

  15. Sleep disturbance in mental health problems and neurodegenerative disease

    National Research Council Canada - National Science Library

    Anderson, Kirstie N; Bradley, Andrew J

    2013-01-01

    ... 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...

  16. Gene Therapy-Based Modeling of Neurodegenerative Disorders: Huntington's Disease.

    Science.gov (United States)

    Young, Deborah

    2016-01-01

    Huntington's disease is a fatal neurodegenerative disease characterized by impairments in motor control, and cognitive and psychiatric disturbances. In this chapter, viral vector-mediated approaches used in modeling the key neuropathological features of the disease including the production of abnormal intracellular protein aggregates, neuronal dysfunction and degeneration and motor impairments in rodents are described.

  17. A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases.

    Science.gov (United States)

    Borza, Liana Rada

    2014-01-01

    Protein aggregates are the defining pathological feature of human neurodegenerative diseases. Studies have revealed that mutant huntingtin, polyglutamine-expanded ataxin-1 and ataxin-3 can cause elevated levels of reactive oxygen species in neuronal cells. It has also been indicated that the normal host prion protein behaves as an antioxidant, while the neurotoxic peptide based on the sequence of the scrapie isoform increases hydrogen peroxide toxicity in neuronal cultures. Additionally, not only can oxidative stress contribute to the aggregation of beta-amyloid and alpha-synuclein, but both beta-amyloid and alpha-synuclein can induce oxidative damage. Furthermore, oxidative stressors have been shown to play a critical role in neurofibrillary pathology leading to tau hyperphosphorylation. In conclusion, the present review supports a cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative disorders.

  18. REM Sleep Behavior Disorder (RBD) as a marker of neurodegenerative disorders.

    Science.gov (United States)

    Ferini-Strambi, L; Marelli, S; Galbiati, A; Rinaldi, F; Giora, E

    2014-01-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) can occur in the absence of any other obvious associated neurologic disorder or in association with a neurodegenerative disease, in which case it is considered as symptomatic RBD. RBD is frequently associated with Parkinson's disease (PD), Lewy body dementia or multiple system atrophy (MSA), and in several cases may even antedate the occurrence of motor symptoms by decades. When no neurologic disorder is obvious, RBD can be considered as idiopathic (iRBD). Several studies have looked at neurophysiologic and neuropsychological functions in iRBD and have found evidence of CNS dysfunction during both wakefulness and sleep in a variable proportion of these patients, challenging the concept of iRBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies. Some prospective results in iRBD showed that potential markers of neurodegeneration are the following: 1) marked EEG slowing on spectral analysis; 2) decreased striatal 123I-FPCIT; 3) impaired color vision.

  19. Proline-rich polypeptides in Alzheimer's disease and neurodegenerative disorders -- therapeutic potential or a mirage?

    Science.gov (United States)

    Gladkevich, A; Bosker, F; Korf, J; Yenkoyan, K; Vahradyan, H; Aghajanov, M

    2007-10-01

    The development of effective and safe drugs for a growing Alzheimer disease population is an increasing need at present. Both experimental and clinical evidence support a beneficial effect of proline-rich polypeptides in a number of neurodegenerative diseases, including Alzheimer disease. Experimental data have shown that proline-rich polypeptides isolated from bovine neurohypophisis possess neuroprotective and neuromodulatory properties in mice with aluminum neurotoxicosis or neuronal damage caused by venoms and toxins. Proline-rich polypeptides from ovine colostrums, so called Colostrinin, have been shown to produce cognitive improvement in an experimental model and in patients with Alzheimer disease. However, the precise mechanism underlying the neuroprotective action of proline-rich polypeptides is not very well established. Moreover, studies pointing at a neuroprotective effect of proline-rich polypeptides from bovine neurohypophisis in humans have not been reported thus far. The authors conclude that more detailed information on the mode of action of proline-rich polypeptides is needed as well as confirmation of their efficacy in broad clinical trials before this approach can really show its potential in the treatment of neurodegenerative disorders.

  20. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder.

    Science.gov (United States)

    Postuma, R B; Gagnon, J F; Vendette, M; Fantini, M L; Massicotte-Marquez, J; Montplaisir, J

    2009-04-14

    Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

  1. Cognitive performance in REM sleep behaviour disorder: a possible early marker of neurodegenerative disease?

    Science.gov (United States)

    Terzaghi, Michele; Sinforiani, Elena; Zucchella, Chiara; Zambrelli, Elena; Pasotti, Chiara; Rustioni, Valter; Manni, Raffaele

    2008-05-01

    Rapid eye movement [REM] sleep behaviour disorder (RBD) may herald neurodegenerative diseases. Neurobiological deficits similar to those identified in neurodegenerative diseases have been reported in idiopathic RBD. Researchers are looking for early markers supporting a possible role of RBD as a harbinger of impending neurodegenerative disease. To examine the neuropsychological functions in idiopathic RBD subjects. Should they be found to present a neuropsychological dysfunction that overlaps that reported in neurodegenerative diseases, it would be possible to consider cognitive deficits as possible early markers of an underlying degenerative process. Twenty-three subjects with idiopathic RBD (21 males, mean age 67.0+/-7.0 years) and a group of healthy controls matched for sex, age and education underwent a neuropsychological battery evaluating different cognitive domains. Considering mean values, poorer performances were observed in the Word Span (pneurodegenerative disease, but until more prolonged long-term follow-up data are available, the true neurobiological significance of cognitive deficits in RBD will remain unknown.

  2. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

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    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  3. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients.

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    Iranzo, Alex; Fernández-Arcos, Ana; Tolosa, Eduard; Serradell, Mónica; Molinuevo, José Luis; Valldeoriola, Francesc; Gelpi, Ellen; Vilaseca, Isabel; Sánchez-Valle, Raquel; Lladó, Albert; Gaig, Carles; Santamaría, Joan

    2014-01-01

    To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.

  4. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients.

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    Alex Iranzo

    Full Text Available OBJECTIVE: To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD patients with long follow-up. METHODS: Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. RESULTS: The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4% were dementia with Lewy bodies (DLB in 29 subjects, Parkinson disease (PD in 22, multiple system atrophy (MSA in two, and mild cognitive impairment (MCI in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. CONCLUSIONS: In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.

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

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    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

  6. Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials.

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    Zhang, Wei; Chen, Xue-yan; Su, Su-wen; Jia, Qing-zhong; Ding, Tao; Zhu, Zhong-ning; Zhang, Tong

    2016-01-01

    The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from inception to July 2015. We included randomized clinical trials (RCTs) that compared melatonin with placebo and that had the primary aim of improving sleep in people with neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). We pooled data with the weighted mean difference in sleep outcomes. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I (2) statistic. 9 RCTs were included in this research. We found that the treatment with exogenous melatonin has positive effects on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in PD patients (MD: 4.20, 95 % CI: 0.92-7.48; P = 0.01), and by changes in PSQI component 4 in AD patients (MD: 0.67, 95 % CI: 0.04-1.30; P = 0.04), but not on objective sleep outcomes in both AD and PD patients. Treatment with melatonin effectively improved the clinical and neurophysiological aspects of rapid eye movement (REM) sleep behavior disorder (RBD), especially elderly individuals with underlying neurodegenerative disorders. This meta-analysis provided some evidence that melatonin improves sleep quality in patients with AD and PD, and melatonin can be considered as a possible sole or add-on therapy in neurodegenerative disorders patients with RBD.

  7. [Sleep disorder, a potential early diagnostic marker for psychiatric and neurodegenerative diseases].

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    Chen, Yan-Mei; Qin, Dong-Dong; Jiang, Hui-Hui; Hu, Xin-Tian; Ma, Yuan-Ye

    2011-02-01

    Sleep/circadian timing depends on several neurotransmitter systems, including 5-HT, NE, DA, Ach, GABA, etc. These neurotransmitter systems play critical roles in mental, emotional and cognitive functions in the brain. Dysfunctions of these systems not only result in sleep disorder, but are also related to many psychiatric and neurodegenerative diseases. Sleep disruption is tightly associated with an increased susceptibility to a broad range of psychiatric and neurodegenerative diseases, such as depression and Parkinson diseases. Non-human primates, especially the rhesus monkey is an excellent biomedical model for human sleep and CNS diseases. Establishing nonhuman primates' model of mental disorders and monitoring the sleep changes during the development of the model will help us to know more about the relationships between sleep disorder and psychiatric and neurodegenerative diseases. Sleep disorder as an early marker for psychiatric and neurodegenerative diseases would permit early intervention of these diseases and draw attention to the potential therapeutic benefits of normalizing sleep rhythms in individuals with brain pathologies.

  8. DNA methylation in neurodegenerative disorders: a missing link between genome and environment?

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    Iraola-Guzmán, S; Estivill, X; Rabionet, R

    2011-07-01

    The risk of developing neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease is influenced by genetic and environmental factors. Environmental events occurring during development or later in life can be related to disease susceptibility. One way by which the environment may exert its effect is through epigenetic modifications, which might affect the functioning of genes. These include nucleosome positioning, post-translational histone modifications, and DNA methylation. In this review we will focus in the potential role of DNA methylation in neurodegenerative disorders and in the approaches to explore such epigenetic changes. Advances in deciphering the role of epigenetic modifications in phenotype are being uncovered for a variety of diseases, including cancer, autoimmune, neurodevelopmental and cognitive disorders. Epigenetic modifications are now being also associated with cardiovascular and metabolic traits, and they are expected to be especially involved in learning and memory processes, as well as in neurodegenerative disease. The study of the role of methylation and other epigenetic modifications in disease development will provide new insights in the etiopathogenesis of neurodegenerative disorders, and should hopefully shape new avenues in the development of therapeutic strategies. © 2011 John Wiley & Sons A/S.

  9. Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes

    NARCIS (Netherlands)

    Franceschi, L. De; Bosman, G.J.C.G.M.; Mohandas, N.

    2014-01-01

    PURPOSE OF REVIEW: This review discusses the mechanisms involved in the generation of thorny red blood cells (RBCs), known as acanthocytes, in patients with neuroacanthocytosis, a heterogenous group of neurodegenerative hereditary disorders that include chorea-acanthocytosis (ChAc) and McLeod

  10. Motor Abnormalities: From Neurodevelopmental to Neurodegenerative Through "Functional" (Neuro)Psychiatric Disorders.

    Science.gov (United States)

    Peralta, Victor; Cuesta, Manuel J

    2017-09-01

    Motor abnormalities (MAs) of severe mental disorders have been traditionally neglected both in clinical practice and research, although they are an increasing focus of attention because of their clinical and neurobiological relevance. For historical reasons, most of the literature on MAs has been focused to a great extent on schizophrenia, and as a consequence their prevalence and featural properties in other psychiatric or neuropsychiatric disorders are poorly known. In this article, we evaluated the extent to which catatonic, extrapyramidal and neurological soft signs, and their associated clinical features, are present transdiagnostically. We examined motor-related features in neurodevelopmental (schizophrenia, obsessive compulsive disorder, autism spectrum disorders), "functional" (nonschizophrenic nonaffective psychoses, mood disorders) and neurodegenerative (Alzheimer's disease) disorders. Examination of the literature revealed that there have been very few comparisons of motor-related features across diagnoses and we had to rely mainly in disorder-specific studies to compare it transdiagnostically. One or more motor domains had a substantial prevalence in all the diagnoses examined. In "functional" disorders, MAs, and particularly catatonic signs, appear to be markers of episode severity; in chronic disorders, although with different degree of strength or evidence, all motor domains are indicators of both disorder severity and poor outcome; lastly, in Alzheimer's disease they are also indicators of disorder progression. MAs appear to represent a true transdiagnostic domain putatively sharing neurobiological mechanisms of neurodevelopmental, functional or neurodegenerative origin.

  11. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders.

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    Sas, Katalin; Robotka, Hermina; Toldi, József; Vécsei, László

    2007-06-15

    The mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. Other pathogenetic factors are also briefly surveyed. The second part of the review deals with the kynurenine metabolic pathway, its alterations and their potential association with cellular energy impairment in certain neurodegenerative diseases. During energy production, most of the O(2) consumed by the mitochondria is reduced fully to water, but 1-2% of the O(2) is reduced incompletely to give the superoxide anion (O(2)(-)). If the function of one or more respiratory chain complexes is impaired for any reason, the enhanced production of free radicals further worsens the mitochondrial function by causing oxidative damage to macromolecules, and by opening the mitochondrial permeability transition pores thereby inducing apoptosis. These high-conductance pores offer a pathway which can open in response to certain stimuli, leading to the induction of the cells' own suicide program. This program plays an essential role in regulating growth and development, in the differentiation of immune cells, and in the elimination of abnormal cells from the organism. Both failure and exaggeration of apoptosis in a human body can lead to disease. The increasing amount of superoxide anions can react with nitric oxide to yield the highly toxic peroxynitrite anion, which can destroy cellular macromolecules. The roles of oxidative, nitrative and nitrosative damage are discussed. Senescence is accompanied by a higher degree of reactive oxygen species production, and by diminished functions of the endoplasmic reticulum and the proteasome system, which are responsible for maintenance of the

  12. Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal?

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    Postuma, Ronald B; Gagnon, Jean-Francois; Tuineaig, Maria; Bertrand, Josie-Anne; Latreille, Veronique; Desjardins, Catherine; Montplaisir, Jacques Y

    2013-11-01

    Antidepressants, among the most commonly prescribed medications, trigger symptoms of REM sleep behavior disorder (RBD) in up to 6% of users. Idiopathic RBD is a very strong prodromal marker of Parkinson disease and other synuclein-mediated neurodegenerative syndromes. It is therefore critically important to understand whether antidepressant-associated RBD is an independent pharmacologic syndrome or a sign of possible prodromal neurodegeneration. Prospective cohort study. Tertiary sleep disorders center. 100 patients with idiopathic RBD, all with diagnosis confirmed on polysomnography, stratified to baseline antidepressant use, with 45 matched controls. Of 100 patients, 27 were taking antidepressants. Compared to matched controls, RBD patients taking antidepressants demonstrated significant abnormalities of 12/14 neurodegenerative markers tested, including olfaction (P = 0.007), color vision (P = 0.004), Unified Parkinson Disease Rating Scale II and III (P neurodegenerative disease than those without antidepressant use (5-year risk = 22% vs. 59%, RR = 0.22, 95%CI = 0.06, 0.74). Although patients with antidepressant-associated RBD have a lower risk of neurodegeneration than patients with "purely-idiopathic" RBD, markers of prodromal neurodegeneration are still clearly present. Development of RBD with antidepressants can be an early signal of an underlying neurodegenerative disease.

  13. The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases.

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    Iranzo, Alex; Santamaria, Joan; Tolosa, Eduard

    2009-12-01

    REM sleep behavior disorder (RBD) is characterized by vigorous movements associated with unpleasant dreams and increased electromyographic activity during REM sleep. Polysomnography with audiovisual recording is needed to confirm the diagnosis of RBD and to exclude other sleep disorders that can mimic its symptoms including obstructive sleep apnea, nocturnal hallucinations and confusional awakenings. RBD may be idiopathic or related to neurodegenerative diseases, particularly multiple system atrophy, Parkinson's disease and dementia with Lewy bodies. RBD may be the first manifestation of these disorders, antedating the onset of parkinsonism, cerebellar syndrome, dysautonomia, and dementia by several years. RBD should thus be considered an integral part of the disease process. When effective, neuroprotective strategies should be considered in subjects with idiopathic RBD. Patients with other neurodegenerative diseases, though, such as spinocerebellar ataxias, may also present with RBD. When clinically required, clonazepam at bedtime is effective in decreasing the intensity of dream-enacting behaviors and unpleasant dreams in both the idiopathic and secondary forms. When part of a neurodegenerative disorder the development of RBD is thought to reflect the location and extent of the underlying lesions involving the REM sleep centers of the brain (e.g., locus subceruleus, amygdala, etc.), leading to a complex multiple neurotransmitter dysfunction that involves GABAergic, glutamatergic and monoaminergic systems. RBD is mediated neither by direct abnormal alpha-synuclein inclusions nor by striatonigral dopaminergic deficiency alone.

  14. Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders

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    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.

  15. Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders.

    Science.gov (United States)

    Covarrubias-Pinto, Adriana; Acuña, Aníbal Ignacio; Beltrán, Felipe Andrés; Torres-Díaz, Leandro; Castro, Maite Aintzane

    2015-11-27

    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.

  16. Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders

    Science.gov (United States)

    Covarrubias-Pinto, Adriana; Acuña, Aníbal Ignacio; Beltrán, Felipe Andrés; Torres-Díaz, Leandro; Castro, Maite Aintzane

    2015-01-01

    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. PMID:26633354

  17. Hydrogel-Based Nanocomposites and Mesenchymal Stem Cells: A Promising Synergistic Strategy for Neurodegenerative Disorders Therapy

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    Diego Albani

    2013-01-01

    Full Text Available Hydrogel-based materials are widely employed in the biomedical field. With regard to central nervous system (CNS neurodegenerative disorders, the design of injectable nanocomposite hydrogels for in situ drug or cell release represents an interesting and minimally invasive solution that might play a key role in the development of successful treatments. In particular, biocompatible and biodegradable hydrogels can be designed as specific injectable tools and loaded with nanoparticles (NPs, to improve and to tailor their viscoelastic properties upon injection and release profile. An intriguing application is hydrogel loading with mesenchymal stem cells (MSCs that are a very promising therapeutic tool for neurodegenerative or traumatic disorders of the CNS. This multidisciplinary review will focus on the basic concepts to design acellular and cell-loaded materials with specific and tunable rheological and functional properties. The use of hydrogel-based nanocomposites and mesenchymal stem cells as a synergistic strategy for nervous tissue applications will be then discussed.

  18. Imaging of neurodegenerative cognitive and behavioral disorders: practical considerations for dementia clinical practice.

    Science.gov (United States)

    Atri, Alireza

    2016-01-01

    This chapter reviews clinical applications and imaging findings useful in medical practice relating to neurodegenerative cognitive/dementing disorders. The preponderance of evidence and consensus guidelines support an essential role of multitiered neuroimaging in the evaluation and management of neurodegenerative cognitive/dementia syndrome that range in severity from mild impairments to frank dementia. Additionally, imaging features are incorporated in updated clinical and research diagnostic criteria for most dementias, including Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal Lobar Degenerations/Frontotemporal Dementia (FTD), and Vascular Cognitive Impairment (VCI). Best clinical practices dictate that structural imaging, preferably with magnetic resonance imaging (MRI) when possible and computed tomography when not, be obtained as a first-tier approach during the course of a thorough clinical evaluation to improve diagnostic confidence and assess for nonneurodegenerative treatable conditions that may cause or substantially contribute to cognitive/behavioral symptoms or which may dictate a substantial change in management. These conditions include less common structural (e.g., mass lesions such as tumors and hematomas; normal-pressure hydrocephalus), inflammatory, autoimmune and infectious conditions, and more common comorbid contributing conditions (e.g., vascular cerebral injury causing leukoaraiosis, infarcts, or microhemorrhages) that can produce a mixed dementia syndrome. When, after appropriate clinical, cognitive/neuropsychologic, and structural neuroimaging assessment, a dementia specialist remains in doubt regarding etiology and appropriate management, second-tier imaging with molecular methods, preferably with fluorodexoyglucose positron emission tomography (PET) (or single-photon emission computed tomography if PET is unavailable) can provide more diagnostic specificity (e.g., help differentiate between atypical AD and FTD as

  19. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

    Science.gov (United States)

    Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

    2013-01-01

    Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422

  20. Endocannabinoids and Neurodegenerative Disorders: Parkinson's Disease, Huntington's Chorea, Alzheimer's Disease, and Others.

    Science.gov (United States)

    Fernández-Ruiz, Javier; Romero, Julián; Ramos, José A

    2015-01-01

    This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders. First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy. We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson's disease, Huntington's chorea, and Alzheimer's disease), as well as in other less well-studied disorders. We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders. Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.

  1. 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.

  2. 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.

  3. Glucose 6 phosphatase dehydrogenase (G6PD and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities

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    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.

  4. Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders.

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    Nishi, Akinori; Shuto, Takahide

    2017-03-01

    Alterations in dopamine neurotransmission has been implicated in pathophysiology of neuropsychiatric and neurodegenerative disorders, and DARPP-32 plays a pivotal role in dopamine neurotransmission. DARPP-32 likely influences dopamine-mediated behaviors in animal models of neuropsychiatric and neurodegenerative disorders and therapeutic effects of pharmacological treatment. Areas covered: We will review animal studies on the biochemical and behavioral roles of DARPP-32 in drug addiction, schizophrenia and Parkinson's disease. In general, under physiological and pathophysiological conditions, DARPP-32 in D1 receptor expressing (D1R) -medium spiny neurons (MSNs) promotes dopamine/D1 receptor/PKA signaling, whereas DARPP-32 in D2 receptor expressing (D2R)-MSNs counteracts dopamine/D2 receptor signaling. However, the function of DARPP-32 is differentially regulated in acute and chronic phases of drug addiction; DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase through homeostatic mechanisms. Therefore, DARPP-32 plays a bidirectional role in dopamine neurotransmission, depending on the cell type and experimental conditions, and is involved in dopamine-related behavioral abnormalities. Expert opinion: DARPP-32 differentially regulates dopamine signaling in D1R- and D2R-MSNs, and a shift of balance between D1R- and D2R-MSN function is associated with behavioral abnormalities. An adjustment of this imbalance is achieved by therapeutic approaches targeting DARPP-32-related signaling molecules.

  5. 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.

  6. 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.

    2014-01-01

    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. PMID:25412207

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

    DEFF Research Database (Denmark)

    Winge, Kristian

    2015-01-01

    be present, most commonly in disorders with spinal cord involvement. The systematic and careful tracking of symptoms, evaluation using non-invasive techniques, and conservative management including pharmacologic treatments can often markedly improve the lives of patients and their caregivers....... of dopaminergic neurons in the substantia nigra and possibly also in the ventral tegmental area induces loss of neurogenic bladder control through dysfunction of a complex network in which selective disinhibition of bladder reflexes is lost. In PD, more than 60% of patients have troublesome bladder symptoms...... 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...

  8. Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Douglas eGray

    2013-08-01

    Full Text Available Whereas many cases of neurodegenerative disease feature the abnormal accumulationof protein, an abundance of recent literature highlights loss of RNA homeostasis as aubiquitous and central feature of pathological states. In some diseases expandedrepeats have been identified in non-coding regions of disease-associated transcripts,calling into question the relevance of protein in the disease mechanism. We review theliterature in support of a hypothesis that intrinsically disordered proteins (proteins thatlack a stable three dimensional conformation are particularly sensitive to an age-relateddecline in maintenance of protein homeostasis. The potential consequences forstructurally disordered RNA binding proteins are explored, including their aggregationinto complexes that could be transmitted through a prion-like mechanism. We proposethat the spread of ribonucleoprotein complexes through the nervous system couldpropagate a neuronal error catastrophe at the level of RNA metabolism.

  9. Application of monoterpenoids and their derivatives for treatment of neurodegenerative disorders.

    Science.gov (United States)

    Volcho, Konstantin P; Laev, Sergey S; Ashraf, Ghulam Md; Aliev, Gjumrakch; Salakhutdinov, Nariman F

    2017-01-11

    Neurodegenerative disorders (NDDs) like Alzheimer disease, Parkinson's disease and Huntington's disease are a heterogeneous group of disorders with the progressive and severe loss of neurons. There are no full proof cures for these diseases, and only medicines are available that can alleviate some of the symptoms. Developing effective treatments for the NDDs is a difficult but necessary task. Hence, the investigation of monoterpenoids which modulate targets applicable to many NDDs is highly relevant. Many monoterpenoids have demonstrated promising neuroprotective activity mediated by various systems. It can form the basis for elaboration of agents which will be useful both for the alleviation of symptoms of NDDs and for the treatment of diseases progression and also for prevention of neurodegeneration. The further developments including detections of monoterpenoids and their derivatives with high neuroprotective or neurotrophic activity as well as the results of qualified clinical trials are needed to draw solid conclusions regarding the efficacy of these agents.

  10. Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

    Directory of Open Access Journals (Sweden)

    Sehgal SA

    2016-05-01

    Full Text Available Sheikh Arslan Sehgal,1–4 Shazia Mannan,1 Sannia Ali1 1Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan; 2State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 3University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 4Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan Abstract: Charcot–Marie–Tooth (CMT disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand–receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT. Keywords: bioinformatics, computer

  11. Targeting innate immunity for neurodegenerative disorders of the central nervous system.

    Science.gov (United States)

    Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco; Ginhoux, Florent; Holmes, Clive; Lamb, Bruce; Landreth, Gary; Lee, Daniel C; Low, Donovan; Lynch, Marina A; Monsonego, Alon; O'Banion, M Kerry; Pekny, Milos; Puschmann, Till; Russek-Blum, Niva; Sandusky, Leslie A; Selenica, Maj-Linda B; Takata, Kazuyuki; Teeling, Jessica; Town, Terrence; Van Eldik, Linda J

    2016-09-01

    Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of

  12. 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.

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

    Science.gov (United States)

    Moreira, Helena S; Costa, Ana S; Castro, São L; Lima, César F; Vicente, Selene G

    2017-01-01

    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.

  14. Epigenetic Research of Neurodegenerative Disorders Using Patient iPSC-Based Models

    Science.gov (United States)

    2016-01-01

    Epigenetic mechanisms play a role in human disease but their involvement in pathologies from the central nervous system has been hampered by the complexity of the brain together with its unique cellular architecture and diversity. Until recently, disease targeted neural types were only available as postmortem materials after many years of disease evolution. Current in vitro systems of induced pluripotent stem cells (iPSCs) generated by cell reprogramming of somatic cells from patients have provided valuable disease models recapitulating key pathological molecular events. Yet whether cell reprogramming on itself implies a truly epigenetic reprogramming, the epigenetic mechanisms governing this process are only partially understood. Moreover, elucidating epigenetic regulation using patient-specific iPSC-derived neural models is expected to have a great impact to unravel the pathophysiology of neurodegenerative diseases and to hopefully expand future therapeutic possibilities. Here we will critically review current knowledge of epigenetic involvement in neurodegenerative disorders focusing on the potential of iPSCs as a promising tool for epigenetic research of these diseases. PMID:26697081

  15. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.

    Science.gov (United States)

    Chin-Chan, Miguel; Navarro-Yepes, Juliana; Quintanilla-Vega, Betzabet

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.

  16. Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders.

    Science.gov (United States)

    Su, Kuo-Hui; Dai, Chengkai

    2016-11-01

    Proteome homeostasis, or proteostasis, is essential to maintain cellular fitness and its disturbance is associated with a broad range of human health conditions and diseases. Cells are constantly challenged by various extrinsic and intrinsic insults, which perturb cellular proteostasis and provoke proteotoxic stress. To counter proteomic perturbations and preserve proteostasis, cells mobilize the proteotoxic stress response (PSR), an evolutionarily conserved transcriptional program mediated by heat shock factor 1 (HSF1). The HSF1-mediated PSR guards the proteome against misfolding and aggregation. In addition to proteotoxic stress, emerging studies reveal that this proteostatic mechanism also responds to cellular energy state. This regulation is mediated by the key cellular metabolic sensor AMP-activated protein kinase (AMPK). In this review, we present an overview of the maintenance of proteostasis by HSF1, the metabolic regulation of the PSR, particularly focusing on AMPK, and their implications in the two major age-related diseases-diabetes mellitus and neurodegenerative disorders.

  17. Brain Atrophy of Secondary REM-Sleep Behavior Disorder in Neurodegenerative Disease.

    Science.gov (United States)

    Kim, Hee-Jin; Im, Hyung Kyun; Kim, Juhan; Han, Jee-Young; de Leon, Mony; Deshpande, Anup; Moon, Won-Jin

    2016-04-05

    Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy. We investigated that dementia with RBD might show distinctive cortical atrophic patterns. A total of 31 patients with idiopathic Parkinson's disease (IPD), 23 with clinically probable Alzheimer's disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects. Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes. The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α-synucleinopathy.

  18. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

    Science.gov (United States)

    Boeve, B F; Silber, M H; Saper, C B; Ferman, T J; Dickson, D W; Parisi, J E; Benarroch, E E; Ahlskog, J E; Smith, G E; Caselli, R C; Tippman-Peikert, M; Olson, E J; Lin, S-C; Young, T; Wszolek, Z; Schenck, C H; Mahowald, M W; Castillo, P R; Del Tredici, K; Braak, H

    2007-11-01

    REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in

  19. Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases.

    Science.gov (United States)

    Shan, Ling; Hofman, Michel A; van Wamelen, Daniel J; Van Someren, Eus J W; Bao, Ai-Min; Swaab Dick, F

    2012-05-01

    Neuronal histamine shows diurnal rhythms in rodents and plays a major role in the maintenance of vigilance. No data are available on its diurnal fluctuation in humans, either in health or in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD), or Huntington disease (HD), all of which are characterized by sleep-wake disturbances. Quantitative in situ hybridization was used to study the mRNA expression of histidine decarboxylase (HDC), the key enzyme of histamine production in the tuberomammillary nucleus (TMN) in postmortem human hypothalamic tissue, obtained from 33 controls and 31 patients with a neurodegenerative disease-PD (n = 15), AD (n = 9), and HD (n = 8)-and covering the full 24-h cycle with respect to clock time of death. HDC-mRNA levels in controls were found to be significantly higher during the daytime than at night (e.g., 08:01-20:00 versus 20:01-08:00, P = 0.004). This day-night fluctuation was markedly different in patients with neurodegenerative diseases. The diurnal fluctuation of HDC-mRNA expression in human TMN supports a role for neuronal histamine in regulating day-night rhythms. Future studies should investigate histamine rhythm abnormalities in neurodegenerative disorders. Shan L; Hofman MA; van Wamelen DJ; Van Someren EJW; Bao AM; Swaab DF. Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases.

  20. Molecular underpinnings of neurodegenerative disorders: striatal-enriched protein tyrosine phosphatase signaling and synaptic plasticity.

    Science.gov (United States)

    Lombroso, Paul J; Ogren, Marilee; Kurup, Pradeep; Nairn, Angus C

    2016-01-01

    This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer's and Parkinson's disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity.

  1. Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.

    Science.gov (United States)

    Beach, Thomas G; Adler, Charles H; Sue, Lucia I; Serrano, Geidy; Shill, Holly A; Walker, Douglas G; Lue, LihFen; Roher, Alex E; Dugger, Brittany N; Maarouf, Chera; Birdsill, Alex C; Intorcia, Anthony; Saxon-Labelle, Megan; Pullen, Joel; Scroggins, Alexander; Filon, Jessica; Scott, Sarah; Hoffman, Brittany; Garcia, Angelica; Caviness, John N; Hentz, Joseph G; Driver-Dunckley, Erika; Jacobson, Sandra A; Davis, Kathryn J; Belden, Christine M; Long, Kathy E; Malek-Ahmadi, Michael; Powell, Jessica J; Gale, Lisa D; Nicholson, Lisa R; Caselli, Richard J; Woodruff, Bryan K; Rapscak, Steven Z; Ahern, Geoffrey L; Shi, Jiong; Burke, Anna D; Reiman, Eric M; Sabbagh, Marwan N

    2015-08-01

    The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200

  2. 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

  3. 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

    2015-01-01

    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 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. PMID:26295258

  4. Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders

    NARCIS (Netherlands)

    Kos, Claire; van Tol, Marie-Jose; Marsman, Jan-Bernard C.; Knegtering, Henderikus; Aleman, Andre

    2016-01-01

    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

  5. Recommendations for the Use of Serious Games in Neurodegenerative Disorders: 2016 Delphi Panel

    Directory of Open Access Journals (Sweden)

    Valeria Manera

    2017-07-01

    Full Text Available The use of Serious Games (SG in the health domain is expanding. In the field of neurodegenerative disorders (ND such as Alzheimer’s disease, SG are currently employed both to support and improve the assessment of different functional and cognitive abilities, and to provide alternative solutions for patients’ treatment, stimulation, and rehabilitation. As the field is quite young, recommendations on the use of SG in people with ND are still rare. In 2014 we proposed some initial recommendations (Robert et al., 2014. The aim of the present work was to update them, thanks to opinions gathered by experts in the field during an expert Delphi panel. Results confirmed that SG are adapted to elderly people with mild cognitive impairment (MCI and dementia, and can be employed for several purposes, including assessment, stimulation, and improving wellbeing, with some differences depending on the population (e.g., physical stimulation may be better suited for people with MCI. SG are more adapted for use with trained caregivers (both at home and in clinical settings, with a frequency ranging from 2 to 4 times a week. Importantly, the target of SG, their frequency of use and the context in which they are played depend on the SG typology (e.g., Exergame, cognitive game, and should be personalized with the help of a clinician.

  6. 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.

  7. 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

  8. 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.

  9. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases

    OpenAIRE

    Chin-Chan, Miguel; Navarro-Yepes, Juliana; Quintanilla-Vega, Betzabet

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, ...

  10. Gut Microbiota, Nitric Oxide, and Microglia as Prerequisites for Neurodegenerative Disorders.

    Science.gov (United States)

    Tse, Joyce K Y

    2017-07-19

    Regulating fluctuating endogenous nitric oxide (NO) levels is necessary for proper physiological functions. Aberrant NO pathways are implicated in a number of neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease. The mechanism of NO in oxidative and nitrosative stress with pathological consequences involves reactions with reactive oxygen species (e.g., superoxide) to form the highly reactive peroxynitrite, hydrogen peroxide, hypochloride ions and hydroxyl radical. NO levels are typically regulated by endogenous nitric oxide synthases (NOS), and inflammatory iNOS is implicated in the pathogenesis of neurodegenerative diseases, in which elevated NO mediates axonal degeneration and activates cyclooxygenases to provoke neuroinflammation. NO also instigates a down-regulated secretion of brain-derived neurotrophic factor, which is essential for neuronal survival, development and differentiation, synaptogenesis, and learning and memory. The gut-brain axis denotes communication between the enteric nervous system (ENS) of the GI tract and the central nervous system (CNS) of the brain, and the modes of communication include the vagus nerve, passive diffusion and carrier by oxyhemoglobin. Amyloid precursor protein that forms amyloid beta plaques in AD is normally expressed in the ENS by gut bacteria, but when amyloid beta accumulates, it compromises CNS functions. Escherichia coli and Salmonella enterica are among the many bacterial strains that express and secrete amyloid proteins and contribute to AD pathogenesis. Gut microbiota is essential for regulating microglia maturation and activation, and activated microglia secrete significant amounts of iNOS. Pharmacological interventions and lifestyle modifications to rectify aberrant NO signaling in AD include NOS inhibitors, NMDA receptor antagonists, potassium channel modulators, probiotics, diet, and exercise.

  11. Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease

    National Research Council Canada - National Science Library

    Geuens, Thomas; De Winter, Vicky; Rajan, Nicholas; Achsel, Tilmann; Mateiu, Ligia; Almeida-Souza, Leonardo; Asselbergh, Bob; Bouhy, Delphine; Auer-Grumbach, Michaela; Bagni, Claudia; Timmerman, Vincent

    2017-01-01

    .... So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

  12. The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review.

    Science.gov (United States)

    Pang, Shirley Yin-Yu; Teo, Kay-Cheong; Hsu, Jacob Shujui; Chang, Richard Shek-Kwan; Li, Miaoxin; Sham, Pak-Chung; Ho, Shu-Leong

    2017-01-01

    The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.

  13. Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Rockenstein Edward

    2011-09-01

    Full Text Available Abstract Background Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain. Abnormal activation of CDK5 is associated with neurodegenerative disorders, and recently a critical role for CDK5 in adult neurogenesis has been identified. We have developed an in vitro model of abnormal CDK5 activation during adult hippocampal neurogenesis, and here we used this model to investigate aberrantly phosphorylated downstream targets of CDK5. Results Abnormal CDK5 activation in an in vitro model of adult neurogenesis results in hyperphosphorylation of collapsin-response mediator protein-2 (CRMP2 and impaired neurite outgrowth. Inhibition of CDK5, or expression of a non-phosphorylatable (S522A CRMP2 construct reduced CRMP2 hyperphosphorylation, and reversed neurite outgrowth deficits. CRMP2 plays a role in microtubule dynamics; therefore we examined the integrity of microtubules in this model using biochemical and electron microscopy techniques. We found that microtubule organization was disrupted under conditions of CDK5 activation. Finally, to study the relevance of these findings to neurogenesis in neurodegenerative conditions associated with HIV infection, we performed immunochemical analyses of the brains of patients with HIV and transgenic mice expressing HIV-gp120 protein. CDK5-mediated CRMP2 phosphorylation was significantly increased in the hippocampus of patients with HIV encephalitis and in gp120 transgenic mice, and this effect was rescued by genetic down-modulation of CDK5 in the mouse model. Conclusions These results reveal a functional mechanism involving microtubule destabilization through which abnormal CDK5 activation and CRMP2 hyperphosphorylation might contribute to defective neurogenesis in neurodegenerative disorders such as HIV encephalitis.

  14. Genetic Causes of Cerebrovascular Disorders in Childhood

    NARCIS (Netherlands)

    M.E.C. Meuwissen (Marije)

    2014-01-01

    markdownabstract__Abstract__ Cerebrovascular disorders in childhood comprise ischemic stroke and hemorrhagic stroke. This thesis comprises a escription of genetic causes of childhood cerebrovascular disorders. Two examples of genetic causes of ischemic stroke, comprising a case of ACTA2 mutation

  15. 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.

  16. Proline-rich polypeptides in Alzheimer's disease and neurodegenerative disorders - Therapeutic potential or a mirage?

    NARCIS (Netherlands)

    Gladkevich, A.; Bosker, F.; Korf, J.; Yenkoyan, K.; Vahradyan, H.; Aghajanov, M.

    2007-01-01

    The development of effective and safe drugs for a growing Alzheimer disease population is an increasing need at present. Both experimental and clinical evidence support a beneficial effect of proline-rich polypeptides in a number of neurodegenerative diseases, including Alzheimer disease.

  17. Visual Hallucinations in the Psychosis Spectrum and Comparative Information From Neurodegenerative Disorders and Eye Disease

    NARCIS (Netherlands)

    Waters, Flavie; Collerton, Daniel; Ffytche, Dominic H.; Jardri, Renaud; Pins, Delphine; Dudley, Robert; Blom, Jan Dirk; Mosimann, Urs Peter; Eperjesi, Frank; Ford, Stephen; Laroi, Frank

    Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding

  18. PET Imaging of the Peripheral Benzodiazepine Receptor : Monitoring Disease Progression and Therapy Response in Neurodegenerative Disorders

    NARCIS (Netherlands)

    Doorduin, Janine; de Vries, Erik F. J.; Dierckx, Rudi A.; Klein, Hans C.

    2008-01-01

    It is important to gain more insight into neurodegenerative diseases, because these debilitating diseases can not be cured. A common characteristic of many neurological diseases is neuroinflammation, which is accompanied by the presence of activated microglia cells. In activated microglia cells, an

  19. 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

  20. Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders.

    Science.gov (United States)

    Lee, Sol Moe; Chung, Myungguen; Hyeon, Jae Wook; Jeong, Seok Won; Ju, Young Ran; Kim, Heebal; Lee, Jeongmin; Kim, SangYun; An, Seong Soo A; Cho, Sung Beom; Lee, Yeong Seon; Kim, Su Yeon

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10-15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs.

  1. 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.

  2. Heteronemin, a marine sponge terpenoid, targets TDP-43, a key factor in several neurodegenerative disorders.

    Science.gov (United States)

    Cassiano, Chiara; Esposito, Roberta; Tosco, Alessandra; Zampella, Angela; D'Auria, Maria Valeria; Riccio, Raffaele; Casapullo, Agostino; Monti, Maria Chiara

    2014-01-14

    Trans-activation response DNA-binding protein of 43 kDa (TDP-43), a key factor in several neurodegenerative conditions, was discovered as a novel target of heteronemin by chemical proteomics. Combining bio-physical orthogonal approaches with biological analysis, heteronemin was found to influence the binding of TDP-43-cognate nucleic acids and to modulate the TDP-43 aggregation state and its cellular localization.

  3. 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

  4. 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.

  5. High-speed video gait analysis reveals early and characteristic locomotor phenotypes in mouse models of neurodegenerative movement disorders.

    Science.gov (United States)

    Preisig, Daniel F; Kulic, Luka; Krüger, Maik; Wirth, Fabian; McAfoose, Jordan; Späni, Claudia; Gantenbein, Pascal; Derungs, Rebecca; Nitsch, Roger M; Welt, Tobias

    2016-09-15

    Neurodegenerative diseases of the central nervous system frequently affect the locomotor system resulting in impaired movement and gait. In this study we performed a whole-body high-speed video gait analysis in three different mouse lines of neurodegenerative movement disorders to investigate the motor phenotype. Based on precise computerized motion tracking of all relevant joints and the tail, a custom-developed algorithm generated individual and comprehensive locomotor profiles consisting of 164 spatial and temporal parameters. Gait changes observed in the three models corresponded closely to the classical clinical symptoms described in these disorders: Muscle atrophy due to motor neuron loss in SOD1 G93A transgenic mice led to gait characterized by changes in hind-limb movement and positioning. In contrast, locomotion in huntingtin N171-82Q mice modeling Huntington's disease with basal ganglia damage was defined by hyperkinetic limb movements and rigidity of the trunk. Harlequin mutant mice modeling cerebellar degeneration showed gait instability and extensive changes in limb positioning. Moreover, model specific gait parameters were identified and were shown to be more sensitive than conventional motor tests. Altogether, this technique provides new opportunities to decipher underlying disease mechanisms and test novel therapeutic approaches. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. 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.

  7. RBD and Neurodegenerative Diseases.

    Science.gov (United States)

    Jiang, Haiyang; Huang, Jinsha; Shen, Yan; Guo, Shiyi; Wang, Luxi; Han, Chao; Liu, Ling; Ma, Kai; Xia, Yun; Li, Jie; Xu, Xiaoyun; Xiong, Nian; Wang, Tao

    2017-05-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by enacting one's dreams during the REM sleep, with most of the dreams being violent or aggressive, so that patients often come to see the doctor complaining hurting themselves or bed partners during sleep. Prevalence of RBD, based on population, is 0.38-2.01 %, but much higher in patients with neurodegenerative diseases, especially synucleinopathies. RBD may herald the emergence of synucleinopathies by decades, such that it may be used as an effective early marker of neurodegenerative diseases. Pharmaceutical treatment of RBD includes clonazepam, melatonin, pramipexole, and some newly reported medications. In this review, we summarized the clinical and PSG features of RBD, the pathophysiology and the therapy of it, focusing on the correlation between neurodegenerative diseases and RBD, in order to emphasize the significance of RBD as an early marker of neurodegenerative diseases.

  8. 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.

  9. Progressive and self-limiting neurodegenerative disorders in Africa: a new prominent field of research led by South Africa but without strong health policy.

    Science.gov (United States)

    Poreau, Brice

    2016-01-01

    Neurodegenerative disorders are involved in mortality and morbidity of every country. A high prevalence is estimated in Africa. Neurodegenerative disorders are defined by a progressive or self-limiting alteration of neurons implied in specific functional and anatomical functions. It encompasses a various range of clinical disorders from self-limiting to progressive. Focus on public health policies and scientific research is needed to understand the mechanisms to reduce this high prevalence. We use bibliometrics and mapping tools to explore the area studies and countries involved in scientific research on neurodegenerative disorders in Africa. We used two databases: Web of Science and Pubmed. We analyzed the journals, most cited articles, authors, publication years, organizations, funding agencies, countries and keywords in Web of Science Core collection database and publication years and Medical Subject Headings in Pubmed database. We mapped the data using VOSviewer. We accessed 44 articles published between 1975 and 2014 in Web of Science Core collection Database and 669 from Pubmed database. The majority of which were after 2006. The main countries involved in research on neurodegenerative disorders in Africa the USA, the United Kingdom, France and South Africa representing the main network collaboration. Clinical neurology and Genetics hereditary are the main Web of Science categories whereas Neurosciences and Biochemistry and Molecular Biology are the main Web of Science categories for the general search "neurodegenerative disorders" not restrained to Africa. This is confirmed by Medical Subject Headings analysis from Pubmed with one more area study: Treatment. Neurodegenerative disorders research is leaded by South Africa with a network involving the USA, the UK, as well as African countries such Zambia. The chief field that emerged was on patient and hereditary as well as treatment. Public health policies were lacking fields in research whereas prevalence is

  10. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-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. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward 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.

  11. 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.

  12. 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.

  13. 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)

  14. In search of innovative therapeutics for neuropsychiatric disorders: the case of neurodegenerative diseases.

    Science.gov (United States)

    Féger, J; Hirsch, E C

    2015-01-01

    The recent medical literature highlights the lack of new drugs able to prevent or treat neurodegenerative diseases such as Alzheimer disease or Parkinson disease. Yet, the prevalence of these diseases is growing, related to increasing life expectancy, and is leading to a rise in their economic and social cost. At the same time, pharmaceutical companies are reducing or halting their investment in neuropharmacological research. Why have advances in basic neuroscience and our understanding of these diseases not allowed innovative discoveries in drug research? This review will try to explain this failure and suggest possible solutions: develop basic and clinical research but with the emphasis on translational and truly collaborative research; improve preclinical studies by developing more appropriate animal models, using new biomarkers and methodologies such as imaging suitable for clinical trials, providing worthwhile information on the ability of the drug to reach its intended target and induce significant pharmacological changes; build a new system of research management, based on stronger interdisciplinary relations between preclinical and clinical research and including the introduction of international precompetitive research between academic teams, start-up companies and pharmaceutical laboratories; hold early discussions with the regulatory authorities during preclinical studies and at the beginning of clinical trials in order to validate the methodological approaches; involve patients' associations in this new organization of research. These changes should help to ensure the discovery of effective treatments for these pathologies. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA.

    Science.gov (United States)

    King, Barbara; Hassiotis, Sofia; Rozaklis, Tina; Beard, Helen; Trim, Paul J; Snel, Marten F; Hopwood, John J; Hemsley, Kim M

    2016-05-01

    Repeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained-release (osmotic pump-delivered) enzyme replacement therapy in murine MPS IIIA as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six-week-old MPS IIIA and unaffected mice were implanted with subcutaneous mini-osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7 weeks, with pumps replaced part-way through the experimental period. We observed near-normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the MPS IIIA brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored GM 3 ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump-like conditions for at least 1 month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of MPS IIIA and other lysosomal storage disorders that affect the brain. Clinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre-clinical study, we examined an alternative approach - slow, continual infusion

  16. Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes.

    Science.gov (United States)

    Calabrese, Vittorio; Cornelius, Carolin; Stella, Anna Maria Giuffrida; Calabrese, Edward J

    2010-12-01

    The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre

  17. 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

    nontoxic medication that normalizes physiological functions, disturbed by chronic stress, through correction of imbalances in the neuroendocrine and immune systems [9, 10]. The scientific research that has been carried out on Ashwagandha and other ayurvedic herbal medicines may be classified into three major categories, taking into consideration the endogenous or exogenous phenomena that are known to cause physiological disequilibrium leading to the pathological state; (A) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on specific non-neurological diseases; (B) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on neurodegenerative disorders; and (C) biochemical, physiological and genetic studies on the herbal plants themselves, in order to distinguish between those originating from different habitats, or to improve the known medicinal quality of the indigenous plant. Some of the major points on its use in the treatment of neurodegenerative disorders are described below.

  18. Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?

    Directory of Open Access Journals (Sweden)

    Alessandro Castorina

    2015-01-01

    Full Text Available Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration.Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients. So far, mesenchymal stem cells have proven to be a viable option to ameliorate certain aspects of neurodegeneration, as they possess high proliferative rate and differentiate in vitro into multiple lineages. However, accumulating data have demonstrated that during long-term culture, mesenchymal stem cells undergo spontaneous transformation. Transformed mesenchymal stem cells show typical features of senescence, including the progressive shortening of telomers, which results in cell loss and, as a consequence, hampered regenerative potential. These evidences, in line with those observed in mesenchymal stem cells isolated from old donors, suggest that senescence may represent a limit to mesenchymal stem cells exploitation in therapy, prompting scholars to either find alternative sources of pluripotent cells or to arrest the age-related transformation. In the present review, we summarize findings from recent literature, and critically discuss some of the major hurdles encountered in the search of appropriate sources of mesenchymal stem cells, as well as benefits arising from their use in neurodegenerative diseases. Finally, we provide some insights that may aid in the development of strategies to arrest or, at least, delay the aging of mesenchymal stem cells to improve their therapeutic potential.

  19. Sleep and circadian dysfunction in neurodegenerative disorders: insights from a mouse model of Huntington's disease.

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    Kuljis, Dika; Schroeder, Analyne M; Kudo, Takashi; Loh, Dawn H; Willison, David L; Colwell, Christopher S

    2012-09-01

    Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington's disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD patients and the consequences of circadian disruption. This raises the possibility that the disordered sleep and circadian function experienced by HD patients may be an integral part of the disease. Furthermore, we speculate that circadian dysfunction may accelerate the pathology underlying HD. If these hypotheses are correct, we should focus on treating circadian misalignment and sleep disruptions early in disease progression.

  20. Increased Understanding of Stem Cell Behavior in Neurodegenerative and Neuromuscular Disorders by Use of Noninvasive Cell Imaging

    Directory of Open Access Journals (Sweden)

    Bryan Holvoet

    2016-01-01

    Full Text Available Numerous neurodegenerative and neuromuscular disorders are associated with cell-specific depletion in the human body. This imbalance in tissue homeostasis is in healthy individuals repaired by the presence of endogenous stem cells that can replace the lost cell type. However, in most disorders, a genetic origin or limited presence or exhaustion of stem cells impairs correct cell replacement. During the last 30 years, methods to readily isolate and expand stem cells have been developed and this resulted in a major change in the regenerative medicine field as it generates sufficient amount of cells for human transplantation applications. Furthermore, stem cells have been shown to release cytokines with beneficial effects for several diseases. At present however, clinical stem cell transplantations studies are struggling to demonstrate clinical efficacy despite promising preclinical results. Therefore, to allow stem cell therapy to achieve its full potential, more insight in their in vivo behavior has to be achieved. Different methods to noninvasively monitor these cells have been developed and are discussed. In some cases, stem cell monitoring even reached the clinical setting. We anticipate that by further exploring these imaging possibilities and unraveling their in vivo behavior further improvement in stem cell transplantations will be achieved.

  1. Lysosomal dysfunction in neurodegenerative diseases

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    Klaudia Tomala

    2017-05-01

    Full Text Available Recent data advocate for the implication of lysosomes in the development of programmed cell death. Lysosomal dysfunction decreased the efficiency of autophagosome/lysosome fusion that leads to vacuolation of cells. Autophagic vacuoles containing damaged organelles and altered proteins are hallmarks in most neurodegenerative disorders. These aggregates consequently disrupt cellular homeostasis causing neuronal cell death due apoptosis or necrosis. Moreover calpain mediated or mutation inducted lysosomal rupture result in release of lysosomal cathepsins into the cytoplasm and inducing neuronal cell death. In this review we emphasize the pathophysiological mechanism connecting disrupting autophagy – lysosomal pathway and lysosomal dysfunction in neuronal cell death called lysosomal cell death.

  2. Sleep disturbance in mental health problems and neurodegenerative disease.

    Science.gov (United States)

    Anderson, Kirstie N; Bradley, Andrew J

    2013-01-01

    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.

  3. Engineering enhanced protein disaggregases for neurodegenerative disease

    OpenAIRE

    Jackrel, Meredith E.; Shorter, James

    2015-01-01

    Abstract Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by...

  4. Prodromal Parkinsonism and Neurodegenerative Risk Stratification in REM Sleep Behavior Disorder.

    Science.gov (United States)

    Barber, Thomas R; Lawton, Michael; Rolinski, Michal; Evetts, Samuel; Baig, Fahd; Ruffmann, Claudio; Gornall, Aimie; Klein, Johannes C; Lo, Christine; Dennis, Gary; Bandmann, Oliver; Quinnell, Timothy; Zaiwalla, Zenobia; Ben-Shlomo, Yoav; Hu, Michele T M

    2017-08-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Clinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson's (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations. Compared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson's Disease Rating Scale (UPDRS)-III, timed "get-up-and-go", Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson's compared to 0.3% (95% CI 0.009%, 2%) of controls. RBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions.

  5. Sleep in Neurodegenerative Diseases.

    Science.gov (United States)

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders

    Science.gov (United States)

    Brzdak, Patrycja; Nowak, Daria; Wiera, Grzegorz; Mozrzymas, Jerzy W.

    2017-01-01

    The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs) and astacins in physiological and pathological processes in the central nervous system (CNS). The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins). Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer’s disease (AD). We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ) peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors that mediate the uptake of Aβ peptide. Controlling the proteolytic activity of metzincins in Aβ-induced pathological changes in AD patients’ brains may be a promising therapeutic strategy. PMID:28713245

  7. Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Patrycja Brzdak

    2017-06-01

    Full Text Available The extracellular matrix (ECM and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs, A Disintegrin and Metalloproteinases (ADAMs, A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs and astacins in physiological and pathological processes in the central nervous system (CNS. The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins. Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer’s disease (AD. We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB and blood-cerebrospinal fluid barrier (BCSFB that contain specific receptors that mediate the uptake of Aβ peptide. Controlling the proteolytic activity of metzincins in Aβ-induced pathological changes in AD patients’ brains may be a promising therapeutic strategy.

  8. Relevance of the chronobiological and non-chronobiological actions of melatonin for enhancing therapeutic efficacy in neurodegenerative disorders.

    Science.gov (United States)

    Cecon, Erika; Markus, Regina P

    2011-05-01

    Melatonin is an indolamine with a large spectrum of functions that can be divided into chronobiotic and nonchronobiotic. Chronobiotic effects are mediated by the daily rhythm of melatonin in the plasma due to nocturnal pineal synthesis, whereas the melatonin produced by other cells, such as gastrointestinal and immune competent cells, is independent of the light/dark cycle and exert non-chronobiotic effects. The concentrations achieved by the two sources are significantly different, varying in the pM-nM range in the plasma, and may achieve concentrations in the mM range when released locally by activated immune-competent cells. Consequently, the effects of the melatonin produced in these two situations are distinct. Much has been reported about the beneficial response to exogenous melatonin administration in several pathological conditions. However, the relationship between the establishment of a disease and the state of the physiological activity of the pineal gland is still poorly understood. Here, we review the state of art in the modulation of pineal melatonin synthesis, relevant patents, and discuss its relationship with neurodegenerative disorders that involve a central inflammatory response, such as Alzheimer's disease, to suggest the putative relevance of new therapeutic protocols that replace this pineal hormone.

  9. The impact of obesity on neurodegenerative diseases.

    Science.gov (United States)

    Mazon, Janaína Niero; de Mello, Aline Haas; Ferreira, Gabriela Kozuchovski; Rezin, Gislaine Tezza

    2017-08-01

    Neurodegenerative diseases are a growing health concern. The increasing incidences of these disorders have a great impact on the patients' quality of life. Although the mechanisms of neurodegenerative diseases are still far from being clarified, several studies look for new discoveries about their pathophysiology and prevention. Furthermore, evidence has shown a strong correlation between obesity and the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Metabolic changes caused by overweight are related to damage to the central nervous system (CNS), which can lead to neural death, either by apoptosis or cell necrosis, as well as alter the synaptic plasticity of the neuron. This review aims to show the association between neurodegenerative diseases, focusing on AD and PD, and metabolic alterations. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Potential contribution of the neurodegenerative disorders risk loci to cognitive performance in an elderly male gout population.

    Science.gov (United States)

    Han, Lin; Jia, Zhaotong; Cao, Chunwei; Liu, Zhen; Liu, Fuqiang; Wang, Lin; Ren, Wei; Sun, Mingxia; Wang, Baoping; Li, Changgui; Chen, Li

    2017-09-01

    Cognitive impairment has been described in elderly subjects with high normal concentrations of serum uric acid. However, it remains unclear if gout confers an increased poorer cognition than those in individuals with asymptomatic hyperuricemia. The present study aimed at evaluating cognitive function in patients suffering from gout in an elderly male population, and further investigating the genetic contributions to the risk of cognitive function.This study examined the cognitive function as assessed by Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in 205 male gout patients and 204 controls. The genetic basis of these cognitive measures was evaluated by genome-wide association study (GWAS) data in 102 male gout patients. Furthermore, 7 loci associated with cognition in GWAS were studied for correlation with gout in 1179 male gout patients and 1848 healthy male controls.Compared with controls, gout patients had significantly lower MoCA scores [22.78 ± 3.01 vs 23.42 ± 2.95, P = .023, adjusted by age, body mass index (BMI), education, and emotional disorder]. GWAS revealed 7 single-nucleotide polymorphisms (SNPs) associations with MoCA test at a level of conventional genome-wide significance (P gout in further analysis (all P > .05).Elderly male subjects with gout exhibit accelerated decline in cognition performance. Several neurodegenerative disorders risk loci were identified for genetic contributors to cognitive performance in our Chinese elderly male gout population. Larger prospective studies of the cognitive performance and genetic analysis in gout subjects are recommended.

  11. 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

  12. Adenyl cyclase activator forskolin protects against Huntington's disease-like neurodegenerative disorders

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    Sidharth Mehan

    2017-01-01

    Full Text Available Long term suppression of succinate dehydrogenase by selective inhibitor 3-nitropropionic acid has been used in rodents to model Huntington's disease where mitochondrial dysfunction and oxidative damages are primary pathological hallmarks for neuronal damage. Improvements in learning and memory abilities, recovery of energy levels, and reduction of excitotoxicity damage can be achieved through activation of Adenyl cyclase enzyme by a specific phytochemical forskolin. In this study, intraperitoneal administration of 10 mg/kg 3-nitropropionic acid for 15 days in rats notably reduced body weight, worsened motor cocordination (grip strength, beam crossing task, locomotor activity, resulted in learning and memory deficits, greatly increased acetylcholinesterase, lactate dehydrogenase, nitrite, and malondialdehyde levels, obviously decreased adenosine triphosphate, succinate dehydrogenase, superoxide dismutase, catalase, and reduced glutathione levels in the striatum, cortex and hippocampus. Intragastric administration of forskolin at 10, 20, 30 mg/kg dose-dependently reversed these behavioral, biochemical and pathological changes caused by 3-nitropropionic acid. These results suggest that forskolin exhibits neuroprotective effects on 3-nitropropionic acid-induced Huntington's disease-like neurodegeneration.

  13. 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

  14. Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease.

    Science.gov (United States)

    Levesque, Shannon; Surace, Michael J; McDonald, Jacob; Block, Michelle L

    2011-08-24

    Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m³) by inhalation over 6 months. DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m³ significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m³ and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m³) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m³ exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology. Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain.

  15. Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    McDonald Jacob

    2011-08-01

    Full Text Available Abstract Background Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Objective We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Methods Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3 by inhalation over 6 months. Results DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3 in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology. Conclusions Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may

  16. Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports.

    Science.gov (United States)

    Dastsooz, Hassan; Nemati, Hamid; Fard, Mohammad Ali Farazi; Fardaei, Majid; Faghihi, Mohammad Ali

    2017-08-18

    Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. The purpose of this study was to investigate disease-causing mutations in two patients with distinct NBIA disorders. Whole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. In addition, our study revealed a novel missense mutation in PLA2G6 gene (c.3G > T:p.M1I) in one and half-year-old boy with muscle weakness and neurodevelopmental regression (speech, motor and cognition). The novel mutations were also confirmed by Sanger sequencing in the proband and their parents. Current study uncovered two rare novel mutations in PANK2 and PLA2G6 genes in patients with NBIA disorder and such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these types of disorders.

  17. [Voice disorders caused by neurological diseases].

    Science.gov (United States)

    Gamboa, J; Jiménez-Jiménez, F J; Mate, M A; Cobeta, I

    To review voice disorders in neurological diseases, with special emphasis to acoustic analysis. In the first part of this article we describe data regarding neural control of voice, physiology of phonation, and examination of the patient with voice disturbances, including the use of voice laboratory, acoustic analysis fundamentals, phonetometric measures and aerodynamic measures. In the second part, we review the voice disturbances associated to neurological diseases, emphasizing into movement disorders (specially Parkinson s disease, essential tremor, and spasmodic dysphonia). A number of neurological diseases causing alterations of corticospinal pathway, cerebellum, basal ganglia and upper and/or lower motoneurons can induce voice disturbances. Voice examination using ear, nose & throat examination, endoscopy and videorecording of laryngeal movements, acoustic analysis, elecroglottography, laryngeal electromyography, and aerodynamic measures, could be useful in the clinical examination of some neurological diseases.

  18. Indian Herbs for the Treatment of Neurodegenerative Disease.

    Science.gov (United States)

    Mannangatti, Padmanabhan; Naidu, Kamalakkannan Narasimha

    2016-01-01

    Ayurveda, an ancient system of medicine that is indigenous to India, is believed to be the world's oldest comprehensive health-care system and is now one of the most recognized and widely practiced disciplines of alternative medicine in the world. Medicinal herbs have been in use for treating diseases since ancient times in India. Ayurvedic therapies with medicinal herbs and herbomineral products generally provide relief without much adverse effects even after prolonged administration. Neurodegenerative disorders are a major cause of mortality and disability, and increasing life spans represent one of the key challenges of medical research. Ayurvedic medicine describes most neurodegenerative diseases and has defined a number of plants with therapeutic benefits for the treatment of neurodegenerative diseases having antioxidant activities. In this chapter, the role of four important Ayurvedic medicinal plants, viz., Withania somnifera (ashwagandha), Bacopa monnieri (brahmi), Centella asiatica (gotu kola), and Mucuna pruriens (velvet bean), on neurodegenerative diseases are discussed.

  19. Factitious disorder: a rare cause of haematemesis.

    Science.gov (United States)

    McFarlane, Michael; Eaden, Jayne; Burch, Nicola; Disney, Ben

    2017-10-01

    Acute upper gastrointestinal (GI) bleeding is a common condition in the UK with 50-70,000 admissions per year. In 20% of cases no cause can be found on endoscopy. Here, we present the case of a young female patient who was admitted on three occasions with large volume haematemesis and bleeding from other sites. She was extensively investigated and underwent multiple endoscopic procedures. She was eventually diagnosed with factitious disorder after concerns were raised about the inconsistent nature of her presentations. She was found to be venesecting herself from her intravenous cannula, and ingesting the blood to simulate upper GI bleeding. This is a rare cause of 'haematemesis' but perhaps not as rare as is thought.

  20. Idiopathic REM sleep behavior disorder and neurodegenerative risk: To tell or not to tell to the patient? How to minimize the risk?

    Science.gov (United States)

    Arnaldi, Dario; Antelmi, Elena; St Louis, Erik K; Postuma, Ronald B; Arnulf, Isabelle

    2016-11-10

    Most people with idiopathic REM sleep behavior disorder (iRBD) have an underlying synucleinopathy, mainly Parkinson's disease (PD) or dementia with Lewy bodies, with median conversion time of 4-9 y from iRBD diagnosis and of 11-16 y from symptom onset. Subtle signs and imaging tests indicate concomitant neurodegeneration in widespread brain areas. Risk factor studies suggest that iRBD patients may have prior head injury, occupational farming, pesticide exposure, low education level and possibly more frequent family history of dream-enactment behavior (but not of PD), plus unexpected risk factors (smoking, ischemic heart disease and inhaled corticosteroid use). Unlike PD, caffeine and smoking appear not to have a protective role. Prior depression and antidepressant use may be early neurodegenerative signs rather than exclusively causative factors. Age, hyposmia, impaired color vision, abnormal dopaminergic imaging, mild cognitive impairment and possibly sleepiness, may identify patients at greater risk of more rapid conversion. The consensus is to generally disclose the neurodegenerative risk to patients (with the caveat that phenoconversion and its temporal course remain uncertain in individuals without "soft neurodegenerative signs" and those under 50 y of age), to suggest a healthy lifestyle and to take part in prospective cohort studies in anticipation of eventual neuroprotective trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. 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.

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

    OpenAIRE

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

    2015-01-01

    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 i...

  3. Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Tran, Christel; Hewson, Stacy; Steinberg, Steven J; Mercimek-Mahmutoglu, Saadet

    2014-08-01

    Zellweger spectrum disorder is an autosomal recessively inherited multisystem disorder caused by one of the 13 different PEX gene defects resulting in defective peroxisomal assembly and multiple peroxisomal enzyme deficiencies. We report a new patient with late-onset Zellweger spectrum disorder mimicking X-linked adrenoleukodystrophy. This 8.5-year-old boy with normal development until 6.5 years of age presented with bilateral sensorineural hearing loss during a school hearing test. He then developed acute-onset diplopia, clumsiness, and cognitive dysfunction at age 7 years. Magnetic resonance imaging of the brain revealed symmetric leukodystrophy, although without gadolinium enhancement. Elevated plasma very long chain fatty acid levels were suggestive of X-linked adrenoleukodystrophy, but his ABCD1 gene had normal coding sequence and dosage. Additional studies of cultured skin fibroblasts were consistent with Zellweger spectrum disorder. Molecular testing identified disease-causing compound heterozygous mutations in the PEX6 gene supporting the Zellweger spectrum disorder diagnosis in this patient. We describe a new patient with late-onset Zellweger spectrum disorder caused by PEX6 mutations who presented with an acute neurodegenerative disease course mimicking X-linked adrenoleukodystrophy. This finding provides an additional reason that molecular confirmation is important for the genetic counseling and management of patients with a clinical and biochemical diagnosis of X-linked adrenoleukodystrophy. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Metals and neurodegenerative diseases. A systematic review.

    Science.gov (United States)

    Cicero, Calogero Edoardo; Mostile, Giovanni; Vasta, Rosario; Rapisarda, Venerando; Signorelli, Salvatore Santo; Ferrante, Margherita; Zappia, Mario; Nicoletti, Alessandra

    2017-11-01

    Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical presentation such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease (AD) and Parkinson's disease (PD). Genetic mutations have a known causative role, but the majority of cases are likely to be probably caused by a complex gene-environment interaction. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies and it is likely that each metal could be toxic through specific pathways. The possible pathogenic role of different metals has been supported by some epidemiological evidences coming from occupational and ecological studies. In order to assess the possible association between metals and neurodegenerative disorders, several case-control studies have also been carried out evaluating the metals concentration in different biological specimens such as blood/serum/plasma, cerebrospinal fluid (CSF), nail and hair, often reporting conflicting results. This review provides an overview of our current knowledge on the possible association between metals and ALS, AD and PD as main neurodegenerative disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. New strategies for the treatment of Parkinson's disease hold considerable promise for future management of neurodegenerative disorders

    DEFF Research Database (Denmark)

    Bjarkam, Carsten Reidies; Sørensen, Jens Christian; Sunde, Niels Å

    2001-01-01

    or more. Parkinson's disease ischaracterized by a massive loss of dopaminergicneurons in the substantia nigra, leading tosevere functional disturbance of the neuronalcircuitry in the basal ganglia. A thoroughdescription of basal ganglia circuitry inhealth and disease is presented. We describehow...... the functional disturbances seen inParkinson's disease may be corrected atspecific sites in this circuitry by medicaltreatment or, in advanced stages of Parkinson'sdisease, by neurosurgical methods. The latterinclude lesional surgery, neuraltransplantation and deep brain stimulation,together with future......Neurodegenerative diseases are often consideredincurable with no efficient therapies to modifyor halt the progress of disease, and ultimatelylead to reduced quality of life and to death.Our knowledge of the nervous system in healthand disease has, however, increasedconsiderably during the last...

  6. Oxidative Stress and Protein Quality Control Systems in the Aged Canine Brain as a Model for Human Neurodegenerative Disorders.

    Science.gov (United States)

    Romanucci, Mariarita; Della Salda, Leonardo

    2015-01-01

    Aged dogs are considered the most suitable spontaneous animal model for studying normal aging and neurodegenerative diseases. Elderly canines naturally develop cognitive dysfunction and neuropathological hallmarks similar to those seen in humans, especially Alzheimer's disease-like pathology. Pet dogs also share similar living conditions and diets to humans. Oxidative damage accumulates in the canine brain during aging, making dogs a valid model for translational antioxidant treatment/prevention studies. Evidence suggests the presence of detective protein quality control systems, involving ubiquitin-proteasome system (UPS) and Heat Shock Proteins (HSPs), in the aged canine brain. Further studies on the canine model are needed to clarify the role of age-related changes in UPS activity and HSP expression in neurodegeneration in order to design novel treatment strategies, such as HSP-based therapies, aimed at improving chaperone defences against proteotoxic stress affecting brain during aging.

  7. 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

  8. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study.

    Science.gov (United States)

    Iranzo, Alex; Tolosa, Eduard; Gelpi, Ellen; Molinuevo, José Luis; Valldeoriola, Francesc; Serradell, Mónica; Sanchez-Valle, Raquel; Vilaseca, Isabel; Lomeña, Francisco; Vilas, Dolores; Lladó, Albert; Gaig, Carles; Santamaria, Joan

    2013-05-01

    We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB). Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB. Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (-1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case

  9. Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

    Directory of Open Access Journals (Sweden)

    Saba Sheikh

    2013-01-01

    Full Text Available Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

  10. Causes of Childhood Disorders: New Findings

    Science.gov (United States)

    Whittaker, James K.

    1976-01-01

    The influence of parents on the origin and perpetuation of the developmental disorders of childhood has once again become a matter of controversy with important implications for social work education and practice. Reviewed here is recent research on two disorders--infantile autism and learning disabilities. (Author)

  11. Cerebral blood flow and Aβ-amyloid estimates by WARM analysis of [11C]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

    Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [11C]Pittsburgh Compound B ([11C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including...... 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......) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [11C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [11C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among...

  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. [Neuropathological diagnosis of neurodegenerative and dementia diseases].

    Science.gov (United States)

    Kretzschmar, H A; Neumann, M

    2000-09-01

    Neurodegenerative and dementing disorders such as Parkinson disease and Alzheimer disease are among the most common diseases of advanced age. Despite progress in the clinical diagnosis of neurodegenerative disorders, definite diagnosis for most of these disorders is still possible only by neuropathological examination of the brain. The neuropathological diagnosis and classification of neurodegenerative disorders has made clear advances in recent years, particularly due to the results of genetic and biochemical studies, resulting in the development of new disease-specific antibodies. Internationally recognized consensus criteria for most neurodegenerative disorders allow a definite and standardized diagnosis to be made. To obtain further knowledge about the etiopathogenesis, particularly with regard to new therapeutic strategies, studies with clinically and neuropathologically well-documented cases are needed. The project "Brain-Net" has therefore been established with the aim of setting up a German Brain and Tissue Bank for Diseases of the Central Nervous System. The project is funded by the Federal Ministry of Education and Research.

  14. Depressive symptoms in neurodegenerative diseases

    Science.gov (United States)

    Baquero, Miquel; Martín, Nuria

    2015-01-01

    Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer’s disease and related conditions like Parkinson’s disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have a particular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment. PMID:26301229

  15. Causes of Speech Disorders in Primary School Students of Zahedan

    Directory of Open Access Journals (Sweden)

    Saeed Fakhrerahimi

    2013-02-01

    Full Text Available Background: Since making communication with others is the most important function of speech, undoubtedly, any type of disorder in speech will affect the human communicability with others. The objective of the study was to investigate reasons behind the [high] prevalence rate of stammer, producing disorders and aglossia.Materials and Methods: This descriptive-analytical study was conducted on 118 male and female students, who were studying in a primary school in Zahedan; they had referred to the Speech Therapy Centers of Zahedan University of Medical Sciences in a period of seven months. The speech therapist examinations, diagnosis tools common in speech therapy, Spielberg Children Trait and also patients' cases were used to find the reasons behind the [high] prevalence rate of speech disorders. Results: Psychological causes had the highest rate of correlation with the speech disorders among the other factors affecting the speech disorders. After psychological causes, family history and age of the subjects are the other factors which may bring about the speech disorders (P<0.05. Bilingualism and birth order has a negative relationship with the speech disorders. Likewise, another result of this study shows that only psychological causes, social causes, hereditary causes and age of subjects can predict the speech disorders (P<0.05.Conclusion: The present study shows that the speech disorders have a strong and close relationship with the psychological causes at the first step and also history of family and age of individuals at the next steps.

  16. The vitamin D, ionised calcium and parathyroid hormone axis of cerebral capillary function: therapeutic considerations for vascular-based neurodegenerative disorders.

    Science.gov (United States)

    Lam, Virginie; Takechi, Ryusuke; Pallabage-Gamarallage, Menuka; Giles, Corey; Mamo, John C L

    2015-01-01

    Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular

  17. The vitamin D, ionised calcium and parathyroid hormone axis of cerebral capillary function: therapeutic considerations for vascular-based neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Virginie Lam

    Full Text Available Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX, or exogenous infusion of parathyroid hormone (PTH on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX and hippocampal formation (HPF. Vitamin D was also associated with increased plasma ionised calcium (iCa and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP, a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of

  18. Neuroprotective effects of the anti-cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders.

    Science.gov (United States)

    Wrasidlo, Wolf; Crews, Leslie A; Tsigelny, Igor F; Stocking, Emily; Kouznetsova, Valentina L; Price, Diana; Paulino, Amy; Gonzales, Tania; Overk, Cassia R; Patrick, Christina; Rockenstein, Edward; Masliah, Eliezer

    2014-12-01

    Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier. We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders. © 2014 The British Pharmacological Society.

  19. Essential Tremor: A Neurodegenerative Disease?

    Directory of Open Access Journals (Sweden)

    Julian Benito-Leon

    2011-08-01

    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.

  20. Selenium, selenoproteins and neurodegenerative diseases.

    Science.gov (United States)

    Cardoso, Bárbara Rita; Roberts, Blaine R; Bush, Ashley I; Hare, Dominic J

    2015-08-01

    It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a 'cause or effect' of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.

  1. Automatic sleep scoring in normals and in individuals with neurodegenerative disorders according to new international sleep scoring criteria

    DEFF Research Database (Denmark)

    Jensen, Peter S.; Sørensen, Helge Bjarup Dissing; Jennum, P. J.

    2010-01-01

    Introduction: Reliable polysomnographic classification is the basis for evaluation of sleep disorders in neurological diseases. Aim: To develop a fully automatic sleep scoring algorithm on the basis of a reproduction of new international sleep scoring criteria from the American Academy of Sleep...... Medicine (AASM). Methods: A biomedical signal processing algorithm was developed, allowing for automatic sleep depth quantification of routine polysomnographic (PSG) recordings through feature extraction, supervised probabilistic Bayesian classification, and heuristic rule-based smoothing. The performance...... of the algorithm was tested using 28 manually classified day-night PSGs from 18 normal subjects and 10 patients with Parkinson's disease (PD) or multiple system atrophy (MSA). This led to quantification of automaticversus- manual epoch-by-epoch agreement rates for both normal and abnormal recordings. Results...

  2. Meditation and neurodegenerative diseases

    National Research Council Canada - National Science Library

    Newberg, Andrew B; Serruya, Mijail; Wintering, Nancy; Moss, Aleezé Sattar; Reibel, Diane; Monti, Daniel A

    2014-01-01

    .... Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform...

  3. Perceptions of the causes of eating disorders: a comparison of individuals with and without eating disorders

    OpenAIRE

    Blodgett Salafia, Elizabeth H.; Jones, Maegan E.; Haugen, Emily C.; Schaefer, Mallary K.

    2015-01-01

    Background In this study, we examined perceptions regarding the causes of eating disorders, both among those with eating disorders as well as those without. By understanding the differences in perceived causes between the two groups, better educational programs for lay people and those suffering from eating disorders can be developed. Method This study used open-ended questions to assess the beliefs of 57 individuals with self-reported eating disorders and 220 without. Participants responded ...

  4. The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile

    Directory of Open Access Journals (Sweden)

    Di Benedetto Giulia

    2008-09-01

    Full Text Available Abstract This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.

  5. A review of the potential role of nano-enabled drug delivery technologies in amyotrophic lateral sclerosis: lessons learned from other neurodegenerative disorders.

    Science.gov (United States)

    Mazibuko, Zamanzima; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Naidoo, Dinesh; Pillay, Viness

    2015-04-01

    Amyotrophic lateral sclerosis (ALS) has a multitude of factors implicated in its etiology. The complex neuro-etiology and the restrictive nature of the blood-brain barrier (BBB) have significantly hindered the drug therapy of ALS. Riluzole, a moderately performing drug, is the only agent approved for treating ALS. However, several promising nanocarrier approaches are surfacing that can provide more efficient drug delivery. In addition, biologicals such as stem cells are able to carry neurotrophic factors to their target site, providing motor neurons with the benefits of both, stem cells and neurotrophic factors. This review examines the current drug delivery strategies investigated for optimally treating ALS and related neurodegenerative disorders. Examples include cerium oxide nanoparticles in Alzheimer's disease, odorranalectin, and lactoferrin-coupled PEG-PLGA nanoparticles for urocortin transportation in Parkinson's disease that can also be employed in ALS to bypass the BBB and increase drug bioavailability. A concise incursion into the progress (and lack thereof) made in ALS clinical trials is also discussed. Nanocarriers can potentially eliminate the challenges of poor drug bioavailability in ALS as they have been proven to cross the BBB and reach target sites while minimizing systemic side-effects. Nanocarrier-based delivery of ALS drugs is an area that requires much needed investigation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  6. When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

    Science.gov (United States)

    Huang, Chuen-Lin; Kuo, Tsun-Yung; Lin, Jung-Hsin; Yang, De-Ming; Huang, Nai-Kuei

    2012-01-01

    It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A2A receptor (A2A-R), which was blocked by an A2A-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A2A-R signaling event. Since the A2A-R was implicated as a therapeutic target in treating Huntington’s disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders. PMID:22719969

  7. Engineering enhanced protein disaggregases for neurodegenerative disease.

    Science.gov (United States)

    Jackrel, Meredith E; Shorter, James

    2015-01-01

    Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.

  8. Composition, standardization and chemical profiling of Banisteriopsis caapi, a plant for the treatment of neurodegenerative disorders relevant to Parkinson's disease.

    Science.gov (United States)

    Wang, Yan-Hong; Samoylenko, Volodymyr; Tekwani, Babu L; Khan, Ikhlas A; Miller, Loren S; Chaurasiya, Narayan D; Rahman, Md Mostafizur; Tripathi, Lalit M; Khan, Shabana I; Joshi, Vaishali C; Wigger, Frank T; Muhammad, Ilias

    2010-04-21

    Banisteriopsis caapi, a woody vine from the Amazonian basin, is popularly known as an ingredient of a sacred drink ayahuasca, widely used throughout the Amazon as a medicinal tea for healing and spiritual exploration. The usefulness of Banisteriopsis caapi has been established for alleviating symptoms of neurological disorders including Parkinson's disease. Primary objective of this study was to develop the process for preparing standardized extracts of Banisteriopsis caapi to achieve high potency for inhibition of human monoamine oxidases (MAO) and antioxidant properties. The aqueous extracts prepared from different parts of the plant collected from different geographical locations and seasons were analyzed by HPLC for principal bioactive markers. The extracts were simultaneously tested in vitro for inhibition of human MAOs and antioxidant activity for analysis of correlation between phytochemical composition of the extracts and bioactivities. Reversed-phase HPLC with photodiode array detection was employed to profile the alkaloidal and non-alkaloidal components of the aqueous extract of Banisteriopsis caapi. The Banisteriopsis caapi extracts and standardized compositions were tested in vitro for inhibition of recombinant preparations of human MAO-A and MAO-B. In vitro cell-based assays were employed for evaluation of antioxidant property and mammalian cell cytotoxicity of these preparations. Among the different aerial parts, leaves, stems/large branches and stem bark of Banisteriopsis caapi, HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7-9) were present in high concentrations in dried bark of large branch. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied Banisteriopsis caapi species. The correlation between potency of MAO inhibition and antioxidant activity with the content of the main active constituents of the aqueous Banisteriopsis caapi extracts

  9. Perceptions of the causes of eating disorders: a comparison of individuals with and without eating disorders.

    Science.gov (United States)

    Blodgett Salafia, Elizabeth H; Jones, Maegan E; Haugen, Emily C; Schaefer, Mallary K

    2015-01-01

    In this study, we examined perceptions regarding the causes of eating disorders, both among those with eating disorders as well as those without. By understanding the differences in perceived causes between the two groups, better educational programs for lay people and those suffering from eating disorders can be developed. This study used open-ended questions to assess the beliefs of 57 individuals with self-reported eating disorders and 220 without. Participants responded to the questions, "What do you think was (were) the cause(s) of your eating disorder?" and "What do you think is (are) the cause(s) of eating disorders?". A list of possible codes for the causes of eating disorders was created based on a thorough review of the literature. A manually-generated set of eight codes was then created from individuals' actual responses. Frequencies and chi square analyses demonstrated differences in rates of endorsement between those with eating disorders and those without. Participants with eating disorders most frequently endorsed psychological/emotional and social problems, with genetics/biology and media/culture ideals least endorsed. Participants without eating disorders most frequently endorsed psychological/emotional problems and media/culture ideals, with traumatic life events and sports/health least endorsed. There was a difference between groups in the endorsement of the media as a cause of eating disorders, suggesting that those without eating disorders may overly attribute the media as the main cause while those with eating disorders may not be fully aware of the media's impact. Additionally, while both groups highly endorsed psychological/emotional problems, there was a noticeable stigma about eating disorders among those without eating disorders. There were noteworthy differences between samples; such differences suggest that there is a need for more education on the topic of eating disorders. Furthermore, despite empirical support for the effects of

  10. Lay theories of bipolar disorder: the causes, manifestations and cures for perceived bipolar disorder.

    Science.gov (United States)

    Furnham, Adrian; Anthony, Elizabeth

    2010-05-01

    This study aimed to investigate lay theories of the cause and treatment of bipolar disorder, and the recognition of its symptoms. This questionnaire-based study included vignette descriptions of mental disorders and 70 items relating to bipolar disorder. It was completed by 173 participants. Bipolar disorder was recognized less than depression but at the same rate as schizophrenia. Contrary to previous research, analysis showed that lay beliefs of the causes of bipolar disorder generally concur with scientific academic theories. Drug treatment was favoured as a cure rather than psychotherapy. Theories of cause and treatment were logically correlated. Overall, the results suggest that lay people have reasonably informed beliefs about the causes and treatments of bipolar disorder, however recognition of the symptoms is poor.

  11. Longitudinal Study of Neurodegenerative Disorders

    Science.gov (United States)

    2018-01-31

    MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

  12. Diagnostic Value of Isolated Mentalis Versus Mentalis Plus Upper Limb Electromyography in Idiopathic REM Sleep Behavior Disorder Patients Eventually Developing a Neurodegenerative Syndrome.

    Science.gov (United States)

    Fernández-Arcos, Ana; Iranzo, Alex; Serradell, Mónica; Gaig, Carles; Guaita, Marc; Salamero, Manel; Santamaria, Joan

    2017-04-01

    To compare two electromyographic (EMG) montages, isolated mentalis muscle versus mentalis in combination with upper limb muscles in the baseline diagnostic video-polysomnography (V-PSG) of patients with idiopathic REM sleep behaviors disorder (IRBD) who eventually were diagnosed with a clinically defined neurodegenerative syndrome. Forty-nine patients were included. At baseline, diagnosis of RBD was based on a typical history of dream enactment behaviors plus V-PSG showing REM sleep with qualitative increased EMG activity and/or abnormal behaviors. Quantification of EMG activity (tonic, phasic and "any") in the mentalis and upper limb muscles (biceps brachii-BB, n = 36 or flexor digitorum superficialis-FDS, n = 13) was performed manually and compared with published cut-offs. Nine (18.4%) patients had either tonic or phasic EMG below the cut-offs for the isolated mentalis and four of them (11.1 %) also had values below the cut-off for the mentalis combined with BB. All 13 patients recorded with the FDS were above the mentalis combined with FDS cut-off. For the diagnosis of IRBD, sensitivity of isolated mentalis was 81.6% and of the combination of mentalis plus upper limb muscles was 91.8% (p = .03). Audiovisual analysis showed abnormal REM sleep behaviors in all nine patients with values below the cut-offs. Quantification of EMG activity in the upper limbs combined with the mentalis increases the ability to diagnose IRBD when compared with the isolated measurement of the mentalis. Detection of typical abnormal behaviors during REM sleep with audiovisual analysis is essential for the diagnosis of IRBD in patients with EMG values below the published cut-offs.

  13. Fractality of sensations and the brain health: the theory linking neurodegenerative disorder with distortion of spatial and temporal scale-invariance and fractal complexity of the visible world

    Science.gov (United States)

    Zueva, Marina V.

    2015-01-01

    The theory that ties normal functioning and pathology of the brain and visual system with the spatial–temporal structure of the visual and other sensory stimuli is described for the first time in the present study. The deficit of fractal complexity of environmental influences can lead to the distortion of fractal complexity in the visual pathways of the brain and abnormalities of development or aging. The use of fractal light stimuli and fractal stimuli of other modalities can help to restore the functions of the brain, particularly in the elderly and in patients with neurodegenerative disorders or amblyopia. Non-linear dynamics of these physiological processes have a strong base of evidence, which is seen in the impaired fractal regulation of rhythmic activity in aged and diseased brains. From birth to old age, we live in a non-linear world, in which objects and processes with the properties of fractality and non-linearity surround us. Against this background, the evolution of man took place and all periods of life unfolded. Works of art created by man may also have fractal properties. The positive influence of music on cognitive functions is well-known. Insufficiency of sensory experience is believed to play a crucial role in the pathogenesis of amblyopia and age-dependent diseases. The brain is very plastic in its early development, and the plasticity decreases throughout life. However, several studies showed the possibility to reactivate the adult’s neuroplasticity in a variety of ways. We propose that a non-linear structure of sensory information on many spatial and temporal scales is crucial to the brain health and fractal regulation of physiological rhythms. Theoretical substantiation of the author’s theory is presented. Possible applications and the future research that can experimentally confirm or refute the theoretical concept are considered. PMID:26236232

  14. Obstructive sleep apnea and neurodegenerative diseases: A bidirectional relation

    OpenAIRE

    Christianne Martins Corrêa da Silva Bahia; João Santos Pereira

    2015-01-01

    Sleep disorders are common during the clinical course of the main neurodegenerative diseases. Among these disorders, obstructive sleep apnea has been extensively studied in the last decade and recent knowledge regarding its relationship with the neurodegenerative process points a bidirectional relationship. Neurodegenerative diseases can lead to functional changes in the respiratory system that facilitate the emergence of apnea. On the other hand, obstructive sleep apnea itself can lead to ac...

  15. Age-related impairment of ultrasonic vocalization in Tau.P301L mice: possible implication for progressive language disorders

    National Research Council Canada - National Science Library

    Menuet, Clément; Cazals, Yves; Gestreau, Christian; Borghgraef, Peter; Gielis, Lies; Dutschmann, Mathias; Van Leuven, Fred; Hilaire, Gérard

    2011-01-01

    Tauopathies, including Alzheimer's Disease, are the most frequent neurodegenerative diseases in elderly people and cause various cognitive, behavioural and motor defects, but also progressive language disorders...

  16. Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex

    Science.gov (United States)

    Pérez-Victoria, F. Javier; Abascal-Palacios, Guillermo; Tascón, Igor; Kajava, Andrey; Magadán, Javier G.; Pioro, Erik P.; Bonifacino, Juan S.; Hierro, Aitor

    2010-01-01

    The multisubunit Golgi-associated retrograde protein (GARP) complex is required for tethering and fusion of endosome-derived transport vesicles to the trans-Golgi network. Mutation of leucine-967 to glutamine in the Vps54 subunit of GARP is responsible for spinal muscular atrophy in the wobbler mouse, an animal model of amyotrophic lateral sclerosis. The crystal structure at 1.7 Å resolution of the mouse Vps54 C-terminal fragment harboring leucine-967, in conjunction with comparative sequence analysis, reveals that Vps54 has a continuous α-helical bundle organization similar to that of other multisubunit tethering complexes. The structure shows that leucine-967 is buried within the α-helical bundle through predominantly hydrophobic interactions that are critical for domain stability and folding in vitro. Mutation of this residue to glutamine does not prevent integration of Vps54 into the GARP complex but greatly reduces the half-life and levels of the protein in vivo. Severely reduced levels of mutant Vps54 and, consequently, of the whole GARP complex underlie the phenotype of the wobbler mouse. PMID:20615984

  17. 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

  18. Reward processing in neurodegenerative disease

    Science.gov (United States)

    Perry, David C.; Kramer, Joel H.

    2015-01-01

    Representation of reward value involves a distributed network including cortical and subcortical structures. Because neurodegenerative illnesses target specific anatomic networks that partially overlap with the reward circuit they would be predicted to have distinct impairments in reward processing. This review presents the existing evidence of reward processing changes in neurodegenerative diseases including mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, as well as in healthy aging. Carefully distinguishing the different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decision-making) and using tasks that differentiate the stages of processing reward will lead to improved understanding of this fundamental process and clarify a contributing cause of behavioral change in these illnesses. PMID:24417286

  19. Level of neurotic disorders among drivers causing traffic accidents

    OpenAIRE

    Đurić Predrag; Filipović Danka

    2007-01-01

    Different aspects of driver personality may affect traffic safety. Extended driver reaction time causes deceleration of the reflexes, which is a major cause of traffic accidents. Cornell index was used in 30 drivers responsible for traffic accidents, with the aim to measure their level of neurotic disorder and compare them with results of controls (drivers not responsible for traffic accidents). Reaction time was measured and compared among subjects with normal results of Cornell test and tho...

  20. Visual Spatial Cognition in Neurodegenerative Disease

    OpenAIRE

    Possin, Katherine L.

    2010-01-01

    Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician in making an early and accurate diagnosis. This article will...

  1. Obstructive sleep apnea and neurodegenerative diseases: A bidirectional relation

    Directory of Open Access Journals (Sweden)

    Christianne Martins Corrêa da Silva Bahia

    Full Text Available Sleep disorders are common during the clinical course of the main neurodegenerative diseases. Among these disorders, obstructive sleep apnea has been extensively studied in the last decade and recent knowledge regarding its relationship with the neurodegenerative process points a bidirectional relationship. Neurodegenerative diseases can lead to functional changes in the respiratory system that facilitate the emergence of apnea. On the other hand, obstructive sleep apnea itself can lead to acceleration of neuronal death due to intermittent hypoxia. Considering that obstructive sleep apnea is a potentially treatable condition, its early identification and intervention could have a positive impact on the management of patients with neurodegenerative diseases.

  2. 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

    that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.

  3. Mitochondrial Iron-Sulfur Cluster Dysfunction In Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Grazia eIsaya

    2014-03-01

    Full Text Available Growing evidence supports a role for mitochondrial iron metabolism in the pathophysiology of neurodegenerative disorders such as Friedreich ataxia and Parkinson disease as well as in the motor and cognitive decline associated with the aging process. Iron-sulfur enzyme deficits and regional iron accumulation have been observed in each of these conditions. In spite of significant etiological, clinical and pathological differences that exist between Friedreich ataxia and Parkinson disease, it is possible that defects in mitochondrial iron-sulfur clusters biogenesis represent a common underlying mechanism leading to abnormal intracellular iron distribution with mitochondrial iron accumulation, OXPHOS deficits and oxidative stress in susceptible cells and specific regions of the nervous system. Moreover, a similar mechanism may contribute to the age-dependent iron accumulation that occurs in certain brain regions such as the globus pallidus and the substantia nigra. Targeting chelatable iron and reactive oxygen species appear as possible therapeutic options for Friedreich ataxia and Parkinson disease, and possibly other age-related neurodegenerative conditions. However, new technology to interrogate iron-sulfur cluster synthesis in humans is needed to (i assess how defects in this pathway contribute to the natural history of neurodegenerative disorders and (ii develop treatments to correct those defects early in the disease process, before they cause irreversible neuronal cell damage.

  4. Sleep and neurodegenerative diseases.

    Science.gov (United States)

    Chokroverty, Sudhansu

    2009-09-01

    Sleep disturbances are common in neurodegenerative diseases. Disturbed sleep can result in fatigue, irritability, morning headaches, impaired motor and cognitive skills, depression, and daytime somnolence. The major sleep complaints include insomnia, hypersomnia, parasomnia, excessive nocturnal motor activity, circadian sleep-wake rhythm disturbance, and respiratory dysrhythmia. The pathogenetic mechanisms of sleep disturbances may be secondary to direct structural alteration of the sleep-wake generating neurons or from several other indirect mechanisms. At the biochemical level, neurodegenerative diseases may be largely classified as tauopathies, alpha-synucleinopathies, and other diseases. Overnight polysomnography (PSG), Multiple Sleep Latency Test, Maintenance of Wakefulness Test, and actigraphy are some important diagnostic laboratory tests in the evaluation of sleep disturbances. Management of sleep disturbances is complex and is based primarily on the nature of the sleep disturbance. The clinical profiles, pathogenetic mechanisms, PSG findings, and management issues are discussed here with reference to some common neurodegenerative diseases. Thieme Medical Publishers.

  5. Surgical improvement of speech disorder caused by amyotrophic lateral sclerosis.

    Science.gov (United States)

    Saigusa, Hideto; Yamaguchi, Satoshi; Nakamura, Tsuyoshi; Komachi, Taro; Kadosono, Osamu; Ito, Hiroyuki; Saigusa, Makoto; Niimi, Seiji

    2012-12-01

    Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurological disease. ALS disturbs the quality of life by affecting speech, swallowing and free mobility of the arms without affecting intellectual function. It is therefore of significance to improve intelligibility and quality of speech sounds, especially for ALS patients with slowly progressive courses. Currently, however, there is no effective or established approach to improve speech disorder caused by ALS. We investigated a surgical procedure to improve speech disorder for some patients with neuromuscular diseases with velopharyngeal closure incompetence. In this study, we performed the surgical procedure for two patients suffering from severe speech disorder caused by slowly progressing ALS. The patients suffered from speech disorder with hypernasality and imprecise and weak articulation during a 6-year course (patient 1) and a 3-year course (patient 2) of slowly progressing ALS. We narrowed bilateral lateral palatopharyngeal wall at velopharyngeal port, and performed this surgery under general anesthesia without muscle relaxant for the two patients. Postoperatively, intelligibility and quality of their speech sounds were greatly improved within one month without any speech therapy. The patients were also able to generate longer speech phrases after the surgery. Importantly, there was no serious complication during or after the surgery. In summary, we performed bilateral narrowing of lateral palatopharyngeal wall as a speech surgery for two patients suffering from severe speech disorder associated with ALS. With this technique, improved intelligibility and quality of speech can be maintained for longer duration for the patients with slowly progressing ALS.

  6. High GC content causes orphan proteins to be intrinsically disordered.

    Directory of Open Access Journals (Sweden)

    Walter Basile

    2017-03-01

    Full Text Available De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population. These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC and Drosophila (high GC. GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

  7. Ultrasonographic Findings of Extratesticular Diseases Causing Acute Scrotal Disorders

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Jae Joon; Lee, Tack; Chang, So Yong; Kim, Myeong Jin; Yoo, Hyung Sik; Lee, Jong Tae [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1996-12-15

    To evaluate the kinds of extratesticular diseases causing acute scrotal disorders by emergent sonography of the scrotum. Scrotal sonography in sixty-five patients, with age ranging from 5months to 82 years (mean : 27.3 years), with acute scrotal pain and swelling, was prospectively carried out by either a 10 or 7.5 MHz transducer. We evaluated the size and echogenicity of the epididymis, the presence of extratesticular solid mass or cyst, testicular involvement by extratesticular diseases, calcification, hydrocele and scrotal wall thickening. The most common cause of acute scrotal disorders was acute epididymitis (n= 50), followed by acute epididymo-orchitis (n = 4), mumps epididymo-orchitis (n = 2), enlarged epididymis secondary to testicular torsion (n = 2), infected hydrocele (n = 2), epididymal cyst (n = 2), rupture of varicocele (n = 1), angioneurotic edema (n = 1), and sperm granuloma (n = 1). Hydrocele was seen in 20 cases, and epididymal calcification was noted in 6 cases. Emergent scrotal sonography was useful for correct diagnosis and proper treatment in patients with acute scrotal disorders, especially in the differentiation of the acute epididymitis from other intrascrotal diseases

  8. Sleep Disorders as a Cause of Motor Vehicle Collisions

    Science.gov (United States)

    de Mello, Marco Túlio; Narciso, Fernanda Veruska; Tufik, Sergio; Paiva, Teresa; Spence, David Warren; BaHammam, Ahmed S.; Verster, Joris C.; Pandi-Perumal, Seithikurippu R.

    2013-01-01

    Studies have shown that a large proportion of traffic accidents around the world are related to inadequate or disordered sleep. Recent surveys have linked driver fatigue to 16% to 20% of serious highway accidents in the UK, Australia, and Brazil. Fatigue as a result of sleep disorders (especially obstructive sleep apnea), excessive workload and lack of physical and mental rest, have been shown to be major contributing factors in motor vehicle accidents. A number of behavioral, physiological, and psychometric tests are being used increasingly to evaluate the impact of fatigue on driver performance. These include the oculography, polysomnography, actigraphy, the maintenance of wakefulness test, and others. Various strategies have been proposed for preventing or reducing the impact of fatigue on motor vehicle accidents. These have included: Educational programs emphasizing the importance of restorative sleep and the need for drivers to recognize the presence of fatigue symptoms, and to determine when to stop to sleep; The use of exercise to increase alertness and to promote restorative sleep; The use of substances or drugs to promote sleep or alertness (i.e. caffeine, modafinil, melatonin and others), as well as specific sleep disorders treatment; The use of CPAP therapy for reducing excessive sleepiness among drivers who have been diagnosed with obstructive sleep apnea. The evidence cited in this review justifies the call for all efforts to be undertaken that may increase awareness of inadequate sleep as a cause of traffic accidents. It is strongly recommended that, for the purpose of promoting highway safety and saving lives, all disorders that cause excessive sleepiness should be investigated and monitored. PMID:23626880

  9. Sleep disorders as a cause of motor vehicle collisions

    Directory of Open Access Journals (Sweden)

    Marco Túlio de Mello

    2013-01-01

    Full Text Available Studies have shown that a large proportion of traffic accidents around the world are related to inadequate or disordered sleep. Recent surveys have linked driver fatigue to 16% to 20% of serious highway accidents in the UK, Australia, and Brazil. Fatigue as a result of sleep disorders (especially obstructive sleep apnea, excessive workload and lack of physical and mental rest, have been shown to be major contributing factors in motor vehicle accidents. A number of behavioral, physiological, and psychometric tests are being used increasingly to evaluate the impact of fatigue on driver performance. These include the oculography, polysomnography, actigraphy, the maintenance of wakefulness test, and others. Various strategies have been proposed for preventing or reducing the impact of fatigue on motor vehicle accidents. These have included: Educational programs emphasizing the importance of restorative sleep and the need for drivers to recognize the presence of fatigue symptoms, and to determine when to stop to sleep; The use of exercise to increase alertness and to promote restorative sleep; The use of substances or drugs to promote sleep or alertness (i.e. caffeine, modafinil, melatonin and others, as well as specific sleep disorders treatment; The use of CPAP therapy for reducing excessive sleepiness among drivers who have been diagnosed with obstructive sleep apnea. The evidence cited in this review justifies the call for all efforts to be undertaken that may increase awareness of inadequate sleep as a cause of traffic accidents. It is strongly recommended that, for the purpose of promoting highway safety and saving lives, all disorders that cause excessive sleepiness should be investigated and monitored.

  10. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL in humans.

    Directory of Open Access Journals (Sweden)

    Vafa Bayat

    Full Text Available An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS, and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants.

  11. Sleep disorders in Parkinson's disease: many causes, few therapeutic options.

    Science.gov (United States)

    Diederich, Nico J; McIntyre, Deborah J

    2012-03-15

    Sleep symptoms in Parkinson's disease (PD) are frequent and have multifactorial and multilayered causes. Primary involvement of sleep/wake regulating centers in the brainstem, sleep problems caused by the nocturnal manifestation of motor and dysautonomic signs and medication-induced sleep problems are often impossible to disentangle in the individual patient. Two syndromes, hypersomnia and REM sleep behavior disorder (RBD), are increasingly recognized as harbingers of the core PD motor syndrome. RBD, associated with a panoply of other nonmotor symptoms, may predispose to a specific PD phenotype. Long-acting dopaminergic stimulation, when abating nocturnal akinesia, also improves subjective sleep quantity. While this strategy is backed up by several randomized controlled trials (RCT), other treatment recommendations are mostly based on case series or expert opinion. Thus we identified only two other RCT, one treating insomnia with eszopiclone, the other nocturnal behavioral abnormalities in demented PD patients with memantine. While the causal complexity of sleep problems in PD certainly hampers the design of therapeutic studies, multiple general treatment strategies against sleep disorders can however be applied efficiently in PD patients as well. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Mitochondrial disorder caused Charles Darwin's cyclic vomiting syndrome

    Directory of Open Access Journals (Sweden)

    Finsterer J

    2014-01-01

    Full Text Available Josef Finsterer,1 John Hayman21Krankenanstalt Rudolfstiftng, Vienna, Austria; 2Department of Pathology, University of Melbourne, Victoria, AustraliaBackground: Charles Darwin (CD, “father of modern biology,” suffered from multisystem illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS. This study aims at finding the possible cause of CVS in CD.Methods: A literature search using the PubMed database was carried out, and CD's complaints, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, were compared with various manifestations of mitochondrial disorders (MIDs, known to cause CVS, described in the literature.Results: Organ tissues involved in CD's disease were brain, nerves, muscles, vestibular apparatus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual disturbance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy.Conclusion: CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diagnosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress

  13. Temporomandibular Joint Disorders as a Cause of Aural Fullness.

    Science.gov (United States)

    Peng, Yongxin

    2017-09-01

    Temporomandibular joint disorders (TMD) are often associated with aural manifestations. However, it is not clear whether aural fullness could be induced by TMD. The purpose was to investigate the TMD and effectiveness of TMD treatments in patients with mainly or exclusively aural fullness complaint. One hundred and twelve patients, who had aural fullness as the main or sole complaint, presented to the Otolaryngology Department, PLA Army General Hospital, Beijing, China, between January 2010 and January 2015. Patients' medical history indicated that they had previously been diagnosed and treated for otitis media or sensorineural hearing loss but without positive results. Patients were subjected to pure tone audiometry and acoustic immittance screening using GSI-61 clinical audiometer and GSI TympStar middle ear analyzer respectively. Patients were examined by questionnaire, X-ray and/or computed tomography scan of temporomandibular joint. TMD was categorized according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Patients were then treated for TMD. All the patients showed normal eardrum and type A tympanogram. The patients of 60.7% (68/112) were classified as group I TMD disorders (muscle disorders), 34.8% (39/112) were group II (disc displacements), and 4.5% (5/112) were group III (arthralgia, osteoarthritis, and osteoarthrosis). Aural fullness was completely resolved or significantly improved in 67 and 34 patients respectively following treatments aimed at improving TMD, with a combined effectiveness of 90.2% (101/112). TMD treatments are especially effective (94.1%) in group I TMD. TMD as a potential cause of aural fullness should be considered in otolaryngology practice.

  14. Early noninvasive diagnosis of neurodegenerative diseases.

    Science.gov (United States)

    Danev, Stoyan I; St Stoyanov, Drozdstoy

    2010-01-01

    This paper reviews the contemporary trends in the pathobiochemistry of neurodegenerative disorders with respect to their early predictive diagnosis and possible treatment interventions. If we consider the current epidemiological data related to neurodegenerative disorders, medicine is going to face in the near future latent pandemic situations. The introduction puts an emphasis on the emerging importance of one major cluster of neurodegenerative disorders: diseases of the abnormal protein beta-conformation. The cluster includes such significant diseases as Alzheimer, Pick, Huntington, Parkinson disease, as well as the transmissible spongiform encephalopathies (Creuzfeldt-Jakob disease). The pathogenetic mechanisms in the determination of this group of disorders are explored with an emphasis on the impairment of post-synthetic chaperone correction. The central role of a number of such protein products is discussed. In particular the pathobiochemical mechanisms concerning the formation of beta-amyloid, alpha and beta synucleins, scrapie isoform of the prion protein are presented. A new diagnostic principle allowing the early and specific diagnosis of the conformation diseases protein via amplification techniques is presented. These methods compete in sensitivity with the PCR methods and shows promises for effective treatment. In conclusion, beta-pathies are considered a suitable example for the modern concept of cluster and prototype diagnosis in medicine and especially in clinical neurosciences.

  15. Visual spatial cognition in neurodegenerative disease.

    Science.gov (United States)

    Possin, Katherine L

    2010-12-01

    Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician in making an early and accurate diagnosis. This article will review the literature on visual spatial cognition in neurodegenerative disease clinical syndromes, and where research is available, by neuropathologic diagnoses. Visual spatial cognition will be organized primarily according to the following schemes: bottom-up/top-down processing, dorsal/ventral stream processing, and egocentric/allocentric frames of reference.

  16. 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.

  17. Autonomic Function in Neurodegenerative Diseases

    DEFF Research Database (Denmark)

    Sørensen, Gertrud Laura; Jennum, Poul Jørgen

    2013-01-01

    control, indicating that the disorder may serve as a human model for the sleep-wake and REM sleep flip-flop switches. The increased frequency of transitions may cause increased sympathetic activity during sleep and thereby increased heart rate, or the increased heart rate could be caused by decreased...

  18. Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder.

    Science.gov (United States)

    King, Barbara; Setford, Meghan L; Hassiotis, Sofia; Trim, Paul J; Duplock, Stephen; Tucker, Justin N; Hattersley, Kathryn; Snel, Marten F; Hopwood, John J; Hemsley, Kim M

    2016-04-01

    To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility. Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed. Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed. Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. [A patient with vision problems: first manifestation of a neurodegenerative condition].

    Science.gov (United States)

    de Beer, Marlijn; Leeuwis, Annebet; Pijnenburg, Yolande

    2015-01-01

    Vision problems are common and the causes are diverse. This case illustrates the fact that vision problems may also be the first manifestation of a neurodegenerative disorder. A 46-year-old male developed progressive, incapacitating vision problems. Multiple pairs of glasses with lenses of different strengths did not improve symptoms. No ophthalmological explanation of the problems could be found. Oculomotor apraxia and visual extinction were seen on neurological examination. Visuoperceptual impairment was the main finding on neuropsychological examination. Impairment was also identified in visuoconstruction, memory and praxis. Cognitive problems in several areas, interference with activities of daily living, and young age of onset complete the clinical picture of presenile dementia. Posterior cortical atrophy is a spectrum of neurodegenerative disorders, characterized by progressive, incapacitating visuospatial and visuoperceptual impairment. The most prevalent underlying pathology is Alzheimer's disease. At present there is no curative therapy for posterior cortical atrophy.

  20. 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.

  1. Causes and consequences of voice disorders among teachers

    NARCIS (Netherlands)

    L.C. Cantor Cutiva (Lady Catherine)

    2015-01-01

    markdownabstractAbstract Voice disorders are a major problem among teachers. However, the reported prevalence of these disorders have a wide range, and the natural variation of voice disorders among teachers is unknown due to the lack of longitudinal studies. Moreover, there is not a consensus

  2. Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression

    DEFF Research Database (Denmark)

    Hjorthøj, Carsten; Østergaard, Marie Louise Drivsholm; Benros, Michael Eriksen

    2015-01-01

    BACKGROUND: People with severe mental illness have both increased mortality and are more likely to have a substance use disorder. We assessed the association between mortality and lifetime substance use disorder in patients with schizophrenia, bipolar disorder, or unipolar depression. METHODS......: In this prospective, register-based cohort study, we obtained data for all people with schizophrenia, bipolar disorder, or unipolar depression born in Denmark in 1955 or later from linked nationwide registers. We obtained information about treatment for substance use disorders (categorised into treatment for alcohol......, cannabis, or hard drug misuse), date of death, primary cause of death, and education level. We calculated hazard ratios (HRs) for all-cause mortality and subhazard ratios (SHRs) for cause-specific mortality associated with substance use disorder of alcohol, cannabis, or hard drugs. We calculated...

  3. Myeloproliferative disorders: complications, survival and causes of death.

    Science.gov (United States)

    Brodmann, S; Passweg, J R; Gratwohl, A; Tichelli, A; Skoda, R C

    2000-06-01

    This retrospective single-center study compared thromboembolic and hemorrhagic complications, survival and causes of death in a cohort of 102 consecutive patients with myeloproliferative disorders (MPD). We included 17 patients with essential thrombocythemia (ET), 59 with polycythemia vera (PV), and 26 with osteomyelofibrosis (OMF). The median follow-up was 3.7 years. Estimated 8-year probability of complications for the entire cohort was 80 +/- 11% (95% confidence interval), without significant differences among MPD subgroups. The rate of thromboembolic complications, expressed as the number of events per 100 patient years, was 16.7 for patients with PV, 13.8 for OMF, and 7.5 for ET. Fifty-four percent of thromboembolic events in PV involved cerebral or limb arteries. The rate of bleeding complications was highest in patients with OMF (31.8 per 100 patient years), followed by ET and PV (11.8). Ninety percent of bleeding episodes affected the skin. mucosal membranes, and the gastrointestinal tract. Eight-year survival was highest in ET with 91 +/- 17%, followed by PV (66 +/- 18%) and OMF (40 +/- 31%) (P< 0.01). Twenty-four patients died during the observation period, and fatal thrombosis (in five patients) represented the leading cause of death. Only two patients with MPD died from fatal hemorrhage and one from acute leukemia. We conclude that survival is highest in ET and lowest in OMF. Both thromboembolic and hemorrhagic complications are frequent. However, thrombosis appears to be more often fatal than bleeding complications. Prophylaxis of thromboembolic events remains a key issue in the management of MPD.

  4. Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders.

    Science.gov (United States)

    Kristofiková, Zdena; Stástný, Frantisek; Bubeniková, Vera; Druga, Rastislav; Klaschka, Jan; Spaniel, Filip

    2004-04-01

    symmetrical drop in the number of choline carriers of lesioned male rats but a asymmetrical decrease in the activity of remaing carriers, suggesting defects in processes of sexual brain differentiation, leading under normal conditions to the higher activity of carriers in the left hippocampus. The data demonstrate viral infection-mediated alterations in normal patterns of brain asymmetry and are discussed in relation to animal models of neurodevelopmental and neurodegenerative diseases.

  5. The impact of metabotropic glutamate receptors into active neurodegenerative processes: A "dark side" in the development of new symptomatic treatments for neurologic and psychiatric disorders.

    Science.gov (United States)

    Bruno, Valeria; Caraci, Filippo; Copani, Agata; Matrisciano, Francesco; Nicoletti, Ferdinando; Battaglia, Giuseppe

    2017-03-15

    Metabotropic glutamate (mGlu) receptor ligands are under clinical development for the treatment of CNS disorders with high social and economic burden, such as schizophrenia, major depressive disorder (MDD), and Parkinson's disease (PD), and are promising drug candidates for the treatment of Alzheimer's disease (AD). So far, clinical studies have shown symptomatic effects of mGlu receptor ligands, but it is unknown whether these drugs act as disease modifiers or, at the opposite end, they accelerate disease progression by enhancing neurodegeneration. This is a fundamental issue in the treatment of PD and AD, and is also an emerging theme in the treatment of schizophrenia and MDD, in which neurodegeneration is also present and contribute to disease progression. Moving from in vitro data and preclinical studies, we discuss the potential impact of drugs targeting mGlu2, mGlu3, mGlu4 and mGlu5 receptor ligands on active neurodegeneration associated with AD, PD, schizophrenia, and MDD. We wish to highlight that our final comments on the best drug candidates are not influenced by commercial interests or by previous or ongoing collaborations with drug companies. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Causes of Speech Disorders in Primary School Students of Zahedan

    OpenAIRE

    Saeed Fakhrerahimi; Ali Dehghan; Nour-Mohammad Bakhshani

    2013-01-01

    Background: Since making communication with others is the most important function of speech, undoubtedly, any type of disorder in speech will affect the human communicability with others. The objective of the study was to investigate reasons behind the [high] prevalence rate of stammer, producing disorders and aglossia.Materials and Methods: This descriptive-analytical study was conducted on 118 male and female students, who were studying in a primary school in Zahedan; they had referred to t...

  7. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

    Science.gov (United States)

    Bhullar, Khushwant S.; Rupasinghe, H. P. Vasantha

    2013-01-01

    Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders. PMID:23840922

  8. [An inherited hemostatic disorder as the cause of menorrhagia

    NARCIS (Netherlands)

    Leebeek, F.W.; Lotgering, F.K.

    2002-01-01

    Two women aged 39 and 30 years were investigated for possible coagulation disorders because of menorrhagia, anaemia and postoperative haemorrhages. These investigations revealed that they had type 1 Von Willebrand's disease. During the treatment with desmopressin, factor VIII and Von Willebrand

  9. Quantification of the neurodegenerative status in patients with multiple sclerosis by optical coherence tomography in respect to functional vision

    OpenAIRE

    Bock, Markus

    2014-01-01

    Multiple sclerosis is the most frequent, non-traumatic, neurological disorder in young adults in western countries which leads to chronic impairment. The cause of the immune mediated illness remains elusive. Neither clinical nor paraclinical measures can estimate the disability degree or the course of multiple sclerosis (MS). It is crucial to improve the methods which can be a window to the neurodegenerative status of individuals. Structural investigations of the ZNS by MRI own a key position...

  10. Temporomandibular Joint Disorders as a Cause of Aural Fullness

    OpenAIRE

    Peng, Yongxin

    2017-01-01

    Objectives Temporomandibular joint disorders (TMD) are often associated with aural manifestations. However, it is not clear whether aural fullness could be induced by TMD. The purpose was to investigate the TMD and effectiveness of TMD treatments in patients with mainly or exclusively aural fullness complaint. Methods One hundred and twelve patients, who had aural fullness as the main or sole complaint, presented to the Otolaryngology Department, PLA Army General Hospital, Beijing, China, bet...

  11. Sleep disorders in children beginning school: their causes and effects.

    Science.gov (United States)

    Lehmkuhl, Gerd; Fricke-Oerkermann, Leonie; Wiater, Alfred; Mitschke, Alexander

    2008-11-01

    Sleep disorders are a common problem among children beginning school and may be associated both with impaired school performance and with behavioral difficulties. Because these disorders manifest themselves highly variably among children of any given age, and even in an individual affected child, they need an appropriate diagnostic evaluation so that the many environmental and background factors that may be relevant to the further course of the problem can be assessed. Extensive data were obtained on approximately 1400 children who were tested before beginning school in 2005 by means of a special sleep questionnaire and another screening instrument that is used to assess behavioral strengths and difficulties (the SDQ, Strengths and Difficulties Questionnaire). Five percent of the children were found to have difficulty falling asleep, difficulty staying asleep, or nocturnal awakening. Less frequent problems included parasomnias such as pavor nocturnus (0.5%), sleepwalking (0.1%), and frequent nightmares (1.7%). Sleep disorders increase the risk of daytime fatigue and of psychological problems in general, including both hyperactivity and excessive emotional stress. These results imply that sleep problems and emotional disturbances are intimately connected and underscore the importance of diagnosing sleep problems in young children.

  12. Composition, Standardization and Chemical Profiling of Banisteriopsis caapi, a Plant for the Treatment of Neurodegenerative Disorders Relevant to Parkinson’s Disease†

    Science.gov (United States)

    Wang, Yan-Hong; Samoylenko, Volodymyr; Tekwani, Babu L.; Khan, Ikhlas A.; Miller, Loren S.; Chaurasiya, Narayan D.; Rahman, Md. Mostafizur; Tripathi, Lalit M.; Khan, Shabana I.; Joshi, Vaishali C.; Wigger, Frank T.; Muhammad, Ilias

    2010-01-01

    Ethnopharmacological relevance Banisteriopsis caapi, a woody vine from the Amazonian basin, is popularly known as an ingredient of a sacred drink ayahuasca, widely used throughout the Amazon as a medicinal tea for healing and spiritual exploration. The usefulness of B. caapi has been established for alleviating symptoms of neurological disorders including Parkinson’s disease. Aim of the study Primary objective of this study was to develop the process for preparing standardized extracts of B. caapi to achieve high potency for inhibition of human monoamine oxidases (MAO) and antioxidant properties. The aqueous extracts prepared from different parts of the plant collected from different geographical locations and seasons were analyzed by HPLC for principal bioactive markers. The extracts were simultaneously tested in vitro for inhibition of human MAOs and antioxidant activity for analysis of correlation between phytochemical composition of the extracts and bioactivities. Materials and methods Reversed-phase HPLC with photodiode array detection was employed to profile the alkaloidal and non-alkaloidal components of the aqueous extract of B. caapi. The B. caapi extracts and standardized compositions were tested in vitro for inhibition of recombinant preparations of human MAO-A and MAO-B. In vitro cell-based assays were employed for evaluation of antioxidant property and mammalian cell cytotoxicity of these preparations. Results Among the different aerial parts, leaves, stems/large branches and stem bark of B. caapi, HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7-9) were present in high concentrations in dried bark of large branch. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied B. caapi species. The correlation between potency of MAO inhibition and antioxidant activity with the content of the main active constituents of the aqueous B. caapi extracts and

  13. Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Wenbin Wan

    2015-01-01

    Full Text Available Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer’s disease (AD and Parkinson’s disease (PD show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs, which displayed similar pluripotency potential to embryonic stem cells (ESCs. Currently, iPSCs studies are permeating many sectors of disease research. Patient sample-derived iPSCs can be used to construct patient-specific disease models to elucidate the pathogenic mechanisms of disease development and to test new therapeutic strategies. Accordingly, the present review will focus on recent progress in iPSC research in the modeling of neurodegenerative disorders and in the development of novel therapeutic options.

  14. 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.

  15. Chronic neurodegenerative consequences of traumatic brain injury.

    Science.gov (United States)

    Chauhan, Neelima B

    2014-01-01

    Traumatic brain injury (TBI) is a serious public health concern and a major cause of death and disability worldwide. Each year, an estimated 1.7 million Americans sustain TBI of which ~52,000 people die, ~275,000 people are hospitalized and 1,365,000 people are treated as emergency outpatients. Currently there are ~5.3 million Americans living with TBI. TBI is more of a disease process than of an event that is associated with immediate and long-term sensomotor, psychological and cognitive impairments. TBI is the best known established epigenetic risk factor for later development of neurodegenerative diseases and dementia. People sustaining TBI are ~4 times more likely to develop dementia at a later stage than people without TBI. Single brain injury is linked to later development of symptoms resembling Alzheimer's disease while repetitive brain injuries are linked to later development of chronic traumatic encephalopathy (CTE) and/or Dementia Pugilistica (DP). Furthermore, genetic background of ß-amyloid precursor protein (APP), Apolipoprotein E (ApoE), presenilin (PS) and neprilysin (NEP) genes is associated with exacerbation of neurodegenerative process after TBI. This review encompasses acute effects and chronic neurodegenerative consequences after TBI.

  16. Investigation of the possible connection of rock and soil geochemistry to the occurrence of high rates of neurodegenerative diseases on Guam and a hypothesis for the cause of the diseases

    Science.gov (United States)

    Miller, William R.; Sanzolone, Richard F.

    2003-01-01

    High incidences of neurodegenerative diseases, mainly dementia, parkinsonism, and amyotrophic lateral sclerosis, occur on the island of Guam (Koerner, 1952; Kurland and Mulder, 1954). The occurrence and description of the diseases and a summary of the investigations can be found in Perl (1997). The diseases have been more prevalent along the southern coast, particularly the small villages of Umatac, Merizo, and Inarajan (Reed and Brody, 1975; Roman, 1996; and Perl, 1997) (fig. 1), and referred to as the southern villages in this report. Tertiary volcanic rocks underlie most of the southern part of the island, including these villages. The northern part of Guam, with lower incidences of the diseases, consists of carbonate rocks. Epidemiological studies beginning in the early 1950’s failed to show the cause to be genetic etiology (Plato and others, 1986; Zhang and others, 1990). In recent studies, the search for pathogenic mechanisms has shifted to environmental factors. Excesses or deficiencies of various elements from dietary sources including drinking water can have an effect on human health. These deficiencies or excesses can usually be attributed to the geochemical composition of the rocks and derived soils that underlie the area. An example is the high concentration of Se in soil associated with the occurrence of selenosis in adults (Mills, 1996). Yase (1972) suggested that the neurodegenerative diseases on Guam may be related to accumulation of trace elements such as manganese and aluminum, both of which may cause neurodegeneration. It has been suggested that a deficiency in calcium and magnesium in the soil and water along with readily available aluminum could be connected to the occurrence of the diseases (Gajdusek, 1982; Yanagihara and others, 1984; Garruto and others, 1989). Some of the studies investigated metal exposure, particularly aluminum and manganese, and deficiencies in calcium and magnesium (Garruto and others, 1984). Aluminum has been shown to

  17. Chronic sleep disturbance and neural injury: links to neurodegenerative disease.

    Science.gov (United States)

    Abbott, Sabra M; Videnovic, Aleksandar

    2016-01-01

    Sleep-wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep-wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep-wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer's disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson's disease, and the insomnia and circadian dysregulation associated with Huntington's disease.

  18. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Abbott SM

    2016-01-01

    Full Text Available Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep–wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer’s disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson’s disease, and the insomnia and circadian dysregulation associated with Huntington’s disease. Keywords: sleep, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease

  19. Respiratory manifestations of panic disorder: causes, consequences and therapeutic implications.

    Science.gov (United States)

    Sardinha, Aline; Freire, Rafael Christophe da Rocha; Zin, Walter Araújo; Nardi, Antonio Egidio

    2009-07-01

    Multiple respiratory abnormalities can be found in anxiety disorders, especially in panic disorder (PD). Individuals with PD experience unexpected panic attacks, characterized by anxiety and fear, resulting in a number of autonomic and respiratory symptoms. Respiratory stimulation is a common event during panic attacks. The respiratory abnormality most often reported in PD patients is increased CO2 sensitivity, which has given rise to the hypothesis of fundamental abnormalities in the physiological mechanisms that control breathing in PD. There is evidence that PD patients with dominant respiratory symptoms are more sensitive to respiratory tests than are those who do not manifest such symptoms, and that the former group constitutes a distinct subtype. Patients with PD tend to hyperventilate and to panic in response to respiratory stimulants such as CO2, triggering the activation of a hypersensitive fear network. Although respiratory physiology seems to remain normal in these subjects, recent evidence supports the idea that they present subclinical abnormalities in respiration and in other functions related to body homeostasis. The fear network, composed of the hippocampus, the medial prefrontal cortex, the amygdala and its brain stem projections, might be oversensitive in PD patients. This theory might explain why medication and cognitive-behavioral therapy are both clearly effective. Our aim was to review the relationship between respiration and PD, addressing the respiratory subtype of PD and the hyperventilation syndrome, with a focus on respiratory challenge tests, as well as on the current mechanistic concepts and the pharmacological implications of this relationship.

  20. Blau syndrome and related genetic disorders causing childhood arthritis.

    Science.gov (United States)

    Becker, Mara L; Rose, Carlos D

    2005-12-01

    Blau Syndrome (BS) is an inheritable disorder characterized by granulomatous polyarthritis, panuveitis, and exanthema. It was described by Edward Blau in 1985, the same year in which Douglas Jabs reported a very similar family. Clinically indistinguishable from early onset sarcoidosis (EOS), both are now known to share a mutated form of caspase recruitment domain-15 (CARD 15), a protein involved in activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription. An association between BS and EOS was suspected for years given the striking similarities of the core triad (arthritis-uveitis-dermatitis) and a common emerging pattern of systemic involvement. Hence, the familial form (BS) and the sporadic form (EOS) are almost certainly the same illness/defect, inherited in the first and acquired in the second as a result in most cases of a de novo mutation. Another form of granulomatous arthritis with uveitis, Crohn's disease, has also been associated with mutations in CARD 15 (albeit at a different domain) and despite similar phenotypes there are obvious differences including gut inflammation and pyoderma gangrenosum in Crohn's disease. This paper will review the clinical characteristics of these three disorders and their association with mutations in the CARD 15 gene.

  1. [Most common skin disorders caused by excessive exposure to sunlight].

    Science.gov (United States)

    Zitás, Éva; Mészáros, Judit

    2016-01-17

    The healing properties of sunlight has been known for millennia, however the gradual deterioration of the ozone layer and the increased use of sun tanning beds in recent decades are causing an increase in skin damaging ultraviolet exposure. In this article the most common photodermatoses and the principles of their treatments are reviewed.

  2. [New causes of microcytic anaemia: hereditary disorders of iron homeostasis].

    Science.gov (United States)

    van Rooijen, Karlijn L; Raymakers, Reinier A P; Cuijpers, Marloes L H; Brons, Paul P T; Janssen, Mirian C H; Swinkels, Dorine W

    2010-01-01

    Recently various new gene defects have been identified which explain some previously unknown causes of inherited microcytic anaemias. These defects are located in genes that encode for the cellular iron importing protein Divalent Metal Transporter 1 (DMT1), the iron exporting protein ferroportin, the mitochondrial enzyme glutaredoxin-5 and the hepatocyte membrane protein matriptase-2.

  3. Association between low height and eating disorders: cause or effect?

    Science.gov (United States)

    Favaro, Angela; Tenconi, Elena; Degortes, Daniela; Soave, Manuela; Zanetti, Tatiana; Nardi, Maria T; Caregaro, Lorenza; Santonastaso, Paolo

    2007-09-01

    Few studies have explored the relationship between stature and eating disorders (ED). We aimed to investigate the connection between height and risk for ED in a cohort of female subjects. The sample was composed of 1,031 subjects with ED and 832 controls. All participants belonged to the same birth cohort and were living in the same geographical area. ED subjects were, on average, shorter than control subjects, independently from the age of onset. In early-onset anorexia nervosa only, age of onset and lowest body mass index were significant predictors of height. In the whole sample, a lower height was associated with an increased risk of having an ED, even after controlling for possible confounding variables. The association between EDs and low stature is statistically significant. Further studies are necessary to understand which genetic and/or environmental factors might explain this association. (c) 2007 by Wiley Periodicals, Inc.

  4. Does Internalizing Society and Media Messages Cause Body Dissatisfaction, in Turn Causing Disordered Eating?

    Science.gov (United States)

    Dye, Heather

    2016-01-01

    The purpose of this study was to examine the predictive influence that internalization of society and media messages has on body dissatisfaction, as well as the prediction influence that body dissatisfaction has on disordered eating behaviors, such as preoccupation with weight, dieting, and eating restraint. A total of 324 participants completed the demographic questionnaire, the Multidimensional Body Self Relations Questionnaire (Cash, 2001 ), the Sociocultural Attitudes Towards Appearance Questionnaire (Heinberg, Thompson, & Stormer, 1995 ) for women, and the Sociocultural Attitudes Towards Appearance Questionnaire-Revised-Male-Version (Cusumano & Thompson, 1997 ) for men, and the locus of control (Rotter, 1966 ). The results of this study found that high internalization leads to body dissatisfaction, in turn, leading to disordered eating behaviors, such as preoccupation with weight, dieting, and eating restraint. This study proposes the implementation of media literacy and education programs that teach college women and men, girls and boys, to think more critically about the media.

  5. DNA triplex structures in neurodegenerative disorder, Friedreich's ...

    Indian Academy of Sciences (India)

    The unusual DNA structures like DNA-hairpin, cruciform, Z-DNA, triplex and tetraplex are represented as hotspots of chromosomal breaks, homologous recombination and gross chromosomal rearrangements since they are prone to the structural alterations. Friedreich's ataxia (FRDA), the autosomal recessive degenerative ...

  6. 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

  7. A Review on Stuttering and Social Anxiety Disorder in Children: Possible Causes and Therapies/Treatments

    OpenAIRE

    Nadia Nathania

    2016-01-01

    In the past two decades, stuttering and its relation to social anxiety disorder have been researched using different approaches in study fields such as neurolinguistics and neuropsychology. This paper presents a review of research publications about social anxiety disorder in children who stutter. It takes into account studies of stuttering, social anxiety disorders, the possible causes as well as atti-tudes and beliefs towards stuttering. Also, therapies or treatments that have been conducte...

  8. Myelodysplastic Syndromes (MDS) and autoimmune disorders (AD): cause or consequence?

    Science.gov (United States)

    Braun, Thorsten; Fenaux, Pierre

    2013-12-01

    Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are frequently associated with clinical manifestations of autoimmune disorders (AD) and inflammatory response of the immune system. AD accompanying MDS and CMML include vasculitis, seronegative polyarthritis and neutrophilic dermatosis. Rare AD including relapsing polychondritis is strongly associated with MDS as in a high proportion of those patients MDS is diagnosed during disease course. Antinuclear antibodies (ANA) are frequently found among MDS patients without clinical manifestation of AD. In a subset of patients, MDS and resulting cytopenias appear to be the consequence of auto reactive immunologic activity and may respond to immunosuppressive treatment (IST). Increased release of inflammatory cytokines like tumor necrosis factor-(TNF)-α and interferon (IF)-γ triggers apoptosis of myeloid precursor cells leading to cytopenias. Impaired function of immune cells including cytotoxic, regulatory (Treg), helper (Th17) T cells and NK cells also appears to predict response to IST, outcome and occurrence of AD. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Complex seizure disorder caused by Brunol4 deficiency in mice.

    Directory of Open Access Journals (Sweden)

    Yan Yang

    2007-07-01

    Full Text Available Idiopathic epilepsy is a common human disorder with a strong genetic component, usually exhibiting complex inheritance. We describe a new mouse mutation in C57BL/6J mice, called frequent-flyer (Ff, in which disruption of the gene encoding RNA-binding protein Bruno-like 4 (Brunol4 leads to limbic and severe tonic-clonic seizures in heterozygous mutants beginning in their third month. Younger heterozygous adults have a reduced seizure threshold. Although homozygotes do not survive well on the C57BL/6J background, on mixed backgrounds homozygotes and some heterozygotes also display spike-wave discharges, the electroencephalographic manifestation of absence epilepsy. Brunol4 is widely expressed in the brain with enrichment in the hippocampus. Gene expression profiling and subsequent analysis revealed the down-regulation of at least four RNA molecules encoding proteins known to be involved in neuroexcitability, particularly in mutant hippocampus. Genetic and phenotypic assessment suggests that Brunol4 deficiency in mice results in a complex seizure phenotype, likely due to the coordinate dysregulation of several molecules, providing a unique new animal model of epilepsy that mimics the complex genetic architecture of common disease.

  10. Fishing for causes and cures of motor neuron disorders

    Directory of Open Access Journals (Sweden)

    Shunmoogum A. Patten

    2014-07-01

    Full Text Available Motor neuron disorders (MNDs are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA, amyotrophic lateral sclerosis (ALS and hereditary spastic paraplegia (HSP. These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

  11. Pisotriquetral joint disorders: an under-recognized cause of ulnar side wrist pain

    Energy Technology Data Exchange (ETDEWEB)

    Moraux, A. [Hopital Roger Salengro, Service d' Imagerie Musculo-Squelettique, Centre de Consultation de l' Appareil Locomoteur, CHRU Lille (France); Imagerie Medicale Jacquemars Gielee, Lille (France); Lefebvre, G.; Pansini, V.; Aucourt, J.; Vandenbussche, L.; Cotten, A. [Hopital Roger Salengro, Service d' Imagerie Musculo-Squelettique, Centre de Consultation de l' Appareil Locomoteur, CHRU Lille (France); Demondion, X. [Hopital Roger Salengro, Service d' Imagerie Musculo-Squelettique, Centre de Consultation de l' Appareil Locomoteur, CHRU Lille (France); Pole Recherche Faculte de Medecine de Lille, Laboratoire d' Anatomie, Lille (France)

    2014-06-15

    Pisotriquetral joint disorders are often under-recognized in routine clinical practice. They nevertheless represent a significant cause of ulnar side wrist pain. The aim of this article is to present the main disorders of this joint and discuss the different imaging modalities that can be useful for its assessment. (orig.)

  12. [ANXIETY AND DEPRESSIVE DISORDERS IN FUNCTIONAL DYSPEPSIA: CAUSE OR CONSEQUENCE?].

    Science.gov (United States)

    Kugler, T E

    2015-01-01

    The aim of this study was to evaluate the frequency and importance of anxiety and depression in patients with functional dyspepsia (FD), the relationship between these psychological characteristics, symptom severity and the quality of life. We performed a cross-sectional study. 125 patients with FD according to the Rome criteria ill, as well as a control group of 30 healthy volunteers were investigated. All study participants filled out a scale to identify HADS anxiety-depressive disorder, an overall assessment of the quality of life, using a questionnaire SF-8 (standard 4-week form). FD patients were asked to rate the severity of epigastric pain (burning) or abdominal discomfort (early satiation or postprandial fullness) with LPDS scale (Leuven postprandial distress scale). All statistical analyzes were performed in the Medstat program. The results obtained with p Anxiety and depression were observed in 50.4% and 42.4% of FD patients, respectively, and in 13.3% and 6.66% of healthy subjects, respectively (p anxiety and depression in lBS patients were 7.93 ± 3.75 and 6.94 ± 3.78, respectively. Both anxiety and depression were associated with self-reported symptom severity (LPDS) (p anxiety and depression. Self-reported symptom severity, anxiety and depression were clearly and independently associated with the overall health-related quality of life (HRQOL). Biopsychosocial model of FD explained the difficulties of the pathogenesis of this disease. Anxiety and de- pression were frequently observed in FD patients and were related to the severity of their symptoms and the impairment of the patient's HRQOL. Our data suggest that assessing anxiety and depression is important when evaluating FD patients.

  13. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    OpenAIRE

    Abbott SM; Videnovic A

    2016-01-01

    Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are ofte...

  14. An object-oriented Bayesian network modeling the causes of leg disorders in finisher herds

    DEFF Research Database (Denmark)

    Jensen, Tina Birk; Kristensen, Anders Ringgaard; Toft, Niels

    2009-01-01

    The implementation of an effective control strategy against disease in a finisher herd requires knowledge regarding the disease level in the herd. A Bayesian network was constructed that can estimate risk indexes for three cause-categories of leg disorders in a finisher herd. The cause-categories......The implementation of an effective control strategy against disease in a finisher herd requires knowledge regarding the disease level in the herd. A Bayesian network was constructed that can estimate risk indexes for three cause-categories of leg disorders in a finisher herd. The cause...... of performing systematic collection of additional information (i.e. clinical, pathological and bacteriological examination) when identifying causes of leg disorders at herd level....

  15. Red cell glycolytic enzyme disorders caused by mutations: an update.

    Science.gov (United States)

    Climent, Fernando; Roset, Feliu; Repiso, Ada; Pérez de la Ossa, Pablo

    2009-06-01

    Glycolysis is one of the principle pathways of ATP generation in cells and is present in all cell tissues; in erythrocytes, glycolysis is the only pathway for ATP synthesis since mature red cells lack the internal structures necessary to produce the energy vital for life. Red cell deficiencies have been detected in all erythrocyte glycolytic pathways, although their frequencies differ owing to diverse causes, such as the affected enzyme and severity of clinical manifestations. The number of enzyme deficiencies known is endless. The most frequent glycolysis abnormality is pyruvate kinase deficiency, since around 500 cases are known, the first of which was reported in 1961. However, only approximately 200 cases were due to mutations. In contrast, only one case of phosphoglycerate mutase BB type mutation, described in 2003, has been detected. Most mutations are located in the coding sequences of genes, while others, missense, deletions, insertions, splice defects, premature stop codons and promoter mutations, are also frequent. Understanding of the crystal structure of enzymes permits molecular modelling studies which, in turn, reveal how mutations can affect enzyme structure and function.

  16. Animal models of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Fabiola Mara Ribeiro

    2013-01-01

    Full Text Available The prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD and Parkinson's disease (PD, increases with age, and the number of affected patients is expected to increase worldwide in the next decades. Accurately understanding the etiopathogenic mechanisms of these diseases is a crucial step for developing disease-modifying drugs able to preclude their emergence or at least slow their progression. Animal models contribute to increase the knowledge on the pathophysiology of neurodegenerative diseases. These models reproduce different aspects of a given disease, as well as the histopathological lesions and its main symptoms. The purpose of this review is to present the main animal models for AD, PD, and Huntington's disease.

  17. Role of psychological trauma in the cause and treatment of anxiety and depressive disorders.

    Science.gov (United States)

    Laugharne, Jonathan; Lillee, Alyssa; Janca, Aleksandar

    2010-01-01

    The role of traumatic events in the development of post-traumatic stress disorder is well established but their importance in the other anxiety disorders and in depression is less clear. We have reviewed recent publications in the medical literature which add to current knowledge regarding the possible causative role of trauma and the efficacy of trauma-focused treatments in these disorders. A number of recent studies add further support to the notion that traumatic events increase vulnerability to a range of psychiatric disorders. Furthermore, pretrauma risk factors are shared across different anxiety and depressive disorders. Patients with partial rather than full post-traumatic stress disorder often have their post-traumatic symptoms subsumed within another anxiety or depressive diagnosis. There is very little data relating to trauma-focused treatment of disorders other than post-traumatic stress disorder. There is increasing evidence that clinicians should be cognizant of the possible role of traumatic experience in the cause of patients with diagnoses other than post-traumatic stress disorder. There is, however, a paucity of data for the efficacy of trauma-focused psychological interventions for disorders other than post-traumatic stress disorder and further research is therefore needed.

  18. Metal imaging in neurodegenerative diseases

    Science.gov (United States)

    Bourassa, Megan W.

    2014-01-01

    Metal ions are known to play an important role in many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases. In these diseases, aberrant metal binding or improper regulation of redox active metal ions can induce oxidative stress by producing cytotoxic reactive oxygen species (ROS). Altered metal homeostasis is also frequently seen in the diseased state. As a result, the imaging of metals in intact biological cells and tissues has been very important for understanding the role of metals in neurodegenerative diseases. A wide range of imaging techniques have been utilized, including X-ray fluorescence microscopy (XFM), particle induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), laser ablation inductively coupled mass spectrometry (LA-ICP-MS), and secondary ion mass spectrometry (SIMS), all of which allow for the imaging of metals in biological specimens with high spatial resolution and detection sensitivity. These techniques represent unique tools for advancing the understanding of the disease mechanisms and for identifying possible targets for developing treatments. In this review, we will highlight the advances in neurodegenerative disease research facilitated by metal imaging techniques. PMID:22797194

  19. Causes of decreased life expectancy over the life span in bipolar disorder

    DEFF Research Database (Denmark)

    Kessing, Lars Vedel; Vradi, Eleni; McIntyre, Roger S

    2015-01-01

    BACKGROUND: Accelerated aging has been proposed as a mechanism explaining the increased prevalence of comorbid general medical illnesses in bipolar disorder. AIMS: To test the hypothesis that lost life years due to natural causes starts in early and mid-adulthood, supporting the hypothesis...... of accelerated aging. METHODS: Using individual data from nationwide registers of patient with a diagnosis of bipolar disorder we calculated remaining life expectancies before age 90 years for values of age 15, 25, 35…75 years among all individuals alive in year 2000. Further, we estimated the reduction in life......, remaining life expectancy before age 90 years was decreased 12.7 and 8.9 life years, respectively, for men and women with bipolar disorder. For 15-year old boys with bipolar disorder, natural causes accounted for 58% of all lost life years and for 15-year old girls, natural causes accounted for 67...

  20. 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.

  1. Stem Cells for the Treatment of Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Ning Zhang

    2010-09-01

    Full Text Available Neurodegenerative diseases are characterized by neurodegenerative changes or apoptosis of neurons involved in networks, leading to permanent paralysis and loss of sensation below the site of the injury. Cell replacement therapy has provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. In recent years, neurons and glial cells have successfully been generated from stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable previously published experimental and preclinical studies involving stem cell-based cell for neurodegenerative diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.

  2. Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

    Directory of Open Access Journals (Sweden)

    Ali G. Hamedani

    2017-07-01

    Full Text Available Eye movement abnormalities are among the earliest clinical manifestations of inherited and acquired neurodegenerative diseases and play an integral role in their diagnosis. Eyelid movement is neuroanatomically linked to eye movement, and thus eyelid dysfunction can also be a distinguishing feature of neurodegenerative disease and complements eye movement abnormalities in helping us to understand their pathophysiology. In this review, we summarize the various eyelid abnormalities that can occur in neurodegenerative, neurogenetic, and neurometabolic diseases. We discuss eyelid disorders, such as ptosis, eyelid retraction, abnormal spontaneous and reflexive blinking, blepharospasm, and eyelid apraxia in the context of the neuroanatomic pathways that are affected. We also review the literature regarding the prevalence of eyelid abnormalities in different neurologic diseases as well as treatment strategies (Table 1.

  3. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Antonio Paoli

    2014-01-01

    Full Text Available 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.

  4. 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

  5. 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

  6. Biology of Mitochondria in Neurodegenerative Diseases

    Science.gov (United States)

    Martin, Lee J.

    2012-01-01

    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 degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. 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 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 programmed 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 chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS. PMID:22482456

  7. Personality and social cognition in neurodegenerative disease.

    Science.gov (United States)

    Shany-Ur, Tal; Rankin, Katherine P

    2011-12-01

    Neurodegenerative diseases often cause focal damage to brain structures mediating social cognition and personality, resulting in altered interpersonal communication and behavior. We review recent research describing this phenomenon in various aspects of social cognition. Corresponding to their pervasive socioemotional deficits, patients with frontotemporal dementia perform poorly on laboratory-based tasks including recognizing emotions, attending to salient information that guides social behavior, representing social knowledge, comprehending others' mental states, and maintaining insight to their own difficulties. Together with poor executive and regulation mechanisms, these social cognition deficits ultimately impact behavior. Patients with logopenic and nonfluent primary progressive aphasia have some deficits recognizing emotional prosody, whereas those with the semantic variant show more widespread deficits in social comprehension. Although Alzheimer's disease patients perform poorly on some social cognition tasks, this typically reflects general cognitive impairment, and their real-life social functioning is less affected than in diseases targeting frontotemporal structures. Studies in motor diseases such as Parkinson's suggest some degradation of emotion recognition and social comprehension, which should be investigated further. We summarize recent findings concerning perception and evaluation of socioemotional information, social knowledge storage and access, advanced information processing mechanisms, and behavioral response selection and regulation across various neurodegenerative diseases.

  8. Persistent Genital Arousal Disorder Caused by Spinal Meningeal Cysts in the Sacrum: Successful Neurosurgical Treatment.

    Science.gov (United States)

    Feigenbaum, Frank; Boone, Kaitlynn

    2015-10-01

    To evaluate whether treatment of spinal meningeal cysts that compress sacral spinal nerve roots is associated with relief of persistent genital arousal disorder. In this case series we encountered a group of patients with persistent genital arousal disorder among a larger cohort undergoing a prospective outcomes study on the surgical treatment of symptomatic spinal meningeal cysts. Epidemiologic data were collected and the type, number, and location of the meningeal cysts in each patient were determined on magnetic resonance imaging. Postoperatively patients were asked to self-report whether their persistent genital arousal disorder was eliminated, significantly better, the same, or worse. In a cohort of 1,045 patients with symptomatic spinal meningeal cysts, we identified 11 with persistent genital arousal disorder; all were female and all had meningeal cysts in the sacral spinal canal causing sacral nerve root compression. In addition to persistent genital arousal disorder, all patients had other symptoms typical of sacral nerve root compression such as perineal, bladder, and bowel symptoms. Although multiple types of meningeal cysts were encountered, Tarlov cysts were the most common (8/11). Postoperatively, seven (64%) patients reported elimination of their persistent genital arousal disorder, three (27%) noted significant improvement, one (9%) said they were unchanged, and none experienced worsening with an average follow-up of 23 months ranging from 2 months to 6 years. Although Tarlov cysts were more numerous, the presence of persistent genital arousal disorder and the surgical outcomes appeared unrelated to the type of spinal meningeal cyst treated. Our case series suggests that sacral nerve root compression caused by spinal meningeal cysts can cause persistent genital arousal disorder. The presence of nerve root compression appears to be more important than the particular type of meningeal cyst involved. Microsurgical cyst treatment cured or significantly

  9. A Review on Stuttering and Social Anxiety Disorder in Children: Possible Causes and Therapies/Treatments

    Directory of Open Access Journals (Sweden)

    Nadia Nathania

    2016-12-01

    Full Text Available In the past two decades, stuttering and its relation to social anxiety disorder have been researched using different approaches in study fields such as neurolinguistics and neuropsychology. This paper presents a review of research publications about social anxiety disorder in children who stutter. It takes into account studies of stuttering, social anxiety disorders, the possible causes as well as atti-tudes and beliefs towards stuttering. Also, therapies or treatments that have been conducted on both English-speaking children who stutter in the Western context and Mandarin-speaking children stut-terers in Asia, Taiwan in particular; will be looked at

  10. 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.

  11. 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.

  12. 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.)

  13. 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.

  14. Neurodegenerative Diseases: Exercising Toward Neurogenesis and Neuroregeneration

    Science.gov (United States)

    Ang, Eng-Tat; Tai, Yee-Kit; Lo, Shun-Qiang; Seet, Raymond; Soong, Tuck-Wah

    2010-01-01

    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. PMID:20725635

  15. A brainstem inflammatory lesion causing REM sleep behavior disorder and sleepwalking (parasomnia overlap disorder).

    Science.gov (United States)

    Limousin, Nadège; Dehais, Caroline; Gout, Olivier; Héran, Françoise; Oudiette, Delphine; Arnulf, Isabelle

    2009-10-01

    A 40-year-old woman with no prior parasomnia developed an acute inflammatory rhombencephalitis with multiple cranial nerve palsies and cerebellar ataxia, followed by myelitis 6 months later, and by an intracranial thrombophlebitis 1 month after. Between and after these episodes, she had a persistent, mild right internuclear ophtalmoplegia, a mild cerebellar ataxia, and a severe REM sleep behavior disorder (RBD) lasting for 2 years. She talked, sang and moved nightly while asleep, and injured her son (cosleeping with her) while asleep. In addition, she walked asleep nightly. During video-polysomnography, there were two arousals during slow wave sleep without abnormal behavior, while 44% of REM sleep was without chin muscle atonia with bilateral arm and leg movements. There were small hypointensities in the right pontine tegmentum and in the right dorsal medulla on T1-weighted magnetic resonance imaging, suggesting post-inflammatory lesions that persisted between acute episodes. The RBD and sleepwalking did not improve with clonazepam, but improved with melatonin 9 mg/d. The unilateral small lesion of the pontine tegmentum could be responsible for the parasomnia overlap disorder as in other rare lesional cases.

  16. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease.

    Science.gov (United States)

    Wulff, Katharina; Gatti, Silvia; Wettstein, Joseph G; Foster, Russell G

    2010-08-01

    Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep-wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of--and permit early intervention of--psychiatric and neurodegenerative disease.

  17. Sleep-wake changes and cognition in neurodegenerative disease.

    Science.gov (United States)

    Naismith, Sharon L; Lewis, Simon J G; Rogers, Naomi L

    2011-01-01

    With the increasing aging population, neurodegenerative disorders will become more common in clinical practice. These disorders involve multiple pathophysiological mechanisms that differentially affect cognition, mood, and physical functions. Possibly due to the involvement of common underlying neurobiological circuits, sleep and/or circadian (sleep-wake) changes are also common in this disease group. Of significance, sleep-wake changes are often a prodromal feature and are predictive of cognitive decline, psychiatric symptoms, quality of life, need for institutional care, and caregiver burden. Unfortunately, in neurodegenerative disease, few studies have included detailed polysomnography or neuropsychological assessments although some data indicate that sleep and neurocognitive features are related. Further studies are also required to address the effects of pharmacological and nonpharmacological treatments on cognitive functioning. Such research will hopefully lead to targeted early intervention approaches for cognitive decline in older people. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Cause-specific life-years lost in people with mental disorders

    DEFF Research Database (Denmark)

    Erlangsen, Annette; Andersen, Per Kragh; Toender, Anita

    2017-01-01

    -specific differences between those with and without mental disorders in terms of excess life-years lost were for respiratory diseases (men: 0·9; women: 1·4) and alcohol misuse (men: 2·8; women: 1·2). Between 1995 and 2014, we noted an increase in excess life-years lost for neoplasms (men: 0·7; women: 0·4), heart...... mortality due to medical diseases and disorders among people with mental disorders emphasises the need for future interventions to address these aspects as well as the continued high shares of excess mortality due to alcohol misuse, suicide, and accidents. FUNDING: The Lundbeck Foundation Initiative......BACKGROUND: People with mental disorders have higher mortality rates than the general population and more detailed estimates of mortality differences are needed to address this public health issue. We aimed to assess whether differences in cause-specific mortality between people with and without...

  19. Mental disorder is a cause of crime: the cornerstone of forensic psychiatry.

    Science.gov (United States)

    Anckarsäter, Henrik; Radovic, Susanna; Svennerlind, Christer; Höglund, Pontus; Radovic, Filip

    2009-01-01

    The assumption that mental disorder is a cause of crime is the foundation of forensic psychiatry, but conceptual, epistemological, and empirical analyses show that neither mental nor crime, or the causation implied, are clear-cut concepts. "Mental" denotes heterogeneous aspects of a person such as inner experiences, cognitive abilities, and behaviour patterns described in a non-physical vocabulary. In psychology and psychiatry, mental describes law-bound, caused aspects of human functioning that are predictable and generalizable. Problems defined as mental disorders are end-points of dimensional inter-individual differences rather than natural categories. Deficits in cognitive faculties, such as attention, verbal understanding, impulse control, and reality assessment, may be susceptibility factors that relate to behaviours (such as crimes) by increasing the probability (risk) for a negative behaviour or constitute causes in the sense of INUS conditions (Insufficient but Non-redundant parts of Unnecessary but Sufficient conditions). Attributing causes to complex behaviours such as crimes is not an unbiased process, and mental disorders will attract disproportionate attention when it comes to explanations of behaviours that we wish to distance ourselves from. Only by rigorous interpretation of what psychiatry actually can inform us about, using empirical analyses of quantified aggressive antisocial behaviours and their possible explanatory factors, can we gain a clearer notion of the relationship between mental disorder and crime.

  20. Mortality and Causes of Death in Autism Spectrum Disorders: An Update

    Science.gov (United States)

    Mouridsen, Svend Erik; Bronnum-Hansen, Henrik; Rich, Bente; Isager, Torben

    2008-01-01

    This study compared mortality among Danish citizens with autism spectrum disorders (ASDs) with that of the general population. A clinical cohort of 341 Danish individuals with variants of ASD, previously followed over the period 1960-93, now on average 43 years of age, were updated with respect to mortality and causes of death. Standardized…

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

    OpenAIRE

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

    2012-01-01

    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 s...

  2. CT and MRI of dementia disorders

    Energy Technology Data Exchange (ETDEWEB)

    Momoshima, Suketaka; Fujiwara, Hirokazu [Keio Univ., Tokyo (Japan). School of Medicine

    2002-06-01

    Imaging diagnosis plays a critical role in the initial evaluation of dementia disorders despite its limited specificity. The two major causes of dementia are neurodegenerative disorders including Alzheimer disease and diffuse vascular disorders, some of which show characteristic findings on CT and MRI. Although effective treatment is not yet available for most of these entities, there is possibility that early diagnosis by imaging could lead to preventive measures in future. Some illustrative cases of dementia diseases are demonstrated. (author)

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

    Directory of Open Access Journals (Sweden)

    Marina de Tommaso

    2016-01-01

    Full Text Available 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, spinocerebellar ataxia (SCA, and spinal muscular atrophy (SMA, is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed.

  4. Hypothesis: grandiosity and guilt cause paranoia; paranoid schizophrenia is a psychotic mood disorder; a review.

    Science.gov (United States)

    Lake, Charles Raymond

    2008-11-01

    Delusional paranoia has been associated with severe mental illness for over a century. Kraepelin introduced a disorder called "paranoid depression," but "paranoid" became linked to schizophrenia, not to mood disorders. Paranoid remains the most common subtype of schizophrenia, but some of these cases, as Kraepelin initially implied, may be unrecognized psychotic mood disorders, so the relationship of paranoid schizophrenia to psychotic bipolar disorder warrants reevaluation. To address whether paranoia associates more with schizophrenia or mood disorders, a selected literature is reviewed and 11 cases are summarized. Comparative clinical and recent molecular genetic data find phenotypic and genotypic commonalities between patients diagnosed with schizophrenia and psychotic bipolar disorder lending support to the idea that paranoid schizophrenia could be the same disorder as psychotic bipolar disorder. A selected clinical literature finds no symptom, course, or characteristic traditionally considered diagnostic of schizophrenia that cannot be accounted for by psychotic bipolar disorder patients. For example, it is hypothesized here that 2 common mood-based symptoms, grandiosity and guilt, may underlie functional paranoia. Mania explains paranoia when there are grandiose delusions that one's possessions are so valuable that others will kill for them. Similarly, depression explains paranoia when delusional guilt convinces patients that they deserve punishment. In both cases, fear becomes the overwhelming emotion but patient and physician focus on the paranoia rather than on underlying mood symptoms can cause misdiagnoses. This study uses a clinical, case-based, hypothesis generation approach that warrants follow-up with a larger representative sample of psychotic patients followed prospectively to determine the degree to which the clinical course observed herein is typical of all such patients. Differential diagnoses, nomenclature, and treatment implications are

  5. Parental perspectives on the causes of an autism spectrum disorder in their children.

    Science.gov (United States)

    Mercer, L; Creighton, S; Holden, J J A; Lewis, M E S

    2006-02-01

    Autism Spectrum Disorders (ASDs) are complex neurodevelopmental disorders with many biological causes, including genetic, syndromic and environmental. Such etiologic heterogeneity impacts considerably upon parents' needs for understanding their child's diagnosis. A descriptive survey was designed to investigate parental views on the cause(s) of ASD in their child. Among the 41 parents who replied to the questionnaire, genetic influences (90.2%), perinatal factors (68.3%), diet (51.2%), prenatal factors (43.9%) and vaccines (40.0%) were considered to be the most significant contributory factors. Parents reported inaccurately high recurrence risks, misperceptions of the contribution of various putative factors, feelings of guilt and blame regarding their child's diagnosis, as well as a lack of advocacy for genetic counseling by non-geneticist professionals. This study offers clinicians and researchers further insight into what parents believe contributed to their child's diagnosis of ASD and will help facilitate genetic counseling for these families.

  6. Epigenetic programming of neurodegenerative diseases by an adverse environment.

    Science.gov (United States)

    Babenko, Olena; Kovalchuk, Igor; Metz, Gerlinde A

    2012-03-20

    Experience and environment can critically influence the risk and progression of neurodegenerative disorders. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications, readily respond to experience and environmental factors. Here we propose that epigenetic regulation of gene expression and environmental modulation thereof may play a key role in the onset and course of common neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. For example, epigenetic mechanisms may mediate long-term responses to adverse experience, such as stress, to affect disease susceptibility and the course of neurodegenerative events. This review introduces the epigenetic components and their possible role in mediating neuropathological processes in response to stress. We argue that epigenetic modifications will affect neurodegenerative events through altered gene function. The study of epigenetic states in neurodegenerative diseases presents an opportunity to gain new insights into risk factors and pathogenic mechanisms. Moreover, research into epigenetic regulation of disease may revolutionize health care by opening new avenues of personalized, preventive and curative medicine. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases

    Science.gov (United States)

    Alexander, Adanna G.; Marfil, Vanessa; Li, Chris

    2014-01-01

    Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer’s disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model. PMID:25250042

  8. Mood, anxiety, and alcohol use disorders and later cause-specific sick leave in young adult employees.

    Science.gov (United States)

    Torvik, Fartein Ask; Reichborn-Kjennerud, Ted; Gjerde, Line C; Knudsen, Gun Peggy; Ystrom, Eivind; Tambs, Kristian; Røysamb, Espen; Østby, Kristian; Ørstavik, Ragnhild

    2016-08-03

    Mental disorders strongly influence work capability in young adults, but it is not clear which disorders that are most strongly associated with sick leave, and which diagnoses that are stated on the sick leave certificates. Better knowledge of the impairments associated with different mental disorders is needed for optimal planning of interventions and prioritization of health services. In the current study, we investigate the prospective associations between eight mood, anxiety, and alcohol use disorders, and later sick leave granted for mental, somatic, or any disorder. Lifetime mental disorders were assessed by structured diagnostic interviews in 2,178 young adults followed for eight years with registry data on sick leave. Relative risk ratios were estimated for the associations between each mental disorder and the different forms of sick leave. All included diagnoses were associated with later sick leave. In adjusted analyses, major depressive disorder and generalized anxiety disorder were the strongest predictors of sick leave granted for mental disorders, whereas social anxiety disorder and specific phobia were the strongest predictors of sick leave granted for somatic disorders. Specific phobia and major depressive disorder had the highest attributable fractions for all-cause sick leave. Mood and anxiety disorders constituted independent risk factors for all cause sick leave, whereas alcohol use disorders seemed to be of less importance in young adulthood. Disorders characterised by distress were most strongly associated with sick leave granted for mental disorders, whereas disorders characterised by fear primarily predicted sick leave granted for somatic conditions. A large part of all sick leave is related to specific phobia, due to the high prevalence of this disorder. The impairment associated with this common disorder may be under-acknowledged, and it could decrease work capacity among individuals with somatic disorders. This disorder has good treatment

  9. Mood, anxiety, and alcohol use disorders and later cause-specific sick leave in young adult employees

    Directory of Open Access Journals (Sweden)

    Fartein Ask Torvik

    2016-08-01

    Full Text Available Abstract Background Mental disorders strongly influence work capability in young adults, but it is not clear which disorders that are most strongly associated with sick leave, and which diagnoses that are stated on the sick leave certificates. Better knowledge of the impairments associated with different mental disorders is needed for optimal planning of interventions and prioritization of health services. In the current study, we investigate the prospective associations between eight mood, anxiety, and alcohol use disorders, and later sick leave granted for mental, somatic, or any disorder. Methods Lifetime mental disorders were assessed by structured diagnostic interviews in 2,178 young adults followed for eight years with registry data on sick leave. Relative risk ratios were estimated for the associations between each mental disorder and the different forms of sick leave. Results All included diagnoses were associated with later sick leave. In adjusted analyses, major depressive disorder and generalized anxiety disorder were the strongest predictors of sick leave granted for mental disorders, whereas social anxiety disorder and specific phobia were the strongest predictors of sick leave granted for somatic disorders. Specific phobia and major depressive disorder had the highest attributable fractions for all-cause sick leave. Conclusions Mood and anxiety disorders constituted independent risk factors for all cause sick leave, whereas alcohol use disorders seemed to be of less importance in young adulthood. Disorders characterised by distress were most strongly associated with sick leave granted for mental disorders, whereas disorders characterised by fear primarily predicted sick leave granted for somatic conditions. A large part of all sick leave is related to specific phobia, due to the high prevalence of this disorder. The impairment associated with this common disorder may be under-acknowledged, and it could decrease work capacity among

  10. Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Suzana Aulić

    2013-01-01

    Full Text Available Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, β-sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrPC. Many lines of evidence suggest that prions (PrPSc act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such, PrPSc may be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer’s disease, Parkinson’s disease, and prion disease. Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics.

  11. The role of mitochondrial DNA mutation on neurodegenerative diseases.

    Science.gov (United States)

    Cha, Moon-Yong; Kim, Dong Kyu; Mook-Jung, Inhee

    2015-03-13

    Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.

  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. Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

    Directory of Open Access Journals (Sweden)

    Fabian Hosp

    2015-05-01

    Full Text Available Several proteins have been linked to neurodegenerative disorders (NDDs, but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP and Presenilin-1 (PSEN1 for Alzheimer’s disease (AD, Huntingtin (HTT for Huntington’s disease, Parkin (PARK2 for Parkinson’s disease, and Ataxin-1 (ATXN1 for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  14. Diagnostics of the genetic causes of autism spectrum disorders – a clinical geneticist’s view

    OpenAIRE

    Szczałuba, Krzysztof

    2014-01-01

    Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different c...

  15. Rare acquired hemostatic disorders as a cause of prolonged bleeding – presentation of two case reports

    Directory of Open Access Journals (Sweden)

    Polona Novak

    2011-10-01

    Full Text Available BACKGROUNDPatient’s anamnesis is of primary importance in determining hemostatic disorders. Based on anamnestic data, a clinician may decide for further laboratory tests. We must consider an acquired bleeding disorder in a patient with unusual, unexpected and prolonged bleeding episodes. In this article we will describe two rare acquired hemostatic disordes.TWO CASE REPORTSOur first patient had prolonged bleeding after a pacemaker implantation. We diagnosed him with acquired von Willebrand syndrome. Further on, the patient required a planned surgical procedure. In our second case we describe a patient with unusual and excessive skin bruising and prolonged bleeding after teeth extractions. He was diagnosed with acquired hemophilia.CONCLUSIONIn the assessment of a patient with a potential acquired bleeding disorder we must first rule out the most common causes, such as iatrogenic ones. But, because of high morbidity and mortality rates, we must also be aware of some rare acquired bleeding disorders. In case of uncertainty, we should consult with a hematologist.

  16. Widespread Aggregation and Neurodegenerative Diseases Are Associated with Supersaturated Proteins

    Directory of Open Access Journals (Sweden)

    Prajwal Ciryam

    2013-11-01

    Full Text Available The maintenance of protein solubility is a fundamental aspect of cellular homeostasis because protein aggregation is associated with a wide variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or aging. A crucial question in this context is why only certain proteins appear to aggregate readily in vivo, whereas others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. We find that these supersaturated proteins represent a metastable subproteome involved in pathological aggregation during stress and aging and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging.

  17. Neurodegenerative diseases and widespread aggregation are associated with supersaturated proteins

    Science.gov (United States)

    Ciryam, Prajwal; Tartaglia, Gian Gaetano; Morimoto, Richard I.; Dobson, Christopher M.; Vendruscolo, Michele

    2013-01-01

    Summary The maintenance of protein solubility is a fundamental aspect of protein homeostasis, as aggregation is associated with cytotoxicity and a variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or ageing. A crucial question in this context is why only certain proteins aggregate in vivo while others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. These supersaturated proteins represent a metastable sub-proteome involved in pathological aggregation during stress and ageing, and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging. PMID:24183671

  18. 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.

  19. Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases?

    Science.gov (United States)

    Galea, Elena; Launay, Nathalie; Portero-Otin, Manuel; Ruiz, Montserrat; Pamplona, Reinald; Aubourg, Patrick; Ferrer, Isidre; Pujol, Aurora

    2012-09-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jean E. Vance

    2012-11-01

    Full Text Available Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD, Niemann-Pick type C (NPC disease and Smith-Lemli Opitz syndrome (SLOS. However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE, a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

  1. Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'

    DEFF Research Database (Denmark)

    Svenstrup, Kirsten; Giraud, Geneviève; Boespflug-Tanguy, Odile

    2010-01-01

    BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic....... No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration....

  2. [Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

    Science.gov (United States)

    Szczaluba, Krzysztof

    2014-01-01

    Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different categories, and include congenital defects/anomalies, dysmorphism and macro-/microcephaly, to name the few. Thus, the choice of the diagnostic strategy depends on the clinical and pedigree information and, under Polish circumstances, the availability of specific diagnostic techniques and the amount of reimbursement under the National Health Service. Overall, the identification of the genetic causes of autism spectrum disorders is possible in about 10-30% of patients. In this paper the practical aspects of the use of different diagnostic techniques are briefly described. Some clinical examples and current recommendations for the diagnosis of patients with autism spectrum disorders are also presented. The point of view of a specialist in clinical genetics, increasingly involved, as part of the multidisciplinary care team, in the diagnostics of an autistic child has been demonstrated.

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

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    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.

  4. Public beliefs about causes and risk factors for mental disorders: a comparison of Japan and Australia

    Directory of Open Access Journals (Sweden)

    Nakane Hideyuki

    2005-09-01

    Full Text Available Abstract Background Surveys of the public in a range of Western countries have shown a predominant belief in social stressors as causes of mental disorders. However, there has been little direct cross-cultural comparison. Here we report a comparison of public beliefs about the causes of mental disorders in Japan and Australia. Methods Surveys of the public were carried out in each country using as similar a methodology as feasible. In both countries, household interviews were carried out concerning beliefs about causes and risk factors in relation to one of four case vignettes, describing either depression, depression with suicidal thoughts, early schizophrenia or chronic schizophrenia. In Japan, the survey involved 2000 adults aged between 20 and 69 from 25 regional sites spread across the country. In Australia, the survey involved a national sample of 3998 adults aged 18 years or over. Results In both countries, both social and personal vulnerability causes were commonly endorsed across all vignettes. The major differences in causal beliefs were that Australians were more likely to believe in infection, allergy and genetics, while Japanese were more likely to endorse "nervous person" and "weakness of character". For risk factors, Australians tended to believe that women, the young and the poor were more at risk of depression, but these were not seen as higher risk groups by Japanese. Conclusion In both Japan and Australia, the public has a predominant belief in social causes and risk factors, with personal vulnerability factors also seen as important. However, there are also some major differences between the countries. The belief in weakness of character as a cause, which was stronger in Japan, is of particular concern because it may reduce the likelihood of seeking professional help and support from others.

  5. Fatty acid oxidation disorders as primary cause of sudden and unexpected death in infants and young children

    DEFF Research Database (Denmark)

    Banner, Jytte; Kølvraa, S; Gregersen, N

    1997-01-01

    Disorders of fatty acid metabolism are known to be responsible for cases of sudden and unexpected death in infancy. At least 14 disorders are known at present. 120 cases of sudden infant death syndrome (SIDS) had been examined for a prevalent mutation (G985) causing medium chain acyl CoA dehydrog......Disorders of fatty acid metabolism are known to be responsible for cases of sudden and unexpected death in infancy. At least 14 disorders are known at present. 120 cases of sudden infant death syndrome (SIDS) had been examined for a prevalent mutation (G985) causing medium chain acyl Co...

  6. Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases

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    Hsi-Lung Hsieh

    2013-01-01

    Full Text Available Reactive oxygen species (ROS, a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS have been detected in patients with neurodegenerative diseases such as Alzheimer’s disease (AD. These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs, cytosolic phospholipase A2 (cPLA2, cyclooxygenase-2 (COX-2, and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases.

  7. The transition metals copper and iron in neurodegenerative diseases.

    Science.gov (United States)

    Rivera-Mancía, Susana; Pérez-Neri, Iván; Ríos, Camilo; Tristán-López, Luis; Rivera-Espinosa, Liliana; Montes, Sergio

    2010-07-30

    Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Gastrointestinal disorders caused by medication and electrolyte solution osmolality during enteral nutrition.

    Science.gov (United States)

    Niemiec, P W; Vanderveen, T W; Morrison, J I; Hohenwarter, M W

    1983-01-01

    Enteral feeding tubes represent convenient avenues for medication administration and electrolyte replacement. The frequent association of medication therapy with gastrointestinal disorders during enteral nutrition prompted this evaluation of medication and electrolyte solution osmolality. It is concluded that the hypertonicity of electrolyte replacement solutions and various medications may cause gastrointestinal intolerance in patients. Electrolyte supplementation by parenteral means or by appropriate dilution and mixture with an enteral formula is preferable to bolus administration of undiluted solutions via the feeding tube. Routine admixture of medications such as antibiotic suspensions to enteral formulas cannot be recommended at this time pending specific study of drug compatibility and availability from enteral tube feeding systems.

  9. Defects in enzyme regulation versus defects in enzyme synthesis as cause of metabolic disorders.

    Science.gov (United States)

    Belfiore, F

    1980-01-01

    Based on the consideration that normal metabolic processes depend upon the activity of key enzymes (and membrane carriers) as modulated by regulatory factors (hormones, diet, endogenous compounds, age, physical activity, environmental agents), metabolic disorders might be classified into two groups: (I) defects in enzyme synthesis, leading to enzyme deficiency (classical inborn errors of metabolism) or to qualitative (structural) enzyme alterations (entailing unresponsiveness to regulation), in the presence of normal regulatory factors; (II) defects in enzyme regulation, which include metabolic syndromes such as diabetes mellitus, obesity and hyperlipoproteinemias (other than type I), and are due to changes in enzyme activities caused by alterations in regulatory factor(s) (secondary to various causes), in the presence of normally responsive enzymes.

  10. Amnestic Disorders

    NARCIS (Netherlands)

    Kessels, R.P.C.; Savage, G.; Cautin, R.L.; Lilienfeld, S.O.

    2015-01-01

    Amnestic disorders may involve deficits in the encoding or storage of information in memory, or in retrieval of information from memory. Etiologies vary and include traumatic brain injury, neurodegenerative disease, and psychiatric illness. Different forms of amnesia can be distinguished:

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

    Indian Academy of Sciences (India)

    Unknown

    DM), fragile X syndrome (FraX), Huntington disease. (HD), several spinocerebellar ataxias and Friedreich ataxia have been associated with the expansion of GGC,. CAG or GAA repeats (Pearson and Sinden 1998). Actually,. GGC, CAG and GAA repeats indicate duplex repeat sequences (GGC)n–(GCC)n [also indicated as ...

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

    Indian Academy of Sciences (India)

    Further, at high salt condition, Greek key type quadruplex structures are energetically comparable with hairpin dimer and B-DNA type duplex structures. All tetrads in the quadruplex structures are well stacked and provide favourable stacking energy values. Interestingly, in the energy minimized hairpin dimer and Greek key ...

  13. 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.

  14. 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.

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

    Science.gov (United States)

    Santiago, Jose A; Bottero, Virginie; Potashkin, Judith A

    2017-01-01

    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.

  16. 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.

  17. Hormone Replacement Therapy and Risk for Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Richelin V. Dye

    2012-01-01

    Full Text Available Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer’s disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson’s disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson’s-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.

  18. Joint disorder; a contributory cause to reproductive failure in beef bulls?

    Directory of Open Access Journals (Sweden)

    Ekman Stina

    2007-11-01

    Full Text Available Abstract The lame sire, unsound for breeding, can cause substantial economic loss due to reduced pregnancies in the beef-producing herd. To test the hypothesis that joint disorder is a possible cause of infertility in beef sires, right and left hind limb bones from 34 beef sires were examined postmortem to identify lesions in the femorotibial, femoropatellar (stifle, tarsocrural, talocalcaneus, and proximal intertarsal (tarsal joints. The bulls were slaughtered during or after the breeding season due to poor fertility results. Aliquots of the cauda epididymal contents taken postmortem from 26 bulls were used for sperm morphology evaluation. As a control, hind limbs (but no semen samples from 11 beef bulls with good fertility results were included. Almost all infertile bulls (30/34 had lesions in at least one joint. Twenty-eight bulls (28/30, 93% had lesions in the stifle joint, and 24 (24/28, 86% of these were bilateral. Fourteen bulls (14/30, 47% had lesions in the tarsal joint, and 10 (10/14, 71% of these were bilateral. Four bulls (4/34, 12% had no lesions, three bulls (3/34, 9% had mild osteoarthritis (OA, 5 (5/34, 15% moderate OA, 17 (17/34, 50% severe OA and 5 (5/34, 15% deformed OA. Almost all OA lesions (97% were characterized as lesions secondary to osteochondrosis dissecans. All the bulls with satisfactory sperm morphology (n = 12/34 had joint lesions, with mostly severe or deformed bilateral lesions (83%. Consequently, the most likely cause of infertility in these 12 bulls was joint disease. Almost all control bulls (10/11 had OA lesions, but most of them were graded as mild (55% or moderate (36%. None of the control bulls had severe lesions or deformed OA. We suggest that joint lesions should be taken into consideration as a contributory cause of reproductive failure in beef sires without symptoms of lameness.

  19. Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Hueng-Chuen Fan

    2015-12-01

    Full Text Available Neurodegenerative diseases (NDs are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD, Huntington’s disease (HD, and Alzheimer’s disease (AD and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM, and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases.

  20. A RETROSPECTIVE OBSERVATIONAL STUDY OF PREVALENCE AND OCULAR MANIFESTATIONS IN VARIOUS OCULAR CAUSES FOR HEADACHE DISORDERS

    Directory of Open Access Journals (Sweden)

    Srinivasan Shanmugam

    2016-10-01

    Full Text Available BACKGROUND Headache or cephalgia is one of the commonest symptoms causing pain in head above eyes or the ears, behind the head in the occipital region or in the back of the upper neck causing pain as well as disability to an individual. WHO reports around 47% of adults worldwide will have experienced headache in the last year. Headache maybe primary or secondary. Tension headache is more common type of primary headache. Almost, 90% of adults have tension headache and it is more common in females than males. Migraine headache is third most prevalent disorder worldwide and ranked as seventh highest cause of disability. Migraine headaches are the second most common type of primary headaches, whereas cluster headache, a relatively uncommon type of primary headache affecting less than 1 in every 1000 adults. 1 Many people suffer from mixed headache disorder in which tension headache or secondary headache may trigger migraine. Headache on 15 or more days in every month affects 1.7-4% of the world adult population. Hospital-based studies of migraine shows India is home over 16% of world inhabitants suffering from migraine. MATERIALS AND METHODS In our study, total screening of 1200 cases was done with headache symptomatology reported to Eye OPD directly as well as referred from ENT, Medical, NeuroMedical, Surgical, Neurosurgical, Psychiatry, Orthopaedics and Trauma Ward. A detailed clinical examination and ophthalmological examination was done in 1200 cases. RESULTS Sexual prevalence in our study indicated female with increased prevalence of 46.67% compared to male of 36%. Among 30 cases of migrainous headache with or without aura, the sexual prevalence in our study has female-to-male ratio as 2:1 (female - 20 cases and male - 10 cases. No cluster headache disorder was reported in our study. Among the tension headache presented with ocular manifestations like association of the refractive error, redness, burning sensation, the female prevalence among

  1. Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: a nationwide, prospective, register-based study.

    Science.gov (United States)

    Hjorthøj, Carsten; Østergaard, Marie Louise Drivsholm; Benros, Michael Eriksen; Toftdahl, Nanna Gilliam; Erlangsen, Annette; Andersen, Jon Trærup; Nordentoft, Merete

    2015-09-01

    People with severe mental illness have both increased mortality and are more likely to have a substance use disorder. We assessed the association between mortality and lifetime substance use disorder in patients with schizophrenia, bipolar disorder, or unipolar depression. In this prospective, register-based cohort study, we obtained data for all people with schizophrenia, bipolar disorder, or unipolar depression born in Denmark in 1955 or later from linked nationwide registers. We obtained information about treatment for substance use disorders (categorised into treatment for alcohol, cannabis, or hard drug misuse), date of death, primary cause of death, and education level. We calculated hazard ratios (HRs) for all-cause mortality and subhazard ratios (SHRs) for cause-specific mortality associated with substance use disorder of alcohol, cannabis, or hard drugs. We calculated standardised mortality ratios (SMRs) to compare the mortality in the study populations to that of the background population. Our population included 41 470 people with schizophrenia, 11 739 people with bipolar disorder, and 88 270 people with depression. In schizophrenia, the SMR in those with lifetime substance use disorder was 8·46 (95% CI 8·14-8·79), compared with 3·63 (3·42-3·83) in those without. The respective SMRs in bipolar disorder were 6·47 (5·87-7·06) and 2·93 (2·56-3·29), and in depression were 6·08 (5·82-6·34) and 1·93 (1·82-2·05). In schizophrenia, all substance use disorders were significantly associated with increased risk of all-cause mortality, both individually (alcohol, HR 1·52 [95% CI 1·40-1·65], pdisorder or depression, only substance use disorders of alcohol (bipolar disorder, HR 1·52 [95% CI 1·27-1·81], pdisorder, 1·89 [1·34-2·66], p=0·0003; depression, 2·27 [1·98-2·60], pdisorders than in those without, particularly in people who misuse alcohol and hard drugs. Mortality-reducing interventions should focus on patients with a dual

  2. Mood and anxiety disorders in patients with chronic low back and neck pain caused by disc herniation.

    Science.gov (United States)

    Kayhan, Fatih; Albayrak Gezer, İlknur; Kayhan, Ayşegül; Kitiş, Serkan; Gölen, Mustafa

    2016-01-01

    We investigated the prevalence of mood and anxiety disorders in patients with chronic low back and neck pain caused by disc herniation and the relationships between pain and mood, and anxiety disorders. In total, 149 patients with disc herniation and 60 healthy subjects were included. Disc herniation was diagnosed based on a physical examination and magnetic resonance imaging. Mood and anxiety disorders were diagnosed using the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Clinical Version. The mean age of the study subjects (n = 209) was 45.96 ± 11.45 years. Seventy (46.6%) patients with disc herniation met the criteria for at least one mood or anxiety disorder. The prevalence rates of mood and anxiety disorders were 16.6% and 35.8%, respectively. The most common specific diagnoses were major depression (n = 25, 16.9%) and generalised anxiety disorder (n = 19, 12.8%). Mood and anxiety disorders were more commonly seen in patients with lumbar or cervical disc herniation than in those without herniation. No relationship was detected between pain severity and mood or anxiety disorders. However, mood and anxiety disorders were associated with neurological deficits.

  3. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    William M. Johnson

    2012-10-01

    Full Text Available Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

  4. Mesenchymal Stem Cells in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Olcay Ergurhan Kiroglu

    2015-03-01

    Full Text Available Neurodegenerative diseases are almost incurable, debilitating, and they might be fatal, because of limited neurogenesis in nervous system, presence of inhibitory substances and inhibition of recovery due to development of glial scar. Despite many treatment strategies of neurodegenerative diseases no full cure has been achieved. The successful results for mesenchymal stem cells applications on muscles, heart and liver diseases and the application of these cells to the damaged area in particular, hypoxia, inflammation and apoptosis promise hope of using them for neurodegenerative diseases. Mesenchymal stem cells applications constitute a vascular and neuronal phenotype in Parkinsons disease, Huntingtons disease, Amyotrophic lateral sclerosis and Alzheimers disease. Stem cells release bioactive agents that lead to suppression of local immune system, reduction of free radicals, increase in angiogenesis, inhibition of fibrosis, and apoptosis. In addition, tissue stem cells, increase neuronal healing, stimulate proliferation and differentiation. These findings show that stem cells might be a hope of a cure in the treatment of neurodegenerative diseases and intensive work on this issue should continue.

  5. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    Science.gov (United States)

    Johnson, William M.; Wilson-Delfosse, Amy L.; Mieyal, John. J.

    2012-01-01

    Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated. PMID:23201762

  6. Management of temporomandibular joint disorders caused by complication of teeth extraction

    Directory of Open Access Journals (Sweden)

    Endang Syamsuddin

    2016-06-01

    Full Text Available Complicated tooth extractions may lead to various post-extraction complications, including Temporomandibular Joint Disorders (TMD. Despite of the rare incidence, a delayed treatment of the TMD will cause more problems in the future as well as increased morbidity rate. The purpose of the current study was to elaborate the symptoms as well as the management of TMD as a post tooth extraction complication. The types of TMD as a post tooth extraction complication includes dislocated condyle, osteoarthritis, fracture condyle and disc displacement. These type of complications may resulted from an extensive opening of the mouth as well as an over pressure on the mandible during tooth extraction. In relation to this, some of the TMD symptoms that might cause a certain level of interference for patients may include pain, limited mouth opening and joint sounds, with pain and limited mouth opening as the initial symptoms. The first measure of the pain management would be warm light compress around the TMJ followed by a soft diet for food intake. A definitive treatment should then be based on the diagnosis of the TMD. It is concluded that TMD may occur as a complication of a tooth extraction that initiated by pain and limited mouth opening. Immediate treatment would be pain relieve and load reduction of the Temporomandibular Joint by employing soft diet and mandibular movement restriction.

  7. Low doses of ivermectin cause sensory and locomotor disorders in dung beetles

    Science.gov (United States)

    Verdú, José R.; Cortez, Vieyle; Ortiz, Antonio J.; González-Rodríguez, Estela; Martinez-Pinna, Juan; Lumaret, Jean-Pierre; Lobo, Jorge M.; Numa, Catherine; Sánchez-Piñero, Francisco

    2015-09-01

    Ivermectin is a veterinary pharmaceutical generally used to control the ecto- and endoparasites of livestock, but its use has resulted in adverse effects on coprophilous insects, causing population decline and biodiversity loss. There is currently no information regarding the direct effects of ivermectin on dung beetle physiology and behaviour. Here, based on electroantennography and spontaneous muscle force tests, we show sub-lethal disorders caused by ivermectin in sensory and locomotor systems of Scarabaeus cicatricosus, a key dung beetle species in Mediterranean ecosystems. Our findings show that ivermectin decreases the olfactory and locomotor capacity of dung beetles, preventing them from performing basic biological activities. These effects are observed at concentrations lower than those usually measured in the dung of treated livestock. Taking into account that ivermectin acts on both glutamate-gated and GABA-gated chloride ion channels of nerve and muscle cells, we predict that ivermectin’s effects at the physiological level could influence many members of the dung pat community. The results indicate that the decline of dung beetle populations could be related to the harmful effects of chemical contamination in the dung.

  8. [Auto-immune disorders as a possible cause of neuropsychiatric syndromes].

    Science.gov (United States)

    Martinez-Martinez, P; Molenaar, P C; Losen, M; Hoffmann, C; Stevens, J; de Witte, L D; van Amelsvoort, T; van Os, J; Rutten, B P F

    2015-01-01

    Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

  9. Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development.

    Science.gov (United States)

    Ledig, Susanne; Hiort, Olaf; Wünsch, Lutz; Wieacker, Peter

    2012-07-01

    Ovotesticular disorder of sexual development (DSD) is an unusual form of DSD, characterized by the coexistence of testicular and ovarian tissue in the same individual. In a subset of patients, ovotesticular DSD is caused by 46,XX/46,XY chimerism or mosaicism. To date, only a few monogenetic causes are known to be associated with XX and XY ovotesticular DSD. Clinical, hormonal, and histopathological data, and results of high-resolution array-comparative genomic hybridization (CGH) were obtained from a female patient with 46,XY ovotesticular DSD with testicular tissue on one side and an ovary harboring germ cells on the other. Results obtained by array-CGH were confirmed by RT-quantitative PCR. We detected a deletion of ∼35 kb affecting exons 3 and 4 of the DMRT1 gene in a female patient with 46,XY ovotesticular DSD. To the best of our knowledge, this is the smallest deletion affecting DMRT1 presented to this point in time. We suggest that haploinsufficiency of DMRT1 is sufficient for both XY gonadal dysgenesis and XY ovotesticular DSD. Furthermore, array-CGH is a very useful tool in the molecular diagnosis of DSD.

  10. Structural Basis for a Human Glycosylation Disorder Caused by Mutation of the COG4 Gene

    Energy Technology Data Exchange (ETDEWEB)

    Richardson, B.; Smith, R; Ungar, D; Nakamura, A; Jeffrey, P; Lupashin, V; Hughson, F

    2009-01-01

    The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 A crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action.

  11. Mercury toxicity and neurodegenerative effects.

    Science.gov (United States)

    Carocci, Alessia; Rovito, Nicola; Sinicropi, Maria Stefania; Genchi, Giuseppe

    2014-01-01

    important mechanism by which mercury causes toxicity appears to bemitochondrial damage via depletion of GSH (Nicole et a!. 1998), coupled with binding to thiol groups ( -SH), which generates free radicals. Mercury has a high affinity for thiol groups ( -SH) and seleno groups ( -SeH) that are present in amino acids as cysteine and N-acetyl cysteine, lipoic acid, proteins, and enzymes. N-acetylcysteine and cysteine are precursors for the biosynthesis of GSH, which is among the most powerful intracellular antioxidants available to protect against oxidative stress and inflammation.Mercury and methylmercury induce mitochondrial dysfunction, which reduces ATP synthesis and increases lipid, protein and DNA peroxidation. The content of metallothioneines, GSH, selenium and fish high in omega-3 fatty acids appear to be strongly related with degree of inorganic and organic mercury toxicity, and with the protective detoxifying mechanisms in humans. In conclusion, depletion of GSH,breakage of mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA in the brain, induced by mercury and his salts, appear to be important factors in conditions such as ALS and AD (Bains and Shaw 1997; Nicole eta!. 1998;Spencer eta!. 1998; Alberti et a!. 1999).

  12. Generalized anxiety disorder, major depressive disorder, and their comorbidity as predictors of all-cause and cardiovascular mortality: the Vietnam experience study.

    Science.gov (United States)

    Phillips, Anna C; Batty, G David; Gale, Catharine R; Deary, Ian J; Osborn, David; MacIntyre, Kate; Carroll, Douglas

    2009-05-01

    To examine whether the 1-year prevalence of major depressive disorder (MDD), generalized anxiety disorder (GAD), and their comorbidity were associated with subsequent all-cause and cardiovascular disease (CVD) mortality during 15 years in Vietnam veterans. Participants (N = 4256) were from the Vietnam Experience Study. Service, sociodemographic, and health data were collected from service files, telephone interviews, and a medical examination. One-year prevalence of MDD and GAD was determined through a diagnostic interview schedule based on the Diagnostic and Statistical Manual of Mental Disorders (version IV) criteria. Mortality over the subsequent 15 years was gathered from US army records. MDD and GAD were positively and significantly associated with all-cause and CVD mortality. The relationships between MDD and GAD and CVD mortality were no longer significant after adjustment for sociodemograhics, health status at entry, health behaviors, and other risk markers. Income was the covariate with the strongest impact on this association. In analyses comparing comorbidity and GAD and MDD alone, with neither diagnosis, comorbidity proved to be the strongest predictor of both all-cause and CVD mortality. GAD and MDD predict all-cause mortality in a veteran population after adjusting for a range of covariates. However, those with both GAD and MDD were at greatest risk of subsequent death, and it would seem that these disorders may interact synergistically to affect mortality. Future research on mental disorders and health outcomes, as well as future clinical interventions, should pay more attention to comorbidity.

  13. Inducerede pluripotente stamceller revolutionerer forskningen i neurodegenerative sygdomme

    DEFF Research Database (Denmark)

    Schmidt, Sissel Ida; Jul Knudsen, Matias; Bogetofte Thomasen, Helle

    2016-01-01

    Research into the causes of neurodegenerative diseases like Parkinson's- and Alzheimer's disease has long been hampered by the lack of access to live disease-afflicted neurons for in vitro studies. The introduction of induced pluripotent stem (iPS) cells has made such studies possible. iPS cells...... can be reprogrammed from somatic patient-derived cells (e.g. skin cells) and differentiated into any cell type of the body. This allows for the production of neurons, which have the genetic background of the patients and show disease-relevant phenotypes....

  14. Non-coding RNA and pseudogenes in neurodegenerative diseases: “The (un)Usual Suspects”

    OpenAIRE

    Costa, Valerio; Esposito, Roberta; Aprile, Marianna; Ciccodicola, Alfredo

    2012-01-01

    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, includi...

  15. Therapeutic approach to pain in neurodegenerative diseases : current evidence and perspectives

    NARCIS (Netherlands)

    de Tommaso, Marina; Kunz, Miriam; Valeriani, Massimiliano

    Introduction: Neurodegenerative diseases are increasing in parallel to the lengthening of survival. The management of Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, and motor neuron diseases (MND), is mainly targeted to motor and cognitive

  16. Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease

    NARCIS (Netherlands)

    Grunt, Sebastian; van der Knaap, Marjo S.; van Ouwerkerk, Willem J. R.; Strijers, Rob L. M.; Becher, Jules G.; Vermeulen, R. Jeroen

    2008-01-01

    Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders.

  17. Poor self-recognition of disordered eating among girls with bulimic-type eating disorders: cause for concern?

    Science.gov (United States)

    Gratwick-Sarll, Kassandra; Bentley, Caroline; Harrison, Carmel; Mond, Jonathan

    2016-08-01

    Bulimic-type eating disorders are common among young women and associated with high levels of distress and disability and low uptake of mental health care. We examined self-recognition of disordered eating and factors associated with this among female adolescents with bulimic-type eating disorders (n = 139) recruited from a large, population-based sample. A vignette of a fictional character with bulimia nervosa was presented, followed by a series of questions addressing the nature and treatment of the problem described. One of these questions required participants to indicate whether they currently had a problem such as the one described. Self-report measures of eating disorder symptoms, general psychological distress and quality of life were also completed. More than half of participants (58%) did not believe that they currently had a problem with their eating. In multivariable analysis, impairment in emotional well-being and self-induced vomiting were the only variables independently associated with self-recognition. Participants who recognized a problem with their eating were more likely to have sought treatment for an eating problem than those who did not. Recognition of disordered eating among adolescents with bulimic-type eating disorders may be poor and this may be a factor in low uptake of mental health care. Health promotion efforts may need to address the misconception that only bulimic-type disorders involving self-induced vomiting are pathological. © 2014 Wiley Publishing Asia Pty Ltd.

  18. Pathogen-specific risk of chronic gastrointestinal disorders following bacterial causes of foodborne illness.

    Science.gov (United States)

    Porter, Chad K; Choi, Daniel; Cash, Brooks; Pimentel, Mark; Murray, Joseph; May, Larissa; Riddle, Mark S

    2013-03-08

    The US CDC estimates over 2 million foodborne illnesses are annually caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp. and Yersinia enterocoltica. While data suggest a number of costly and morbid chronic sequelae associated with these infections, pathogen-specific risk estimates are lacking. We utilized a US Department of Defense medical encounter database to evaluate the risk of several gastrointestinal disorders following select foodborne infections. We identified subjects with acute gastroenteritis between 1998 to 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp. or Yersinia enterocolitica and matched each with up to 4 unexposed subjects. Medical history was analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident chronic gastrointestinal disorders. Relative risks were calculated using modified Poisson regression while controlling for the effect of covariates. A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738, Salmonella: 624, Shigella: 376, Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of PI sequelae among exposed was as follows: irritable bowel syndrome (IBS), 3.0; dyspepsia, 1.8; constipation, 3.9; gastroesophageal reflux disease (GERD), 9.7. In multivariate analyses, we found pathogen-specific increased risk of IBS, dyspepsia, constipation and GERD. These data confirm previous studies demonstrating risk of chronic gastrointestinal sequelae following bacterial enteric infections and highlight additional preventable burden of disease which may inform better food security policies and practices, and prompt further research into pathogenic mechanisms.

  19. Aluminum chloride caused liver dysfunction and mitochondrial energy metabolism disorder in rat.

    Science.gov (United States)

    Xu, Feibo; Liu, Yanfen; Zhao, Hansong; Yu, Kaiyuan; Song, Miao; Zhu, Yanzhu; Li, Yanfei

    2017-09-01

    Aluminum (Al) is known to exert hepatotoxicity. However, the mechanisms mostly are unclear. Liver is a metabolism organ that maintains the energy level and structural stability of body, mitochondria are the main sites of energy metabolism, thus, we hypothesized that mitochondrial energy metabolism disorder contributes to liver dysfunction in aluminum chloride (AlCl 3 ) treatment rat. To verify the hypothesis, forty male Wistar rats were randomly allocated and orally exposed to 0, 64mg/kg, 128mg/kg and 256mg/kg body weight AlCl 3 in drinking water for 120days, respectively. We found that AlCl 3 exposure reduced the electron transport chain complexes I-V activities and adenosine triphosphate (ATP) level, as well as disturbed mitochondrial DNA transcript, presenting as the inhibited mRNA expressions of NADH dehydrogenase 1, NADH dehydrogenase 2, cytochrome b, cytochrome c oxidase subunit 1, cytochrome c oxidase subunit 3 and ATP synthase 6, indicating that AlCl 3 exposure disturbs the mitochondrial energy metabolism, and it caused an increase in liver enzymes (Aspartate aminotransferase and Alanine aminotransferase) and histopathological lesions. Additionally, we found that reactive oxygen species accumulation and decreased superoxide dismutase activity in mitochondria, and increased 8-Hydroxydeoxyguanosine levels in mitochondrial DNA, demonstrating AlCl 3 exposure promotes mitochondrial oxidative stress, which may be a contributing factor to mitochondrial energy metabolism disorder and liver dysfunction. The study displayed that mitochondria are the potential target of liver damage induced by AlCl 3 , providing considerable direction for the prevention and clinical intervention of liver diseases. Copyright © 2017. Published by Elsevier Inc.

  20. [Analysis of the causes and determinants of reaction to severe stress and adjustment disorder patients on mental health clinics].

    Science.gov (United States)

    Golinowska, Danuta; Florkowski, Antoni; Juszczak, Dariusz

    2010-05-01

    In everyday life there are many obstacles that prevent the creation of many important needs. They require a skillful adaptation and may be the cause of stress. Stress of considerable intensity can receive the joy of life and even lead to a temporary mental disorder. To present the main causes and frequency of disturbance determined according to the ICD-10 as a reaction to severe stress and adaptive disorders among patients in psychiatric and psychological counseling and to establish whether the causes of the disorder are dependent on factors such as age, sex or level of education. Analysis was done on a separate group of 754 persons from among patients seeking psychiatric counseling--Psychological Outpatient Mental Health in the 10th Military Clinical Hospital in Bydgoszcz, in 2005. This group were qualified person, who according to the criteria of ICD-10 were found to respond to severe stress and abnormal adaptation. In addition, during the interview determines whether they are long-term somatic illness. They have not been included in the study group. Also excluded persons who were found difficulties in operation prior to the stressful situation and those that have already been treated with psychiatric or psychological benefit from therapy. The collected data were statistically analyzed. The analysis identifies three main causes of adjustment disorder. The first group of reasons is related to difficulties in the workplace, which represents 59% of all patients with the disorder described. In this group identifies three major stressful situations: bullying, job loss, unemployment. Another reason relates to family problems. They are the reason for the emergence of abnormalities in 23% of patients analyzed group. Among these difficulties was divided into four main types of situation causing disorder presented. There are family conflicts, death of spouse, parent death, divorce. The last group of factors are stressful events or incidents which contributed to the

  1. How olfaction disorders can cause depression? The role of habenular degeneration.

    Science.gov (United States)

    Oral, E; Aydin, M D; Aydin, N; Ozcan, H; Hacimuftuoglu, A; Sipal, S; Demirci, E

    2013-06-14

    detected a relationship between a decreased healthy neuronal density of the habenula and depressive symptomatology in rats with OBX. We suggest that olfaction disorders might cause neuropsychiatric disorders by affecting neuronal degeneration in habenular nuclei. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Rapid Eye Movement Sleep Behavior Disorder: A Review of the Literature and Update on Current Concepts.

    Science.gov (United States)

    Rodriguez, Carlos L; Jaimchariyatam, Nattapong; Budur, Kumar

    2017-09-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by abnormal behaviors emerging during REM sleep that may cause injury or sleep disruption. The diagnosis requires polysomnography (PSG) demonstrating a loss of normal skeletal muscle atonia during REM sleep. RBD results from dysfunction of the brain stem circuits responsible for maintaining normal REM sleep atonia and suppressing behaviors during REM sleep. The diagnosis of idiopathic RBD (IRBD), that is, RBD without an identifiable cause, is frequently followed years later by the development of a neurodegenerative disorder, most commonly one of the synucleinopathies. As such, RBD is often a step in the progression of a neurodegenerative disorder. In this circumstance, it is a manifestation of neurodegeneration occurring in the brain stem before spreading to adjacent and other CNS regions, resulting in the development of symptoms and signs that permit recognition of a specific neurodegenerative disorder. RBD has been linked with narcolepsy and has been associated with a variety of other disorders. The management of RBD focuses on preventive/safety measures, counseling, monitoring for the development of a neurodegenerative disorder, and pharmacotherapy, which is typically effective but not well understood. The purpose of this article is to review and update our current understanding of the clinical features, epidemiology, demographics, pathophysiology, evaluation, diagnosis, differential diagnosis, causes, associations, and the clinical management of RBD. Copyright © 2017. Published by Elsevier Inc.

  3. A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders.

    Science.gov (United States)

    Riley, Lisa G; Cowley, Mark J; Gayevskiy, Velimir; Roscioli, Tony; Thorburn, David R; Prelog, Kristina; Bahlo, Melanie; Sue, Carolyn M; Balasubramaniam, Shanti; Christodoulou, John

    2017-03-01

    SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes β-galactosyltransferase and mitochondrial manganese superoxide dismutase.

  4. Disorders in melanopsin effect of pupil constriction as a risk factor causing eye diseases

    Directory of Open Access Journals (Sweden)

    V.A. Kaptsov

    2017-03-01

    Full Text Available Risks of eye damage and eyesight deterioration to a great extent depend on how efficient a biomechanical eye system is under energy-saving lighting conditions. The system's efficiency is determined by its adequacy in managing pupils and ciliary muscle. We analyzed mathematical models describing changes in pupil's diameter which were determined by light-technical parameters of illumination environment (luminance level and brightness. We highlighted the importance of ganglionic cells and the role they play in managing pupil's diameter (miosis when they are exposed to blue light within 480 nm spectrum. Basing on the assessment of a pupil's constriction under exposure to various light stimuli (blue, red, and green ones we worked out a melanopsin effect concept of a pupil's retention at miosis and showed that it could be a diagnostic sign of some diseases (age-related direct retinopathy, pancreatic diabetes under exposure to a blue light impulse with a certain wave length. Under exposure to blue light within 480 nm spectrum ganglionic cells form a managing signal for a sphincter muscle of a pupil and ciliary muscle which provides accommodation (as per Helmholtz and regulates aqueous humor flow in ciliary channel. All modern energy-saving light sources have a low energy level at wave length equal to 480 nm due to gap in their spectrum in comparison with sunlight spectrum with the same light temperature and luminance level. Inadequate management of pupil's diameter under artificial lighting conditions leads to melanopsin effect disorders and causes disharmony in managing aqueous humor outflow. All the above-stated factors under long-term visual load cause eye diseases risks in modern illumination environment. We detected that contemporary mathematic models describing pupil's diameter fluctuations needed to be refined allowing for new knowledge on functional peculiarities of retina cells and energy-saving light sources spectrum.

  5. The armadillo: a model for the neuropathy of leprosy and potentially other neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Rahul Sharma

    2013-01-01

    Full Text Available Leprosy (also known as Hansen’s disease is an infectious peripheral neurological disorder caused by Mycobacterium leprae that even today leaves millions of individuals worldwide with life-long disabilities. The specific mechanisms by which this bacterium induces nerve injury remain largely unknown, mainly owing to ethical and practical limitations in obtaining affected human nerve samples. In addition to humans, nine-banded armadillos (Dasypus novemcinctus are the only other natural host of M. leprae, and they develop a systemically disseminated disease with extensive neurological involvement. M. leprae is an obligate intracellular parasite that cannot be cultivated in vitro. Because of the heavy burdens of bacilli they harbor, nine-banded armadillos have become the organism of choice for propagating large quantities of M. leprae, and they are now advancing as models of leprosy pathogenesis and nerve damage. Although armadillos are exotic laboratory animals, the recently completed whole genome sequence for this animal is enabling researchers to undertake more sophisticated molecular studies and to develop armadillo-specific reagents. These advances will facilitate the use of armadillos in piloting new therapies and diagnostic regimens, and will provide new insights into the oldest known infectious neurodegenerative disorder.

  6. The Role of the Craniocervical Junction in Craniospinal Hydrodynamics and Neurodegenerative Conditions

    Directory of Open Access Journals (Sweden)

    Michael F. Flanagan

    2015-01-01

    Full Text Available The craniocervical junction (CCJ is a potential choke point for craniospinal hydrodynamics and may play a causative or contributory role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, MS, and ALS, as well as many other neurological conditions including hydrocephalus, idiopathic intracranial hypertension, migraines, seizures, silent-strokes, affective disorders, schizophrenia, and psychosis. The purpose of this paper is to provide an overview of the critical role of the CCJ in craniospinal hydrodynamics and to stimulate further research that may lead to new approaches for the prevention and treatment of the above neurodegenerative and neurological conditions.

  7. GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.

    Science.gov (United States)

    Ohba, Chihiro; Shiina, Masaaki; Tohyama, Jun; Haginoya, Kazuhiro; Lerman-Sagie, Tally; Okamoto, Nobuhiko; Blumkin, Lubov; Lev, Dorit; Mukaida, Souichi; Nozaki, Fumihito; Uematsu, Mitsugu; Onuma, Akira; Kodera, Hirofumi; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Tanaka, Fumiaki; Kato, Mitsuhiro; Ogata, Kazuhiro; Saitsu, Hirotomo; Matsumoto, Naomichi

    2015-06-01

    Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

  8. Late Onset Cobalamin Disorder and Hemolytic Uremic Syndrome: A Rare Cause of Nephrotic Syndrome

    Directory of Open Access Journals (Sweden)

    Gianluigi Ardissino

    2017-01-01

    Full Text Available Hemolytic uremic syndrome (HUS is an unrare and severe thrombotic microangiopathy (TMA caused by several pathogenetic mechanisms among which Shiga toxin-producing Escherichia coli infections and complement dysregulation are the most common. However, very rarely and particularly in neonates and infants, disorders of cobalamin metabolism (CblC can present with or be complicated by TMA. Herein we describe a case of atypical HUS (aHUS related to CblC disease which first presented in a previously healthy boy at age of 13.6 years. The clinical picture was initially dominated by nephrotic range proteinuria and severe hypertension followed by renal failure. The specific treatment with high dose of hydroxycobalamin rapidly obtained the remission of TMA and the complete recovery of renal function. We conclude that plasma homocysteine and methionine determinations together with urine organic acid analysis should be included in the diagnostic work-up of any patient with TMA and/or nephrotic syndrome regardless of age.

  9. Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome

    NARCIS (Netherlands)

    M. Gerards (Mike); W. Sluiter (Wim); B. van den Bosch (Bianca); L.E.A. de Wit (Elly); C. Calis (Chantal); M. Frentzen (Margrit); H. Akbari (Hana); K. Schoonderwoerd (Kees); H.R. Scholte (Hans); R.J.E. Jongbloed (Roselie); A. Hendrickx (Alexandra); I.F.M. de Coo (René); H.J.M. Smeets (Hubert)

    2010-01-01

    textabstractBackground: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a

  10. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases.

    Science.gov (United States)

    Southwell, Amber L; Skotte, Niels H; Bennett, C Frank; Hayden, Michael R

    2012-11-01

    The rising median age of our population and the age-dependent risk of neurodegeneration translate to exponentially increasing numbers of afflicted individuals in the coming years. Although symptomatic treatments are available for some neurodegenerative diseases, most are only moderately efficacious and are often associated with significant side effects. The development of small molecule, disease-modifying drugs has been hindered by complex pathogenesis and a failure to clearly define the rate-limiting steps in disease progression. An alternative approach is to directly target the mutant gene product or a defined causative protein. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. 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

  12. Exosomes in the Pathology of Neurodegenerative Diseases.

    Science.gov (United States)

    Howitt, Jason; Hill, Andrew F

    2016-12-23

    More than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Non-coding RNA and pseudogenes in neurodegenerative diseases: "The (un)Usual Suspects".

    Science.gov (United States)

    Costa, Valerio; Esposito, Roberta; Aprile, Marianna; Ciccodicola, Alfredo

    2012-01-01

    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 (miRNAs) - is supposed to have a significant impact. Recently, competitive endogenous RNAs (ceRNAs) - 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 miRNAs in neurogenesis, we hypothesize ceRNAs 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.

  14. 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.

  15. Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

    Science.gov (United States)

    Weaving, Linda S.; Christodoulou, John; Williamson, Sarah L.; Friend, Kathie L.; McKenzie, Olivia L. D.; Archer, Hayley; Evans, Julie; Clarke, Angus; Pelka, Gregory J.; Tam, Patrick P. L.; Watson, Catherine; Lahooti, Hooshang; Ellaway, Carolyn J.; Bennetts, Bruce; Leonard, Helen; Gécz, Jozef

    2004-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G→A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps—but is not identical to—that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations. PMID:15492925

  16. Adeno-associated viral gene delivery in neurodegenerative disease.

    Science.gov (United States)

    Morgenstern, Peter F; Marongiu, Roberta; Musatov, Sergei A; Kaplitt, Michael G

    2011-01-01

    The advent of viral gene therapy technology has contributed greatly to the study of a variety of medical conditions, and there is increasing promise for clinical translation of gene therapy into human treatments. Adeno-associated viral (AAV) vectors provide one of the more promising approaches to gene delivery, and have been used extensively over the last 20 years. Derived from nonpathogenic parvoviruses, these vectors allow for stable and robust expression of desired transgenes in vitro and in vivo. AAV vectors efficiently and stably transduce neurons, with some strains targeting neurons exclusively in the brain. Thus, AAV vectors are particularly useful for neurodegenerative diseases, which have led to numerous preclinical studies and several human trials of gene therapy in patients with Parkinson's disease, Alzheimer's disease, and pediatric neurogenetic disorders. Here, we describe an efficient and reliable method for the production and purification of AAV serotype 2 vectors for both in vitro and in vivo applications.

  17. Nanoparticles and Colloids as Contributing Factors in Neurodegenerative Disease

    Science.gov (United States)

    Bondy, Stephen C.

    2011-01-01

    This review explores the processes underlying the deleterious effects of the presence of insoluble or colloidal depositions within the central nervous system. These materials are chemically unreactive and can have a prolonged residence in the brain. They can be composed of mineral or proteinaceous materials of intrinsic or exogenous origin. Such nanoparticulates and colloids are associated with a range of slow-progressing neurodegenerative states. The potential common basis of toxicity of these materials is discussed. A shared feature of these disorders involves the appearance of deleterious inflammatory changes in the CNS. This may be due to extended and ineffective immune responses. Another aspect is the presence of excess levels of reactive oxygen species within the brain. In addition with their induction by inflammatory events, these may be further heightened by the presence of redox active transition metals to the large surface area afforded by nanoparticles and amphipathic micelles. PMID:21776226

  18. Adult hemophagocytic lymphohistiocytosis causing multi organ dysfunction in a patient with multiple autoimmune disorders: when the immune system runs amok.

    Science.gov (United States)

    Fleischmann, Robert; Böhmerle, Wolfgang; von Laffert, Maximilian; Jöhrens, Korinna; Mengel, Annerose; Hotter, Benjamin; Lindenberg, Robert; Scheibe, Franziska; Köhnlein, Martin; von Bahr Greenwood, Tatiana; Henter, Jan Inge; Meisel, Andreas

    2016-02-01

    We report a case of several autoimmune disorders eventually presenting as severe multi organ dysfunction syndrome caused by adult hemophagocytic lymphohistiocytosis (HLH). Clinical and laboratory tests might lead to fatal misinterpretation without awareness of its diagnostic evaluation, as HLH shares common features with sepsis and immune-mediated systemic inflammatory response syndromes.

  19. 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.

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

    DEFF Research Database (Denmark)

    Maes, Michael; Yirmyia, Raz; Noraberg, Jens

    2009-01-01

    .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......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...

  1. 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.

  2. Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia.

    Science.gov (United States)

    Keiser, Megan S; Kordasiewicz, Holly B; McBride, Jodi L

    2016-04-15

    RNA-targeting approaches are emerging as viable therapeutics that offer an alternative method to modulate traditionally 'undrugable' targets. In the case of dominantly inherited neurodegenerative diseases, gene suppression strategies can target the underlying cause of these intractable disorders. Polyglutamine diseases are caused by CAG expansions in discrete genes, making them ideal candidates for gene suppression therapies. Here, we discuss the current state of gene suppression approaches for Huntington's disease and the spinocerebellar ataxias, including the use of antisense oligonucleotides, short-interfering RNAs, as well as viral vector-mediated delivery of short hairpin RNAs and artificial microRNAs. We focus on lessons learned from preclinical studies investigating gene suppression therapies for these disorders, particularly in rodent models of disease and in non-human primates. In animal models, recent advances in gene suppression technologies have not only prevented disease progression in a number of cases, but have also reversed existing disease, providing evidence that reducing the expression of disease-causing genes may be of benefit in symptomatic patients. Both allele- and non-allele-specific approaches to gene suppression have made great strides over the past decade, showing efficacy and safety in both small and large animal models. Advances in delivery techniques allow for broad and durable suppression of target genes, have been validated in non-human primates and in some cases, are currently being evaluated in human patients. Finally, we discuss the challenges of developing and delivering gene suppression constructs into the CNS and recent advances of potential therapeutics into the clinic. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Deciphering the cause of evolutionary variance within intrinsically disordered regions in human proteins.

    Science.gov (United States)

    Banerjee, Sanghita; Chakraborty, Sandip; De, Rajat K

    2017-02-01

    Why the intrinsically disordered regions evolve within human proteome has became an interesting question for a decade. Till date, it remains an unsolved yet an intriguing issue to investigate why some of the disordered regions evolve rapidly while the rest are highly conserved across mammalian species. Identifying the key biological factors, responsible for the variation in the conservation rate of different disordered regions within the human proteome, may revisit the above issue. We emphasized that among the other biological features (multifunctionality, gene essentiality, protein connectivity, number of unique domains, gene expression level and expression breadth) considered in our study, the number of unique protein domains acts as a strong determinant that negatively influences the conservation of disordered regions. In this context, we justified that proteins having a fewer types of domains preferably need to conserve their disordered regions to enhance their structural flexibility which in turn will facilitate their molecular interactions. In contrast, the selection pressure acting on the stretches of disordered regions is not so strong in the case of multi-domains proteins. Therefore, we reasoned that the presence of conserved disordered stretches may compensate the functions of multiple domains within a single domain protein. Interestingly, we noticed that the influence of the unique domain number and expression level acts differently on the evolution of disordered regions from that of well-structured ones.

  4. Congenital versus Regressive Onset of Autism Spectrum Disorders: Parents' Beliefs about Causes

    Science.gov (United States)

    Goin-Kochel, Robin P.; Myers, Barbara J.

    2005-01-01

    Recent studies have validated the phenomenon of autistic regression, but little is known about how regressive and congenital onsets of the disorder influence parents' thinking about autism and its etiology. Parents (N = 327) of children with autism spectrum disorders completed an online questionnaire about their children's development.…

  5. Premature closure of the upper esophageal sphincter as a cause of severe deglutition disorder in infancy

    DEFF Research Database (Denmark)

    Nielsen, Rasmus; Husby, Steffen; Kruse-Andersen, Søren

    2005-01-01

    Deglutition disorders in infancy are often associated with birth asphyxia or structural abnormalities in the hypopharynx, the trachea, or the esophagus. Manometry can be crucial for clarifying the dynamics of the swallowing disorder in the infant with deglutition problems and without signs...

  6. Annual Research Review: Attachment Disorders in Early Childhood--Clinical Presentation, Causes, Correlates, and Treatment

    Science.gov (United States)

    Zeanah, Charles H.; Gleason, Mary Margaret

    2015-01-01

    Background: Though noted in the clinical literature for more than 50 years, attachment disorders have been studied systematically only recently. In part because of the ubiquity of attachments in humans, determining when aberrant behavior is best explained as an attachment disorder as opposed to insecure attachment has led to some confusion. In…

  7. Research Review: What we have learned about the causes of eating disorders - a synthesis of sociocultural, psychological, and biological research.

    Science.gov (United States)

    Culbert, Kristen M; Racine, Sarah E; Klump, Kelly L

    2015-11-01

    Eating disorders are severe psychiatric disorders with a complex etiology involving transactions among sociocultural, psychological, and biological influences. Most research and reviews, however, focus on only one level of analysis. To address this gap, we provide a qualitative review and summary using an integrative biopsychosocial approach. We selected variables for which there were available data using integrative methodologies (e.g., twin studies, gene-environment interactions) and/or data at the biological and behavioral level (e.g., neuroimaging). Factors that met these inclusion criteria were idealization of thinness, negative emotionality, perfectionism, negative urgency, inhibitory control, cognitive inflexibility, serotonin, dopamine, ovarian hormones. Literature searches were conducted using PubMed. Variables were classified as risk factors or correlates of eating disorder diagnoses and disordered eating symptoms using Kraemer et al.'s (1997) criteria. Sociocultural idealization of thinness variables (media exposure, pressures for thinness, thin-ideal internalization, thinness expectancies) and personality traits (negative emotionality, perfectionism, negative urgency) attained 'risk status' for eating disorders and/or disordered eating symptoms. Other factors were identified as correlates of eating pathology or were not classified given limited data. Effect sizes for risk factors and correlates were generally small-to-moderate in magnitude. Multiple biopsychosocial influences are implicated in eating disorders and/or disordered eating symptoms and several can now be considered established risk factors. Data suggest that psychological and environmental factors interact with and influence the expression of genetic risk to cause eating pathology. Additional studies that examine risk variables across multiple levels of analysis and that consider specific transactional processes amongst variables are needed to further elucidate the intersection of

  8. Proteomic analysis of the human brain in Huntington's Disease indicates pathogenesis by molecular processes linked to other neurodegenerative diseases and to type-2 diabetes.

    Science.gov (United States)

    Schönberger, Sarah J; Jezdic, Dina; Faull, Richard L M; Cooper, Garth J S

    2013-01-01

    Huntington's disease (HD) is a neurodegenerative disorder in which the aetiological defect is inherited or spontaneous mutation in the HTT gene, which alters the structure of the corresponding huntingtin protein and initiates a pathogenetic cascade that ultimately leads to or causes dementia. Here our main objective was to elucidate further the pathogenic processes that underlie neurodegeneration in HD. By using two-dimensional gel electrophoresis we performed a proteomic case-control study of two brain regions in post-mortem human tissue from seven well-characterized HD patients and eight matched controls. In the middle frontal gyrus we identified twenty-two differentially-expressed proteins whereas by contrast in visual cortex only seven were altered. Twenty of these proteins have not to our knowledge been associated with the pathogenesis of HD before although all functional families implicated have previously been linked to other neurodegenerative diseases. Most of the proteins identified play roles in cell stress responses, apoptosis, metabolic regulation linked to type-2 diabetes, the ubiquitin-proteasome system, or protein trafficking/endocytosis. We propose that HTT mutations lead to or cause functional impairment of these pathways and that simultaneous restoration of their functions by targeted pharmacotherapy could ameliorate the signs and symptoms of HD. These studies provide a unique illustration of the interlinked disease processes that underpin/contribute to the pathogenesis of neurodegeneration in a genetically-mediated disorder of protein structure, and provide a signpost towards the design of new therapeutic interventions.

  9. 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.

  10. Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal

    Directory of Open Access Journals (Sweden)

    Arif Tasleem Jan

    2017-09-01

    Full Text Available Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB, exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy.

  11. Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal

    Science.gov (United States)

    Jan, Arif Tasleem; Malik, Mudasir A.; Rahman, Safikur; Yeo, Hye R.; Lee, Eun J.; Abdullah, Tasduq S.; Choi, Inho

    2017-01-01

    Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy. PMID:29033828

  12. 4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

    Science.gov (United States)

    Coccia, Raffaella; Butterfield, D. Allan

    2012-01-01

    Abstract Significance: Among different forms of oxidative stress, lipid peroxidation comprises the interaction of free radicals with polyunsaturated fatty acids, which in turn leads to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. HNE is considered a robust marker of oxidative stress and a toxic compound for several cell types. Proteins are particularly susceptible to modification caused by HNE, and adduct formation plays a critical role in multiple cellular processes. Recent Advances: With the outstanding progress of proteomics, the identification of putative biomarkers for neurodegenerative disorders has been the main focus of several studies and will continue to be a difficult task. Critical Issues: The present review focuses on the role of lipid peroxidation, particularly of HNE-induced protein modification, in neurodegenerative diseases. By comparing results obtained in different neurodegenerative diseases, it may be possible to identify both similarities and specific differences in addition to better characterize selective neurodegenerative phenomena associated with protein dysfunction. Results obtained in our laboratory and others support the common deregulation of energy metabolism and mitochondrial function in neurodegeneration. Future Directions: Research towards a better understanding of the molecular mechanisms involved in neurodegeneration together with identification of specific targets of oxidative damage is urgently required. Redox proteomics will contribute to broaden the knowledge in regard to potential biomarkers for disease diagnosis and may also provide insight into damaged metabolic networks and potential targets for modulation of disease progression. Antioxid. Redox Signal. 17, 1590–1609. PMID:22114878

  13. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

    NARCIS (Netherlands)

    Kohl, S.; Zobor, D.; Chiang, W.C.; Weisschuh, N.; Staller, J.; Menendez, I.G.; Chang, S.; Beck, S.C.; Garrido, M. Garcia; Sothilingam, V.; Seeliger, M.W.; Stanzial, F.; Benedicenti, F.; Inzana, F.; Heon, E; Vincent, A.; Beis, J.; Strom, T.M.; Rudolph, G.; Roosing, S.; Hollander, A.I. den; Cremers, F.P.M.; Lopez, I.; Ren, H.; Moore, A.T.; Webster, A.R.; Michaelides, M.; Koenekoop, R.K.; Zrenner, E.; Kaufman, R.J.; Tsang, S.H.; Wissinger, B.; Lin, J.H.

    2015-01-01

    Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two

  14. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

    NARCIS (Netherlands)

    Wortmann, S.B.; Zietkiewicz, S.; Kousi, M.; Szklarczyk, R.J.; Haack, T.B.; Gersting, S.W.; Muntau, A.C.; Rakovic, A.; Renkema, G.H.; Rodenburg, R.J.; Strom, T.M.; Meitinger, T.; Rubio-Gozalbo, M.E.; Chrusciel, E.; Distelmaier, F.; Golzio, C.; Jansen, J.H.; Karnebeek, C. van; Lillquist, Y.; Lucke, T.; Ounap, K.; Zordania, R.; Yaplito-Lee, J.; Bokhoven, H. van; Spelbrink, J.N.; Vaz, F.M.; Pras-Raves, M.; Ploski, R.; Pronicka, E.; Klein, C.; Willemsen, M.A.A.P.; Brouwer, A.P.M. de; Prokisch, H.; Katsanis, N.; Wevers, R.A.

    2015-01-01

    We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder,

  15. Does Orthognathic Surgery Cause or Cure Temporomandibular Disorders? A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Al-Moraissi, Essam Ahmed; Wolford, Larry M; Perez, Daniel; Laskin, Daniel M; Ellis, Edward

    2017-09-01

    There is still controversy about whether orthognathic surgery negatively or positively affects temporomandibular disorders (TMDs). The purpose of this study was to determine whether orthognathic surgery has a beneficial or deleterious effect on pre-existing TMDs. A systematic review and meta-analysis were conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched 3 major databases to locate all pertinent articles published from 1980 to March 2016. All subjects in the various studies were stratified a priori into 9 categories based on subdiagnoses of TMDs. The predictor variables were those patients with pre-existing TMDs who underwent orthognathic surgery in various subgroups. The outcome variables were maximal mouth opening and signs and symptoms of a TMD before and after orthognathic surgery based on the type of osteotomy. The meta-analysis was performed using Comprehensive Meta-Analysis software (Biostat, Englewood, NJ). A total of 5,029 patients enrolled in 29 studies were included in this meta-analysis. There was a significant reduction in TMDs in patients with a retrognathic mandible after bilateral sagittal split osteotomy (BSSO) (P = .014), but no significant difference after bimaxillary surgery (BSSO and Le Fort I osteotomy) (P = .336). There was a significant difference in patients with prognathism after isolated BSSO or intraoral vertical ramus osteotomy and after combined BSSO and Le Fort I osteotomy (P = .001), but no significant difference after BSSO (P = .424) or bimaxillary surgery (intraoral vertical ramus osteotomy and Le Fort I osteotomy) (P = .728). Orthognathic surgery caused a decrease in TMD symptoms for many patients who had symptoms before surgery, but it created symptoms in a smaller group of patients who were asymptomatic before surgery. The presence of presurgical TMD symptoms or the type of jaw deformity did not identify which patients' TMDs would improve, remain the

  16. [Clinical, vegetative and cognitive disorders in hypertensive postmenopausal women in relation to menopause causes].

    Science.gov (United States)

    Kolbasnikov, S V; Bakhareva, O N

    2006-01-01

    To specify clinical, vegetative and cognitive disorders in hypertensive women depending on the type of menopause. A total of 195 hypertensive women were divided into three groups: group 1 (n = 50, age 45.6 +/- 4.5 years) consisted of premenopausal women, group 2 (n = 100, age 57.4 +/- 4.7 years) - of women with natural menopause, group 3 (n = 45, age 55.1 +/- 5.9 years)--with early and/or surgical menopause. Severity of the menopausal syndrome, anxiety, depression, alexitimia, mental performance, vegetative regulation of heart rhythm were examined. The premenopausal women were characterized by cardial and cerebral disorders, unaffected psychovegetative function and initial symptoms of lowering mental performance. Hypertensive women with natural menopause showed combination of cardial and cerebral symptoms with moderate anxio-depressive disorders, alexitimia, subnormal parasympathetic activity of the autonomic nervous system in high centralization of heart rhythm regulation and attention disturbances. Patients with surgical and/or early menopause had marked cardial and cerebral symptoms, moderate anxiodepressive disorders, alexitimia, inhibition of mental performance, vegetative dysfunction, overcentralization of heart rhythm control. With development of postmenopausal metabolic symptom complex, severity of hypertension grows with emergence of anxiodepressive disorders which combine with vegetative regulation disorders and attenuation of mental performance.

  17. MRI features of neurodegenerative Langerhans cell histiocytosis

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Duverneuil, N.; Guillevin, R.; Chiras, J. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neuroradiology, Paris (France); Idbaih, A.; Hoang-Xuan, K. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neurology, Paris (France); Donadieu, J. [GH Trousseau, Department of Hematology/Oncology Pediatrics, Paris (France); Genereau, T. [Groupe d' etude des Histiocytoses langerhansiennes, Nantes (France)

    2006-09-15

    CNS complications of LCH include ''space occupying'' lesions corresponding to histiocytic granulomas and ''neurodegenerative'' presentation (ND-LCH) characterized by a progressive cerebellar ataxia. Studies analyzing specifically the MRI presentation of ND-LCH are scarce. We present here the MRIs of 13 patients registered as isolated ND-LCH. Posterior fossa was involved in 12 patients (92%), showing a symmetrical T2 hyperintensity of the cerebellar white matter areas in seven cases with a circumscribed T1 hyperintensity of the dentate nuclei in five cases, definite hyperintense T2 areas in the adjacent pontine tegmentum white matter in nine cases associated with a hyperintensity of the pontine pyramidal tracts in four cases. A cerebellar atrophy was noted in eight cases. The supratentorial region was involved in 11 patients, showing T2 hyperintense lesions in the cerebral white matter in eight cases and a discrete symmetrical T1 hyperintense signal in the globus pallidus in eight patients. A diffuse cortical atrophy was present in three cases and a marked focal atrophy of the corpus callosum in three cases. This series allows us to establish a not previously reported evocative semeiologic MR presentation to precisely orientate to the diagnosis of the pure neurodegenerative form of LCH. (orig.)

  18. 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.

  19. 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.

  20. 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.

  1. Mental Disorders

    Science.gov (United States)

    Mental disorders include a wide range of problems, including Anxiety disorders, including panic disorder, obsessive-compulsive disorder, ... disorders, including schizophrenia There are many causes of mental disorders. Your genes and family history may play ...

  2. 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

  3. Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.

    Science.gov (United States)

    Kuljis, R O; Aguila, M C

    1999-05-01

    Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with manifestations that include immune deficiency, sensitivity to ionizing radiation and neoplasms. Many of these manifestations are understood in principle since the identification in A-T patients of mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage. However, the cause of the neurodegeneration that afflicts patients with A-T for at least a decade before they succumb to overwhelming infections or malignancy remains mysterious. Based on our work in a mouse model of A-T and previous evidence of extra-neural autoimmune disorders in A-T, we postulate that the neurodegenerative process in A-T is not due to a function for A-T mutated (ATM) essential for the postnatal brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's term for autoimmune disorder). This hypothetical mechanism may be analogous to that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients with various malignancies. Thus, alterations in the balance between cellular and humoral immunity in A-T probably result in autoantibodies to cerebral epitopes shared with cells of the immune system. This hypothesis has important implications for the understanding and development of effective palliative and even preventative strategies for A-T, and probably for other so far relentlessly progressive neurodegenerative disorders.

  4. Modifying progression of aging and reducing the risk of neurodegenerative diseases by probiotics and synbiotics.

    Science.gov (United States)

    Lye, Huey Shi; Lee, Yee Teng; Ooi, Shao Yin; Teh, Lai Kuan; Lim, Lay Ngor; Wei, Loo Keat

    2018-03-01

    Aging, which affects most of the multi-cellular organisms, is due to a potentially complex set of mechanisms that collectively cause a time-dependent decline of physiological functions. Aging restrains longevity and leads to neurodegenerative diseases including dementia, Alzheimer's disease and lacunar stroke. Human microbiota is now considered to have a strong impact on the progression of aging. The impact of aging and the risk of neurodegenerative diseases can be reduced by using probiotics, or preferably by combining probiotics and prebiotics, also known as synbiotics, that can drastically modify the composition of gut microbiome.

  5. [Are the hormonal status or psychosocial conditions the major cause of female depressive disorders after menopause?].

    Science.gov (United States)

    Walaszek, Paweł; Mazur, Paweł; Płachta, Zenon; Adamiak, Aneta; Azizi, Ilir; Rechberger, Tomasz

    2005-10-01

    The study was aimed to assess if the prevalence of female depressive disorders after menopause depends on their hormonal status (E2, FSH, testosterone, DHEAS) or psychosocial conditions, Moreover, the influence of HRT on female mood disorders was estimated. One hundred women (44=65 ys old) were included into the study. Ali patients were complaining of hot flushes for at least 6 months. Among these women 31% had depressive disorders at baseline. The hormonal status, psychosocial conditions and mood disorders (Beck's and Haniilton's scales) were assessed at the baseline and after 12 months in 50 women on HRT and in 20 control patients. After 1 year the depressive mood disappeared in 59% and worsened in 5,9% of women taking HRT, whereas in the control group 35% of patient experienced depression. Among women on HRT the significant increase of serum DHEAS was observed in patients with improvement of mood as well as in depressed ones. Serum testosterone, 17P-estradiol and FSH levels did not differ between both groups. The higher scores of Beck's and Hamilton's scales were not associated with hormonal status but correlated with worsening of psychosocial conditions. The female depressive disorders after menopause are associated with their psychosocial conditions but not with their hormonal status.

  6. Does neuroinflammation fan the flame in neurodegenerative diseases?

    Directory of Open Access Journals (Sweden)

    McAlpine Fiona E

    2009-11-01

    Full Text Available Abstract While peripheral immune access to the central nervous system (CNS is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS, Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD, amyotrophic lateral sclerosis (ALS, tauopathies, and age-related macular degeneration (ARMD, are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the

  7. Brain studies may alter long-held concepts about likely causes of some voice disorders

    Energy Technology Data Exchange (ETDEWEB)

    1989-02-17

    Two voice disorders long considered to be psychological problems, stuttering and spasmodic dysphonia, have been shown in many persons to have a neurophysiological basis. Investigators at the 155th national meeting of the American Association for the Advancement of Science, in San Francisco, described their findings, which are based on new analytic techniques. The research is being done at the Dallas Center for Vocal Motor Control, Callier Center for Communication Disorders, University of Texas at Dallas Health Science Center. The technology employed to learn what's wrong with the brains, rather than the psyches, of persons with certain speech disorders includes magnetic resonance imaging (MRI), brain electrical activity mapping (BEAM), and single photon emission computerized tomography (SPECT). The results of applying these techniques are combined with quantitative behavioral measures of vocal and nonvocal motor control, language performance, and cognition to arrive at a better understanding of the problem.

  8. Tomophobia, the phobic fear caused by an invasive medical procedure - an emerging anxiety disorder: a case report

    Directory of Open Access Journals (Sweden)

    Schmid Markus

    2009-11-01

    Full Text Available Abstract Introduction Tomophobia refers to fear or anxiety caused by forthcoming surgical procedures and/or medical interventions. Case presentation We present the case of a 69-year-old Caucasian man who refused urgently indicated medical intervention because of severe tomophobia. Conclusion Due to the rising number of surgical interventions in modern medicine, as well as the high number of unrecognised cases of tomophobia, this common but underdiagnosed anxiety disorder should be highlighted.

  9. Recent progress in translational research on neurovascular and neurodegenerative disorders

    DEFF Research Database (Denmark)

    Demuth, Hans-Ulrich; Dijkhuizen, Rick M; Farr, Tracy D

    2017-01-01

    The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve...... on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations....

  10. Tracking the progression of social cognition in neurodegenerative disorders.

    Science.gov (United States)

    Kumfor, Fiona; Irish, Muireann; Leyton, Cristian; Miller, Laurie; Lah, Suncica; Devenney, Emma; Hodges, John R; Piguet, Olivier

    2014-10-01

    Behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) patients experience behavioural and emotion recognition alterations, yet understanding of how socioemotional processing is affected with disease progression is minimal. Additionally, evidence suggests that bvFTD patients with limited brain atrophy on neuroimaging at presentation (bvFTD-la) have a more benign course than those with marked atrophy (bvFTD-ma). Longitudinal investigation of these patients, however, is lacking. We investigated general cognition, emotion recognition and sarcasm detection in 20 bvFTD (8 with limited brain atrophy) and 17 AD patients longitudinally and used mixed models analyses to determine the level and rates of decline across groups over time. At baseline, all patient groups performed worse than controls on general cognition and emotion recognition measures. The bvFTD-ma group showed significant impairment on the sarcasm detection task compared with controls. Longitudinally, an overall effect of time was present for general cognition (psarcasm detection task, the bvFTD-ma and AD patients declined, whereas bvFTD-la patients remained stable over time (p=0.002). Tasks of sarcasm detection represent a clinically useful tool to differentiate between bvFTD and AD at baseline. Furthermore, tasks of socioemotional functioning can track progression within bvFTD and identify bvFTD patients more likely to show a faster rate of decline. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  11. Progressive and self-limiting neurodegenerative disorders in Africa ...

    African Journals Online (AJOL)

    We analyzed the journals, most cited articles, authors, publication years, organizations, funding agencies, countries and keywords in Web of Science Core ... Clinical neurology and Genetics hereditary are the main Web of Science categories whereas Neurosciences and Biochemistry and Molecular Biology are the main ...

  12. Sleep Spindles as Biomarker for Early Detection of Neurodegenerative Disorders

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to the use of sleep spindles as a novel biomarker for early diagnosis of synucleinopathies, in particular Parkinson's disease (PD). The method is based on automatic detection of sleep spindles. The method may be combined with measurements of one or more further...

  13. Spreading of pathology in neurodegenerative diseases: a focus on human studies

    Science.gov (United States)

    Brettschneider, Johannes; Del Tredici, Kelly; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2015-01-01

    The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell–cell transmission of characteristic disease-related proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons — in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile — determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron–neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans. PMID:25588378

  14. Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application.

    Science.gov (United States)

    Jiao, Xiaodan; Ashtari, Niloufar; Rahimi-Balaei, Maryam; Chen, Qi Min; Badbezanchi, Ilnaz; Shojaei, Shahla; Marzban, Adel; Mirzaei, Nima; Chung, Seunghyuk; Guan, Teng; Li, Jiasi; Vriend, Jerry; Mehr, Shahram Ejtemaei; Kong, Jiming; Marzban, Hassan

    2017-01-01

    The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Intensive training of phonological skills in progressive aphasia: a model of brain plasticity in neurodegenerative disease.

    Science.gov (United States)

    Louis, M; Espesser, R; Rey, V; Daffaure, V; Di Cristo, A; Habib, M

    2001-01-01

    Three patients with a typical syndrome of nonfluent primary progressive aphasia (Mesulam's syndrome) were trained daily with a remediation protocol including auditory exercises specifically designed to involve several aspects of phonological processing, a domain known to be specifically affected in the condition. The speech content of the exercises was based on the temporal theory of phonological processes according to which increasing the duration of formant transition should facilitate phoneme discrimination and phoneomic awareness. Significantly improved performance on the trained tasks was demonstrated in the three patients. Improvement further generalized to other tasks such as nonword repetition and reading. We conclude that such results (1) argue for using intensive focused therapy of language impairment in neurodegenerative disorders, (2) may constitute a good model of brain plasticity in neurodegenerative disorders in general, and (3) support theories of phonological processing emphasizing temporal features of the auditory signal.

  16. Causes and Management of Treatment-Resistant Panic Disorder and Agoraphobia: A Survey of Expert Therapists

    Science.gov (United States)

    Sanderson, William C.; Bruce, Timothy J.

    2007-01-01

    Cognitive behavior therapy (CBT) is recognized as an effective psychological treatment for panic disorder (PD). Despite its efficacy, some clients do not respond optimally to this treatment. Unfortunately, literatures on the prediction, prevention, and management of suboptimal response are not well developed. Considering this lack of empirical…

  17. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

    NARCIS (Netherlands)

    Jansen, J.C.; Cirak, S.; Scherpenzeel, M. van; Timal, S.; Reunert, J.; Rust, S.; Perez, B.; Vicogne, D.; Krawitz, P.; Wada, Y.; Ashikov, A.M.; Perez-Cerda, C.; Medrano, C.; Arnoldy, A.; Hoischen, A.; Huijben, K.; Steenbergen, G.; Quelhas, D.; Diogo, L.; Rymen, D.; Jaeken, J.; Guffon, N.; Cheillan, D.; Heuvel, B. van den; Maeda, Y.; Kaiser, O.; Schara, U.; Gerner, P.; Boogert, M.A. van den; Holleboom, A.G.; Nassogne, M.C.; Sokal, E.; Salomon, J.; Bogaart, G. van den; Drenth, J.P.; Huynen, M.A.; Veltman, J.A.; Wevers, R.A.; Morava, E.; Matthijs, G.; Foulquier, F.; Marquardt, T.; Lefeber, D.J.

    2016-01-01

    Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are

  18. Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment.

    Science.gov (United States)

    Wang, Zi-Jun; Zhang, Xue-Qiong; Cui, Xiang-Yu; Cui, Su-Ying; Yu, Bin; Sheng, Zhao-Fu; Li, Sheng-Jie; Cao, Qing; Huang, Yuan-Li; Xu, Ya-Ping; Zhang, Yong-He

    2015-03-24

    Stress induced constant increase of cortisol level may lead to sleep disorder, but the mechanism remains unclear. Here we described a novel model to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). After 7 days treatment of CORT, rats showed significant sleep disturbance, meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO), the remarkable elevation of norepinephrine in LC, VLPO and hypothalamus, as well as increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO after CORT treatment. Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC may play a key role in stress-related sleep disorders and support the hypothesis that repeated CORT treatment may decrease GR levels and induce the activation of noradrenergic neurons in LC, consequently inhibit GABAergic neurons in VLPO and result in sleep disorders. Our findings provide novel insights into the effect of stress-inducing agent CORT on sleep and GRs' role in sleep regulation.

  19. 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.

  20. Genetic convergence of Parkinson's disease and lysosomal storage disorders.

    Science.gov (United States)

    Deng, Hao; Xiu, Xiaofei; Jankovic, Joseph

    2015-01-01

    Parkinson's disease is a common progressive neurodegenerative disorder characterized by predominant degeneration of the dopaminergic neurons in the substantia nigra pars compacta and the presence of intracellular inclusions enriched in α-synuclein, resulting in a variety motor and nonmotor symptoms. Lysosomal storage disorders are a group of disorders including Gaucher disease, Niemann-Pick disease, and neuronal ceroid lipofuscinoses caused by the defective activity of lysosomal and nonlysosomal proteins. In addition to an overlap in some clinical features between lysosomal storage disorders and Parkinson's disease, the two disorders may be also linked pathogenically. There is growing support for the notion that mutations in genes causing lysosomal storage disorders including the glucocerebrosidase gene, the sphingomyelin phosphodiesterase 1 gene, and the NPC1 gene may increase risk for developing Parkinson's disease. In this review, we discuss the recent advances in the genetic convergence of Parkinson's disease and lysosomal storage disorders, shedding new light on the understanding of shared pathogenic pathways.

  1. A Neurodegenerative Disease Sleep Questionnaire: principal component analysis in Parkinson's disease.

    Science.gov (United States)

    Scullin, Michael K; Harrison, Tyler L; Factor, Stewart A; Bliwise, Donald L

    2014-01-15

    Sleep disturbances are common in many neurodegenerative diseases and may include altered sleep duration, fragmented sleep, nocturia, excessive daytime sleepiness, and vivid dreaming experiences, with occasional parasomnias. Although representing the "gold standard," polysomnography is not always cost-effective or available for measuring sleep disturbance, particularly for screening. Although numerous sleep-related questionnaires exist, many focus on a specific sleep disturbance (e.g., restless legs, REM Behavior Disorder) and do not capture efficiently the variety of sleep issues experienced by such patients. We administered the 12-item Neurodegenerative Disease Sleep Questionnaire (NDSQ) and the Epworth Sleepiness Scale to 145 idiopathic Parkinson's disease patients. Principal component analysis using eigenvalues greater than 1 suggested five separate components: sleep quality (e.g., sleep fragmentation), nocturia, vivid dreams/nightmares, restless legs symptoms, and sleep-disordered breathing. These results demonstrate construct validity of our sleep questionnaire and suggest that the NDSQ may be a useful screening tool for sleep disturbances in at least some types of neurodegenerative disorders. © 2013.

  2. 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.

  3. PRRT2: a major cause of infantile epilepsy and other paroxysmal disorders of childhood.

    Science.gov (United States)

    Nobile, Carlo; Striano, Pasquale

    2014-01-01

    In the past 2 years, mutations in the PRRT2 gene have been identified in patients and families with a variety of early-onset paroxysmal disorders, including various paroxysmal dyskinesias, benign familial infantile seizures, hemiplegic migraine, and episodic ataxia. In this chapter, we describe the wide clinical spectrum associated with PRRT2 mutations and present the current hypotheses on the underlying pathophysiology. Through its interaction with the presynaptic plasma membrane protein SNAP25, the PRRT2 protein may play a role in synaptic regulation in the cortex and basal ganglia. PRRT2 mutations likely have a loss-of-function effect and result in synaptic deregulation and neuronal hyperexcitability. The molecular bases underlying phenotypic variability are still unclear. Elucidating the molecular pathways linking the genetic defect to its clinical expression will improve treatment of these disorders. © 2014 Elsevier B.V. All rights reserved.

  4. Does Cannabis Cause, Exacerbate or Ameliorate Psychiatric Disorders? An Oversimplified Debate Discussed

    Science.gov (United States)

    Haney, Margaret; Evins, A Eden

    2016-01-01

    There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the United States, as well as a steady increase in the number of people using the drug on a regular basis. Given these rapid societal changes, defining what is known scientifically about the consequences of cannabis use on mental health takes on added public health significance. The purpose of this circumspectives piece is to discuss evidence of cannabis' effects on two psychiatric conditions: post-traumatic stress disorder and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing to move the field forward. PMID:26286840

  5. Does Cannabis Cause, Exacerbate or Ameliorate Psychiatric Disorders? An Oversimplified Debate Discussed.

    Science.gov (United States)

    Haney, Margaret; Evins, A Eden

    2016-01-01

    There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the United States, as well as a steady increase in the number of people using the drug on a regular basis. Given these rapid societal changes, defining what is known scientifically about the consequences of cannabis use on mental health takes on added public health significance. The purpose of this circumspectives piece is to discuss evidence of cannabis' effects on two psychiatric conditions: post-traumatic stress disorder and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing to move the field forward.

  6. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses

    OpenAIRE

    Won, Hyejung; Mah, Won; Kim, Eunjoon

    2013-01-01

    Autism spectrum disorder (ASD) is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Advances in human genomics have identified a large number of genetic variations associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the patho...

  7. Epigenetics and memory: causes, consequences and treatments for post-traumatic stress disorder and addiction.

    Science.gov (United States)

    Pizzimenti, C L; Lattal, K M

    2015-01-01

    Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress-related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug-seeking responses. This may, in part, account for the fact that individuals with post-traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug-seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress-induced relapse. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  8. Prevalence of Various Reproductive Disorders and Economic Losses Caused by Genital Prolapse in Buffaloes

    Directory of Open Access Journals (Sweden)

    Rasheed A. Rabbani, I. Ahmad*, L. A. Lodhi, N. Ahmad and G. Muhammad1

    2010-01-01

    Full Text Available The present study was conducted to investigate the prevalence of various reproductive disorders and to estimate the economic losses due to genital prolapse in buffaloes in Sir Shamir area of District Faisalabad, Pakistan. The survey was conducted in 8 villages during the 12 months period from June 2005 to May 2006 and the data from 400 farmers (50 farmers from each village were collected. The total buffalo population of this area was 7,785, out of which 2,135 (27.42% animals were included in the study. The overall prevalence of reproductive disorders in buffaloes was recorded as 46.18%. Among all the reproductive disorders, repeat breeding showed the highest prevalence (15.69%, followed by anestrous (9.74%, genital prolapse (7.73%, abortion (5.99%, retained placenta (2.58%, uterine torsion (2.39% and dystocia (2.06%. The total economic losses due to genital prolapse in buffaloes in eight villages during the period of study were estimated to be Rs. 4,59,500/- Among these, the highest losses were due to mortality of dam (39.17%, followed by milk losses (25.14%, service charges (21.33% and medicine cost (14.36%. Thus, repeat breeding, anoestrus and genital prolapse seem to be the major reproductive problems in buffaloes in the study area.

  9. 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.

  10. 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

  11. 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

  12. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Yamasaki Nobuyuki

    2008-09-01

    Full Text Available Abstract Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/- have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG. The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and

  13. Absence of relation between sick leave caused by musculoskeletal disorders and exposure to magnetic fields in an aluminum plant

    Energy Technology Data Exchange (ETDEWEB)

    Moen, B.E. [Univ. of Bergen (Norway). Div. of Occupational Medicine; Drabloes, P.A.; Pedersen, S.; Sjoeen, M. [Norsk Hydro Karmoey Fabrikker, Haavik (Norway); Thommesen, G. [Norwegian Radiation Protection Authority, Oesteraes (Norway)

    1996-04-01

    This is a study of the relationship between occupational exposure to magnetic fields in pot rooms and occurrence of sick leave caused by musculoskeletal disorders. The average exposure to static magnetic fields was 8 mT in the pot rooms. Ripple fields were recorded as well. A cohort of 342 exposed workers and 222 unexposed workers from the same electrolysis plant was retrospectively followed for 5 years. The reference group has a type of work similar to the exposed group except for the expose to magnetic fields. The occurrence of sick leave and the diagnoses causing the sick leave were obtained from the Occupational Health Care Unit: these data were stored in their computer files. The data were complete. No relationship between the occurrence of sick leave caused by musculoskeletal disorders and exposure to magnetic fields was found. This was the case for both the annual number of periods of sick leave and the total number of days with sick leave. The results must be interpreted with caution due to limitations in the design and available data. Also, static magnetic fields constituted the major exposure, and the results may be different when related to work in other types of magnetic-field exposure.

  14. [Depressive disorders in dementia and mild cognitive impairments: is comorbidity a cause or a risk factor?].

    Science.gov (United States)

    Preuss, U W; Siafarikas, N; Petrucci, M; Wong, W M

    2009-07-01

    Both depression and dementia occur by themselves or together in elderly subjects aged 65 and above. The aim of this review is to discuss several hypotheses which try to explain the frequent co-occurrence exceeding chance alone, based on a systematic literature search. A series of studies revealed potential biological similarities between both disorders which, however, were not found in all investigations. Lifetime history of depression can be considered as a distant risk factor for dementias. Depression occurs most frequently within one year before and after the onset of dementia, in which the association between both disorders is probably strongest. In a subgroup of subjects with more "cognitive reserve", depression was found to be a consequence of patient's realisation of beginning cognitive deficits. Several studies indicate that depression in Alzheimer and other dementia forms can be considered as a separate disease entity, as the clinical syndrome differs from depression in earlier periods of life. Studies on the therapy of depression in dementia have aroused increasing interest in recent years. Herewith, certain guidelines in the treatment of older patients with antidepressants must be followed.

  15. [Does mobbing cause posttraumatic stress disorder? Impact of coping and personality].

    Science.gov (United States)

    Kreiner, Barbara; Sulyok, Christoph; Rothenhäusler, Hans-Bernd

    2008-01-01

    Previous research has documented that a variety of anxiety, depressive, and psychosomatic symptoms are present in a substantial portion of mobbing victims. This study aimed to explore the frequency of posttraumatic stress disorder (PTSD) among mobbing victims, and to investigate how PTSD was linked to pertinent psychometric scales. We recruited 20 mobbing victims and conducted the Structural Clinical Interview (SCID) to assess PTSD according to DSM-IV criteria. The trauma criterion was homogeneously defined as mobbing. 55% of our entire sample had a current PTSD, and 70% suffered from severe posttraumatic stress symptoms according to the Impact of Event Scale. Using multivariate analysis of variance (MANOVA), we found that mobbing victims with a current PTSD tended to demonstrate higher levels of stress and depressive symptoms, and less quality of life (SF 36 Short-Form Health Survey), especially in terms of bodily pain, compared with those without a PTSD diagnosis. No significant differences in personality factors (Freiburg Personality Inventory) between mobbing-victims with and without PTSD were evident by multivariate analysis. Univariate statistics, however, revealed that mobbing-related PTSD showed a trend towards higher scores in social orientation and somatic complaints. There was no general evidence that mobbing victims with a PTSD used more often negative and positive coping strategies (SVF - Stress Coping Questionnaire). However, they showed a tendency to employ control strategies, avoidance, social withdrawal, and cognitive preoccupation. Posttraumatic stress disorder subsequent to mobbing can occur frequently. PTSD therefore should be specifically considered in routine care.

  16. Relative variations of gut microbiota in disordered cholesterol metabolism caused by high-cholesterol diet and host genetics.

    Science.gov (United States)

    Bo, Tao; Shao, Shanshan; Wu, Dongming; Niu, Shaona; Zhao, Jiajun; Gao, Ling

    2017-08-01

    Recent studies performed provide mechanistic insight into effects of the microbiota on cholesterol metabolism, but less focus was given to how cholesterol impacts the gut microbiota. In this study, ApoE(-/-) Sprague Dawley (SD) rats and their wild-type counterparts (n = 12) were, respectively, allocated for two dietary condition groups (normal chow and high-cholesterol diet). Total 16S rDNA of fecal samples were extracted and sequenced by high-throughput sequencing to determine differences in microbiome composition. Data were collected and performed diversity analysis and phylogenetic analysis. The influence of cholesterol on gut microbiota was discussed by using cholesterol dietary treatment as exogenous cholesterol disorder factor and genetic modification as endogenous metabolic disorder factor. Relative microbial variations were compared to illustrate the causality and correlation of cholesterol and gut microbiota. It turned out comparing to genetically modified rats, exogenous cholesterol intake may play more effective role in changing gut microbiota profile, although the serum cholesterol level of genetically modified rats was even higher. Relative abundance of some representative species showed that the discrepancies due to dietary variation were more obvious, whereas some low abundance species changed because of genetic disorders. Our results partially demonstrated that gut microbiota are relatively more sensitive to dietary variation. Nevertheless, considering the important effect of bacteria in cholesterol metabolism, the influence to gut flora by "genetically caused cholesterol disorder" cannot be overlooked. Manipulation of gut microbiota might be an effective target for preventing cholesterol-related metabolic disorders. © 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  17. Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system

    Directory of Open Access Journals (Sweden)

    Jonathan eJanssens

    2014-09-01

    Full Text Available With our increasing appreciation of the true complexity of diseases and pathophysiologies it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders the disease mechanism itself is a complex process spanning multiple signaling networks, tissues and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically-effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g. central neurodegenerative disorders such as Alzheimer’s disease (AD, Parkinson’s disease (PD and Huntington’ disease (HD, the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD and HD possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative disease it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems and even diseases. Here we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1 ligand-receptor axis with multiple aspects of the AD, PD and HD neurodegenerative continuum.

  18. Mortality from Musculoskeletal Disorders Including Rheumatoid Arthritis in Southern Sweden: A Multiple-cause-of-death Analysis, 1998-2014.

    Science.gov (United States)

    Kiadaliri, Aliasghar A; Turkiewicz, Aleksandra; Englund, Martin

    2017-05-01

    To assess mortality related to musculoskeletal (MSK) disorders and rheumatoid arthritis (RA), specifically, among adults (aged ≥ 20 yrs) in southern Sweden using the multiple-cause-of-death approach. All death certificates (DC; n = 201,488) from 1998 to 2014 for adults in the region of Skåne were analyzed when mortality from MSK disorders and RA was listed as the underlying and nonunderlying cause of death (UCD/NUCD). Trends in age-standardized mortality rates (ASMR) were evaluated using joinpoint regression, and associated causes were identified by age- and sex-adjusted observed/expected ratios. MSK (RA) was mentioned on 2.8% (0.8%) of all DC and selected as UCD in 0.6% (0.2%), with higher values among women. Proportion of MSK disorder deaths from all deaths increased from 2.7% in 1998 to 3.1% in 2014, and declined from 0.9% to 0.5% for RA. The mean age at death was higher in DC with mention of MSK/RA than in DC without. The mean ASMR for MSK (RA) was 15.5 (4.3) per 100,000 person-years and declined by 1.1% (3.8%) per year during 1998-2014. When MSK/RA were UCD, pneumonia and heart failure were the main NUCD. When MSK/RA were NUCD, the leading UCD were ischemic heart disease and neoplasms. The greatest observed/expected ratios were seen for infectious diseases (including sepsis) and blood diseases. We observed significant reduction in MSK and RA mortality rates and increase in the mean age at death. Further analyses are required to investigate determinants of these improvements in MSK/RA survival and their potential effect on the Swedish healthcare systems.

  19. 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.

  20. Evaluation of workforce perceptions as a means to identify and mitigate the causes of musculoskeletal disorders.

    Science.gov (United States)

    2010-01-01

    An analysis of workers compensation data showed that five job classifications accounted for over 93% of all cases. This analysis also showed that 48% of the cases resulted in sprains and strains, and 70% of those cases were caused by over-exertion...

  1. NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina

    NARCIS (Netherlands)

    Segarra, Nuria Garcia; Ballhausen, Diana; Crawford, Heather; Perreau, Matthieu; Campos-Xavier, Belinda; van Spaendonck-Zwarts, Karin; Vermeer, Cees; Russo, Michel; Zambelli, Pierre-Yves; Stevenson, Brian; Royer-Bertrand, Beryl; Rivolta, Carlo; Candotti, Fabio; Unger, Sheila; Munier, Francis L.; Superti-Furga, Andrea; Bonafé, Luisa

    2015-01-01

    We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting,

  2. Schizoaffective disorder

    Science.gov (United States)

    Mood disorder - schizoaffective disorder; Psychosis - schizoaffective disorder ... The exact cause of schizoaffective disorder is unknown. Changes in genes and chemicals in the brain (neurotransmitters) may play a role. Schizoaffective disorder is thought to ...

  3. Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia

    DEFF Research Database (Denmark)

    Nimsanor, Natakarn; Jørring, Ida; Rasmussen, Mikkel A.

    2016-01-01

    Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the gene coding the microtubule-associated protein tau (MAPT) can cause FTDP-17 but the underlying mechanisms of the disease are still unknown. Induced...

  4. Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder.

    Science.gov (United States)

    Lu, Wei; Karuppagounder, Senthilkumar S; Springer, Danielle A; Allen, Michele D; Zheng, Lixin; Chao, Brittany; Zhang, Yan; Dawson, Valina L; Dawson, Ted M; Lenardo, Michael

    2014-09-15

    Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson's-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson's disease.

  5. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses

    Directory of Open Access Journals (Sweden)

    Hyejung eWon

    2013-08-01

    Full Text Available Autism spectrum disorder (ASD is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive inter-ests/behaviors. Advances in human genomics have identified a large number of genetic varia-tions associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the pathogenesis of ASD, many of which involve synaptic dysfunctions, and have investigated novel, mechanism-based therapeutic strategies. This review will try to integrate these three key aspects of ASD research: human genetics, animal models, and potential treatments. Continued efforts in this direction should ultimately reveal core mechanisms that account for a larger fraction of ASD cases and identify neural mechanisms associated with specific ASD symptoms, providing important clues to efficient ASD treatment.

  6. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses.

    Science.gov (United States)

    Won, Hyejung; Mah, Won; Kim, Eunjoon

    2013-01-01

    Autism spectrum disorder (ASD) is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Advances in human genomics have identified a large number of genetic variations associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the pathogenesis of ASD, many of which involve synaptic dysfunctions, and have investigated novel, mechanism-based therapeutic strategies. This review will try to integrate these three key aspects of ASD research: human genetics, animal models, and potential treatments. Continued efforts in this direction should ultimately reveal core mechanisms that account for a larger fraction of ASD cases and identify neural mechanisms associated with specific ASD symptoms, providing important clues to efficient ASD treatment.

  7. The two fold role of oxytocin in social developmental disorders: A cause and a remedy?

    Science.gov (United States)

    Lefevre, Arthur; Sirigu, Angela

    2016-04-01

    Oxytocin is widely used by obstetricians to induce or facilitate labor. The long lasting consequences of oxytocin administration remain however unknown. Here, we discuss recent evidence suggesting a link between oxytocin labor induction and developmental social impairments such as autism spectrum disorders (ASD). Because these associations are methodologically questionable, we provide a review of animal studies investigating the long term effects of neonatal injection of oxytocin to shed light on the biological mechanisms that mediate the contribution of early oxytocin supplementation on the development of social impairments. In contrast to this potential negative impact on development, oxytocin has been shown to ameliorate social skills of ASD patients. However, results of chronic oxytocin administration from animal experiments are contradictory. We also review recent studies looking at chronic oxytocin effects in animal and in humans. Obstetric and psychiatric uses of exogenous oxytocin both impact on oxytocinergic neurotransmission but the effects may be sharply dissimilar. Copyright © 2016. Published by Elsevier Ltd.

  8. 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.

  9. Autophagy and ageing: implications for age-related neurodegenerative diseases.

    Science.gov (United States)

    Carroll, Bernadette; Hewitt, Graeme; Korolchuk, Viktor I

    2013-01-01

    Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our 'ageing' world.

  10. 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.

  11. Novel prion protein insert mutation associated with prolonged neurodegenerative illness.

    Science.gov (United States)

    Lewis, V; Collins, S; Hill, A F; Boyd, A; McLean, C A; Smith, M; Masters, C L

    2003-05-27

    Mutations in the prion protein gene (PRNP) are found in approximately 13 to 15% of persons classified as dying from a transmissible spongiform encephalopathy. Point and octapeptide repeat insert and deletion mutations are described in the open reading frame (ORF) of PRNP. The authors present a clinicopathologic study of a patient with a family history of a lengthy and progressive neurodegenerative disorder associated with a novel large octapeptide repeat insert mutation. Neuropathologic examination, including immunohistochemistry for the prion protein, was undertaken. The ORF of PRNP was amplified by PCR, cloned, and sequenced. Homogenate of cerebral tissue underwent Western blot analysis for the prion protein before and after proteinase K treatment. The proband died after a 16-year illness commencing at age 29 years. Confident premortem clinical diagnosis was not achieved despite a brain biopsy. Autopsy examination of the brain confirmed a spongiform encephalopathy. Prion protein immunohistochemistry revealed occasional granular deposits in the cerebellar granular layer. The proband was found to harbor a novel PRNP 168 base pair (bp) insert mutation. The authors have identified a novel 168 bp octapeptide repeat insert mutation. Prion protein immunohistochemistry differs from previous cases harboring seven octapeptide repeat and other long insert mutations. Optimization of PRNP analysis, especially PCR conditions, is essential to avoid overlooking this type of mutation and delay the correct molecular genetic diagnosis.

  12. Mood, memory and movement: an age-related neurodegenerative complex?

    Science.gov (United States)

    Granholm, Ann-Charlotte; Boger, Heather; Emborg, Marina E

    2008-07-01

    The following review was constructed as a concept paper based on a recent workshop on neurodegenerative disease sponsored by the National Institute on Aging (NIA), the American Geriatric Society (AGS), and the John A. Hartford Foundation. The meeting was entitled "Thinking, moving and feeling: Common underlying mechanisms? 4(th) Annual Bedside-to-Bench Conference" and had the purpose to connect current basic and clinical findings on common brain-related alterations occurring with aging such as depression, movement disorders, and cognitive decline. Many prominent researchers expressed their opinion on aging and it was revealed that age-related brain dysfunction of any kind seems to share several risk factors and/or pathways. But can something be done to actively achieve "successful aging"? In this review, based largely on the workshop and current literature, we have summarized some of the current theories for depression, movement and cognitive impairment with aging, as well as potential preventive measures. We have also summarized the emerging need for relevant animal models and how these could be developed and utilized.

  13. Exploring mitochondrial system properties of neurodegenerative diseases through interactome mapping.

    Science.gov (United States)

    Vlasblom, James; Jin, Ke; Kassir, Sandy; Babu, Mohan

    2014-04-04

    Mitochondria are double membraned, dynamic organelles that are required for a large number of cellular processes, and defects in their function have emerged as causative factors for a growing number of human disorders and are highly associated with cancer, metabolic, and neurodegenerative (ND) diseases. Biochemical and genetic investigations have uncovered small numbers of candidate mitochondrial proteins (MPs) involved in ND disease, but given the diversity of processes affected by MP function and the difficulty of detecting interactions involving these proteins, many more likely remain unknown. However, high-throughput proteomic and genomic approaches developed in genetically tractable model prokaryotes and lower eukaryotes have proven to be effective tools for querying the physical (protein-protein) and functional (gene-gene) relationships between diverse types of proteins, including cytosolic and membrane proteins. In this review, we highlight how experimental and computational approaches developed recently by our group and others can be effectively used towards elucidating the mitochondrial interactome in an unbiased and systematic manner to uncover network-based connections. We discuss how the knowledge from the resulting interaction networks can effectively contribute towards the identification of new mitochondrial disease gene candidates, and thus further clarify the role of mitochondrial biology and the complex etiologies of ND disease. Biochemical and genetic investigations have uncovered small numbers of candidate mitochondrial proteins (MPs) involved in neurodegenerative (ND) diseases, but given the diversity of processes affected by MP function and the difficulty of detecting interactions involving these proteins, many more likely remain unknown. Large-scale proteomic and genomic approaches developed in model prokaryotes and lower eukaryotes have proven to be effective tools for querying the physical (protein-protein) and functional (gene

  14. Food-Derived Antioxidant Polysaccharides and Their Pharmacological Potential in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Haifeng Li

    2017-07-01

    Full Text Available Oxidative stress is known to impair architecture and function of cells, which may lead to various chronic diseases, and therefore therapeutic and nutritional interventions to reduce oxidative damages represent a viable strategy in the amelioration of oxidative stress-related disorders, including neurodegenerative diseases. Over the past decade, a variety of natural polysaccharides from functional and medicinal foods have attracted great interest due to their antioxidant functions such as scavenging free radicals and reducing oxidative damages. Interestingly, these antioxidant polysaccharides are also found to attenuate neuronal damages and alleviate cognitive and motor decline in a range of neurodegenerative models. It has recently been established that the neuroprotective mechanisms of polysaccharides are related to oxidative stress-related pathways, including mitochondrial function, antioxidant defense system and pathogenic protein aggregation. Here, we first summarize the current status of antioxidant function of food-derived polysaccharides and then attempt to appraise their anti-neurodegeneration activities.

  15. Epigenetics and etiology of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Beata M. Gruber

    2011-08-01

    Full Text Available Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethylation and the transcriptionally non-active sequences are hypermethylated. Covalent histone modifications and DNA methylation are correlated and interacting. Chromatin modeling is regulated not only by specific enzymes but also by protein kinases or phosphatases and coactivators, such as CBP. Such interaction makes the “histone code” which with the chromatin proteins determines gene expression patterns as the response to external agents. Evidence of a major role for epigenetic modifications in neurological disease has come from three converging lines of enquiry: high conservation throughout evolution of the histone residues that are the target for epigenetic modifications; association between mutations in epigenetic components and multisystem disease syndrome in the nervous system; and broad efficacy of small-molecule epigenetic modulators, e.g. histone deacetylase inhibitors, in models of neurological diseases incurable up to now, such as Huntington’s disease, (HD, Parkinson’s disease (PD and Alzheimer’s disease (AD. This article is a survey of the literature concerning the characterization of gene expression patterns correlated with some neurodegenerative diseases. The processes of DNA hypomethylation and histone acetylation are emphasized. The histone deacetylases are indicated as the basis for design of potential drugs.

  16. [Metastases in the temporomandibular joint: a review from 1954 to 2013. Rare causes for temporomandibular disorders].

    Science.gov (United States)

    Pretzl, Christine; Lübbers, Heinz-Theo; Grätz, Klaus W; Kruse, Astrid L

    2014-01-01

    Metastatic lesions make up approximately 1% of all oral cancers.A comparatively rare location is the temporomandibular joint.Leading symptoms can be misdirecting, especially in the beginning,because they are frequently similar or even identical to those occurring in temporomandibular disorders. Therefore it can be quite difficult to confirm the diagnosis of a TMJ metastasis.delayed initiation of therapy and thus a poor prognosis are often the results. A review of the literature from 1954 to 2013 was realized and the published cases between 1954 and January 2013 were evaluated.The results were analyzed according to gender distribution, age,first symptoms, location of the primary tumor, as well as to the occurrence of malignancies in the patients' medical history. The research identified sixty-six patients. Tumors of the lung and breast were the main starting points of the metastatic spread. The histopathological workup showed above all the diagnosis of an adenocarcinoma. In all of the cases, unspecific symptoms led to the diagnosis of a metastatic disease. In the case of nonspecific TMJ affection, diagnostics should consider less-frequent diagnoses, such as the presence of metastasis.A clinical differentiation by additional symptoms like swelling, unexplained weight loss and night sweats, as well as a tumor disease in the past or failure of conservative treatment can provide additional indications. If there is reasonable suspicion,extended medical imaging and diagnostic measures must be performed to allow early treatment initiation and a better prognosis.

  17. Effects of acupuncture on the symptoms of anxiety and depression caused by premenstrual dysphoric disorder.

    Science.gov (United States)

    Carvalho, Fabiana; Weires, Kelly; Ebling, Márcia; Padilha, Maristela de Souza Rabbo; Ferrão, Ygor Arzeno; Vercelino, Rafael

    2013-12-01

    The objective of this investigation was to evaluate the effects of acupuncture and sham acupuncture on the symptoms of anxiety and depression brought on by premenstrual dysphoric disorder (PMDD). In a single-blind randomised clinical trial, 30 volunteers with PMDD were assigned alternately to group 1 (acupuncture) or group 2 (sham acupuncture), and completed an evaluation of symptoms of anxiety and depression using the Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) Rating Scales. The procedure was performed twice a week for two menstrual cycles, for a total of 16 attendances for each participant. Before the intervention the mean HAM-A and HAM-D scores did not differ between groups. Following the intervention symptoms of anxiety and depression were reduced in both groups; however, the improvement was significant in group 1 compared to group 2, as shown by a mean reduction in HAM-A scores of 58.9% in group 1 and 21.2% in group 2 (pacupuncture could be another treatment option for PMDD patients.

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

    Science.gov (United States)

    Kyöstilä, Kaisa; Syrjä, Pernilla; Jagannathan, Vidhya; Chandrasekar, Gayathri; Jokinen, Tarja S; Seppälä, Eija H; Becker, Doreen; Drögemüller, Michaela; Dietschi, Elisabeth; Drögemüller, Cord; Lang, Johann; Steffen, Frank; Rohdin, Cecilia; Jäderlund, Karin H; Lappalainen, Anu K; Hahn, Kerstin; Wohlsein, Peter; Baumgärtner, Wolfgang; Henke, Diana; Oevermann, Anna; Kere, Juha; Lohi, Hannes; Leeb, Tosso

    2015-04-01

    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.

  19. A Missense Change in the ATG4D Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease

    Science.gov (United States)

    Kyöstilä, Kaisa; Syrjä, Pernilla; Jagannathan, Vidhya; Chandrasekar, Gayathri; Jokinen, Tarja S.; Seppälä, Eija H.; Becker, Doreen; Drögemüller, Michaela; Dietschi, Elisabeth; Drögemüller, Cord; Lang, Johann; Steffen, Frank; Rohdin, Cecilia; Jäderlund, Karin H.; Lappalainen, Anu K.; Hahn, Kerstin; Wohlsein, Peter; Baumgärtner, Wolfgang; Henke, Diana; Oevermann, Anna; Kere, Juha; Lohi, Hannes; Leeb, Tosso

    2015-01-01

    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. PMID:25875846

  20. 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.

  1. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Matthew E R Butchbach

    2016-03-01

    Full Text Available Proximal spinal muscular atrophy (SMA, a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1 on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7 and produce a protein that is both unstable and less than fully functional. Although only 10-20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS and progressive muscular atrophy (PMA. This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.

  2. Mortality and causes of death in autism spectrum disorders - An update

    DEFF Research Database (Denmark)

    Mouridsen, S.E.; Hansen, H.B.; Rich, B.

    2008-01-01

    was particularly high in females. The excess mortality risk has remained unchanged since our first study in 1993. Eight of the 26 deaths were associated with epilepsy and four died from epilepsy. Future staff education should focus on better managing of the complex relationships between ASD and physical illness...... to mortality and causes of death. Standardized mortality ratios (SMRs) were calculated for various times after diagnosis. In all, 26 persons with ASD had died, whereas the expected number of deaths was 13.5. Thus the mortality risk among those with ASD was nearly twice that of the general population. The SMR...... to prevent avoidable deaths Udgivelsesdato: 2008/7...

  3. Mortality and causes of death in autism spectrum disorders: An update

    DEFF Research Database (Denmark)

    Mouridsen, Svend Erik; Brønnum-Hansen, Henrik; Rich, Bente

    2008-01-01

    was particularly high in females. The excess mortality risk has remained unchanged since our first study in 1993. Eight of the 26 deaths were associated with epilepsy and four died from epilepsy. Future staff education should focus on better managing of the complex relationships between ASD and physical illness...... to mortality and causes of death. Standardized mortality ratios (SMRs) were calculated for various times after diagnosis. In all, 26 persons with ASD had died, whereas the expected number of deaths was 13.5. Thus the mortality risk among those with ASD was nearly twice that of the general population. The SMR...... to prevent avoidable deaths....

  4. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers : a new canine model for copper-metabolism disorders

    NARCIS (Netherlands)

    Fieten, Hille; Gill, Yadvinder; Martin, Alan J.; Concilli, Mafalda; Dirksen, Karen; van Steenbeek, Frank G.; Spee, Bart; van den Ingh, Ted S. G. A. M.; Martens, Ellen C. C. P.; Festa, Paola; Chesi, Giancarlo; Sluis, van de Bart; Houwen, Roderick H. J. H.; Watson, Adrian L.; Aulchenko, Yurii S.; Hodgkinson, Victoria L.; Zhu, Sha; Petris, Michael J.; Polishchuk, Roman S.; Leegwater, Peter A. J.; Rothuizen, Jan

    2016-01-01

    The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to

  5. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

    NARCIS (Netherlands)

    Fieten, Hille; Gill, Yadvinder; Martin, Alan J.; Concilli, Mafalda; Dirksen, Karen; van Steenbeek, Frank G.; Spee, Bart; van den Ingh, Ted S. G. A. M.; Martens, Ellen C. C. P.; Festa, Paola; Chesi, Giancarlo; van de Sluis, Bart; Houwen, Roderick H. J. H.|info:eu-repo/dai/nl/087887991; Watson, Adrian L.; Aulchenko, Yurii S.; Hodgkinson, Victoria L.; Zhu, Sha; Petris, Michael J.; Polishchuk, Roman S.; Leegwater, Peter A. J.; Rothuizen, Jan

    2016-01-01

    The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to

  6. 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

  7. Perseveration causes automatization of checking behavior in obsessive-compulsive disorder.

    Science.gov (United States)

    Dek, Eliane C P; van den Hout, Marcel A; Engelhard, Iris M; Giele, Catharina L; Cath, Danielle C

    2015-08-01

    Repeated checking leads to reductions in meta-memory (i.e., memory confidence, vividness and detail), and automatization of checking behavior (Dek, van den Hout, Giele, & Engelhard, 2014, 2015). Dek et al. (2014) suggested that this is caused by increased familiarity with the checked stimuli. They predicted that defamiliarization of checking by modifying the perceptual characteristics of stimuli would cause de-automatization and attenuate the negative meta-memory effects of re-checking. However, their results were inconclusive. The present study investigated whether repeated checking leads to automatization of checking behavior, and if defamiliarization indeed leads to de-automatization and attenuation of meta-memory effects in patients with OCD and healthy controls. Participants performed a checking task, in which they activated, deactivated and checked threat-irrelevant stimuli. During a pre- and post-test checking trial, check duration was recorded and a reaction time task was simultaneously administered as dual-task to assess automatization. After the pre- and post-test checking trial, meta-memory was rated. Results showed that relevant checking led to automatization of checking behavior on the RT measure, and negative meta-memory effects for patients and controls. Defamiliarization led to de-automatization measured with the RT task, but did not attenuate the negative meta-memory effects of repeated checking. Clinical implications are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Renin-angiotensin system gene expression and neurodegenerative diseases.

    Science.gov (United States)

    Goldstein, Benjamin; Speth, Robert C; Trivedi, Malav

    2016-07-01

    Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases. Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease. A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis. No single nucleotide polymorphisms in any of the 14 RAS-related protein genes were significantly associated with the five neurodegenerative diseases investigated. There was an inverse association between expression of ATP6AP2, which encodes the (pro)renin receptor, and multiple sclerosis, Alzheimer's disease and Parkinson's disease. An association of AGTR, which encodes the AT1 angiotensin II receptor, and Parkinson's disease and Alzheimer's disease was also observed. To date, no single nucleotide polymorphisms in components of the RAS can be definitively linked to the neurodegenerative diseases evaluated in this study. However, altered gene expression of several components of the RAS is associated with several neurodegenerative diseases, which may indicate that the RAS contributes to the pathology of these diseases. © The Author(s) 2016.

  9. 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

  10. CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases.

    Science.gov (United States)

    Tu, Zhuchi; Yang, Weili; Yan, Sen; Guo, Xiangyu; Li, Xiao-Jiang

    2015-08-04

    Animal models are extremely valuable to help us understand the pathogenesis of neurodegenerative disorders and to find treatments for them. Since large animals are more like humans than rodents, they make good models to identify the important pathological events that may be seen in humans but not in small animals; large animals are also very important for validating effective treatments or confirming therapeutic targets. Due to the lack of embryonic stem cell lines from large animals, it has been difficult to use traditional gene targeting technology to establish large animal models of neurodegenerative diseases. Recently, CRISPR/Cas9 was used successfully to genetically modify genomes in various species. Here we discuss the use of CRISPR/Cas9 technology to establish large animal models that can more faithfully mimic human neurodegenerative diseases.

  11. Kleine-Levin Syndrome in an 8-Year-Old Girl with Autistic Disorder: Does Autism Account a Primary or Secondary Cause?

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    Hakim Shoushtari, Mitra; Ghalebandi, Mirfarhad; Tavasoli, Azita; Pourshams, Maryam

    2015-01-01

    Objective Kleine-Levin syndrome (KLS) is a rare disorder with an unknown etiology. Autism spectrum disorder is characterized by various degrees of impairment in social communication, repetitive behavior and restricted interests. Only four patients of KLS with autistic spectrum disorder (ASD) have been reported so far. This report presents an 8-year-old girl with history of autistic disorder and epilepsy that superimposed KLS. Because of the rarity of KLS and related studies did not address whether autism accounts for a primary or secondary cause, the area required attention further studies.

  12. mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss

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    HoangDinh Huynh

    2017-06-01

    Full Text Available It is unknown whether and how very-low density lipoprotein receptors (VLDLRs impact skeletal homeostasis. Here, we report that maternal and offspring VLDLRs play opposite roles in osteoclastogenesis and bone resorption. VLDLR deletion in the offspring augments osteoclast differentiation by enhancing RANKL signaling, leading to osteoporosis. In contrast, VLDLR deletion in the mother alters milk metabolism, which inhibits osteoclast differentiation and causes osteopetrosis in the offspring. The maternal effects are dominant. VLDLR-null lactating mammary gland exhibits higher mTORC1 signaling and cholesterol biosynthesis. Pharmacological probing reveals that rapamycin, but not statin, treatment of the VLDLR-null mother can prevent both the low bone resorption and our previously described inflammatory fur loss in their offspring. Genetic rescue reveals that maternal mTORC1 attenuation in adipocytes, but not in myeloid cells, prevents offspring osteopetrosis and fur loss. Our studies uncover functions of VLDLR and mTORC1 in lactation and osteoclastogenesis, illuminating key mechanisms and therapeutic insights for bone and metabolic diseases.

  13. Clinical Studies on Treatment of Earthquake-Caused Posttraumatic Stress Disorder Using Electroacupuncture

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    Yu Wang

    2012-01-01

    Full Text Available The objective of this study was to assess the efficacy and safety of electroacupuncture in 138 patients with earthquake-caused PTSD using Randomized Controlled Trials (RCTs. 138 cases enrolled were randomly assigned to an electro-acupuncture group and a paroxetine group. The electro-acupuncture group was treated by scalp electro-acupuncture on Baihui (GV 20, Sishencong (EX-HN 1, Shenting (GV 24, and Fengchi (GB 20, and the paroxetine group was treated with simple oral administration of paroxetine. The efficacy and safety of the electro-acupuncture on treatment of 69 PTSD patients were evaluated using Clinician-Administered PTSD Scale (CAPS, Hamilton Depression Scale (HAMD, Hamilton Anxiety Scale (HAMA, and Treatment Emergent Symptom Scale (TESS according to clinical data. The total scores of CAPS, HAMD, and HAMA in the two groups after treatment showed significant efficacy compared to those before treatment. The comparison of reduction in the scores of CAPS, HAMD, and HAMA between the two groups suggested that the efficacy in the treated group was better than that in the paroxetine group. The present study suggested that the electro-acupuncture and paroxetine groups have significant changes in test PTSD, but the electro-acupuncture 2 group was more significant.

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

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    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.

  15. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence.

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    Kolodkin, Alexey; Simeonidis, Evangelos; Balling, Rudi; Westerhoff, Hans V

    2012-01-01

    Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are "systems biology diseases," or "network diseases." Here we use neurodegenerative diseases, like Parkinson's disease (PD), as an example to show that due to the inherent complexity of these networks, it is difficult to understand multi-factorial diseases with simply our "naked brain." When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system's design crucial for important physiological behavior (the so-called "design principles" of the system). In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design principles that govern behavioral

  16. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence

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    Alexey eKolodkin

    2012-07-01

    Full Text Available Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction is also an emergent property, emerging from a perturbation of the network. On one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are ‘systems biology diseases’, or ‘network diseases’. Here we focus on neurodegenerative diseases, like Parkinson’s disease, as an example. Because of the inherent complexity of these networks, it is difficult to understand multi-factorial diseases using simply our ‘naked brain’. When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system’s design crucial for important physiological behavior (the so-called ‘design principles’ of the system. In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design

  17. Infectious Agents and Neurodegenerative Diseases: Exploring the Links.

    Science.gov (United States)

    Alam, Mohammad Zubair; Alam, Qamre; Kamal, Mohammad Amjad; Jiman-Fatani, Asif Ahmad; Azhar, Esam I; Khan, Mohammad Azhar; Haque, Absarul

    2017-01-01

    Recent studies have shown that bacterial and viral infections are risk factors for various neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), Alzheimer's disease (AD), and Lyme disease (LD). However, it is still controversial how the infections play a role in neurological diseases progression. Infections in central nervous system may lead multiple damages in infected and neighboring cells. The infection leads to the activation of inflammatory processes and host immune responses, which acts as defense mechanism and also causes damage to the host neuronal functions and viability. Several bacterial and viral pathogens have been reported for neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in combination with other factors, like aging, metabolic diseases and the genetic makeup of the host. We will focus in this review on the possible link between neurodegeneration and infections particularly Chlamydophila pneumoniae, Borrelia burgdorferi, Mycoplasma etc. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Excess Mortality, Causes of Death and Life Expectancy in 270,770 Patients with Recent Onset of Mental Disorders in Denmark, Finland and Sweden

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    Nordentoft, Merete; Wahlbeck, Kristian; Hällgren, Jonas; Westman, Jeanette; Ösby, Urban; Alinaghizadeh, Hassan; Gissler, Mika; Laursen, Thomas Munk

    2013-01-01

    Background Excess mortality among patients with severe mental disorders has not previously been investigated in detail in large complete national populations. Objective To investigate the excess mortality in different diagnostic categories due to suicide and other external causes of death, and due to specific causes in connection with diseases and medical conditions. Methods In longitudinal national psychiatric case registers from Denmark, Finland, and Sweden, a cohort of 270,770 recent-onset patients, who at least once during the period 2000 to 2006 were admitted due to a psychiatric disorder, were followed until death or the end of 2006. They were followed for 912,279 person years, and 28,088 deaths were analyzed. Life expectancy and standardized cause-specific mortality rates were estimated in each diagnostic group in all three countries. Results The life expectancy was generally approximately 15 years shorter for women and 20 years shorter for men, compared to the general population. Mortality due to diseases and medical conditions was increased two- to three-fold, while excess mortality from external causes ranged from three- to 77-fold. Mortality due to diseases and medical conditions was generally lowest in patients with affective disorders and highest in patients with substance abuse and personality disorders, while mortality due to suicide was highest in patients with affective disorders and personality disorders, and mortality due to other external causes was highest in patients with substance abuse. Conclusions These alarming figures call for action in order to prevent the high mortality. PMID:23372832

  19. Glycation, Glycolysis, and Neurodegenerative Diseases: Is There Any Connection?

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    Muronetz, V I; Melnikova, A K; Seferbekova, Z N; Barinova, K V; Schmalhausen, E V

    2017-08-01

    This review considers the interrelation between different types of protein glycation, glycolysis, and the development of amyloid neurodegenerative diseases. The primary focus is on the role of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in changing the concentration of carbonyl compounds - first and foremost, glyceraldehyde-3-phosphate and methylglyoxal. It has been suggested that various modifications of the enzyme - from the oxidation of the sulfhydryl groups of the active site to glycation with sugars - can lead to its inactivation, which causes a direct increase in glyceraldehyde-3-phosphate concentration and an indirect increase in the content of other aldehydes. This "primary inactivation" of glyceraldehyde-3-phosphate dehydrogenase promotes its glycation with aldehydes, including its own substrate, and a further irreversible decrease in its activity. Such a cycle can lead to numerous consequences - from the induction of apoptosis, which is activated by modified forms of the enzyme, to glycation of amyloidogenic proteins by glycolytic aldehydes. Of particular importance during the inhibition of glyceraldehyde-3-phosphate dehydrogenase is an increase in the content of the glycating compound methylglyoxal, which is much more active than reducing sugars (glucose, fructose, and others). In addition, methylglyoxal is formed by two pathways - in the cascade of reactions during glycation and from glycolytic aldehydes. The ability of methylglyoxal to glycate proteins makes it the main participant in this protein modification. We consider the effect of glycation on the pathological transformation of amyloidogenic proteins and peptides - β-amyloid peptide, α-synuclein, and prions. Our primary focus is on the glycation of monomeric forms of these proteins with methylglyoxal, although most works are dedicated to the analysis of the presence of "advanced glycation end products" in the already formed aggregates and fibrils of amyloid proteins. In our

  20. Evaluation of risk factors causing work - related musculoskeletal disorders (WMSDS in kerman bakery workers by OCRAIndex method

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    H.R. Ghashghav

    2009-10-01

    Full Text Available Background and aimsthe musculoskeletal disorders over a large percent of occupational  diseases ; therefore, in order to protect workers from such disorders, there is a need to evaluate workers positions at work in different jobs. There are several methods to evaluate risk factors causing work - related musculoskeletal disorders. this study perform on bakers population of four different types of bakeries(Tafton davar,Tafton sonnati,sangak and baget and we evaluated WMSDs causal risk factors by OCRA Index technique.MethodsIn this research four data gathering methods including observational ,interview,questioner and check list were utilized. Totally 423 samples by proportional cluster samplingmethod collected and we used spss15 soft ware for statistical analysisResultsThe results of this investigation demonstrated that maximum mean value of OCRA index in left and right hands were related to shatery task in sangak bakery (OCRAI index=14.99.finally,56.5,67.4,77.3 and 75 percent of all tasks at Tafton davar,Tafton sonnati,sangak and baget bakeries respectively were in the red area also our results showed that only ,left and right hands OCRA index means of nandari , forushandegi and nandara/forushandegi tasks were equivalent.Conclusionwith regarding to this point that major of tasks in the bakery job locate in the red zone therefore attention to this problem is necessary and use of ergonomics controls to eliminate or reduce exposure of workers to the ergonomics stressors associated with the development ofWMSDs is recommended

  1. Modeling Neurodegenerative Microenvironment Using Cortical Organoids Derived from Human Stem Cells.

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    Yan, Yuanwei; Song, Liqing; Bejoy, Julie; Zhao, Jing; Kanekiyo, Takahisa; Bu, Guojun; Zhou, Yi; Li, Yan

    2018-02-27

    Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind Aβ42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.

  2. Persistent reflux symptoms cause anxiety, depression, and mental health and sleep disorders in gastroesophageal reflux disease patients.

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    Kimura, Yoshihide; Kamiya, Takeshi; Senoo, Kyouji; Tsuchida, Kenji; Hirano, Atsuyuki; Kojima, Hisayo; Yamashita, Hiroaki; Yamakawa, Yoshihiro; Nishigaki, Nobuhiro; Ozeki, Tomonori; Endo, Masatsugu; Nakanishi, Kazuhisa; Sando, Motoki; Inagaki, Yusuke; Shikano, Michiko; Mizoshita, Tsutomu; Kubota, Eiji; Tanida, Satoshi; Kataoka, Hiromi; Katsumi, Kohei; Joh, Takashi

    2016-07-01

    Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients.

  3. Correlation of the anxiety caused by postoperative chemotherapy with endocrine disorder and immune response in patients with colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Xin Zhang

    2017-01-01

    Objective:To study the correlation of the anxiety caused by postoperative chemotherapy with endocrine disorder and immune response in patients with colorectal cancer.Methods:A total of 110 patients who received radical operation for colorectal cancer and postoperative chemotherapy in the hospital between August 2014 and December 2016 were divided into the non-anxiety group (SAS<50 points) (n=29), mild-to-moderate anxiety group (50≤SAS≤69) (n=63) and severe anxiety group (SAS 70 points) (n=18) according to self-rating anxiety scale (SAS) score after one course of chemotherapy. The differences in the levels of RAAS indexes, monoamine neurotransmitters, Th1/Th2 cytokines and Th17/Treg cytokines were compared among three groups of patients before and after chemotherapy.Results: Before chemotherapy, the differences in serum levels of RAAS indexes, monoamine neurotransmitters, Th1/Th2 cytokines and Th17/Treg cytokines were not statistically significant among the three groups of patients. After one course of chemotherapy, serum RAAS indexes REN, AngⅡ and ALD levels of mild-to-moderate anxiety group and severe anxiety group were higher than those of non-anxiety group; monoamine neurotransmitters NE and DA levels were higher than those of no anxiety group; serum IL-2 level was higher than that of non-anxiety group while IL-4 level was lower than that of non-anxiety group; serum IL-17 level was higher than of non-anxiety group while IL-10 was lower than that of non-anxiety group; the changes in serum levels of the above indexes of severe anxiety group were greater than those of mild-to-moderate anxiety group.Conclusion: The anxiety caused by postoperative chemotherapy in patients with colorectal cancer can directly lead to the endocrine disorder and the decrease of cellular immune function, and the negative changes increase with the aggravation of anxiety.

  4. Parent Beliefs about the Causes of Learning and Developmental Problems among Children with Autism Spectrum Disorder: Results from a National Survey

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    Zuckerman, Katharine E.; Lindly, Olivia J.; Sinche, Brianna

    2016-01-01

    This study aimed to assess variation in parent beliefs about causes of learning and developmental problems in U.S. children with autism spectrum disorder, using data from a nationally representative survey. Results showed that beliefs about a genetic/hereditary cause of learning/developmental problems were most common, but nearly as many parents…

  5. Capgras syndrome and its relationship to neurodegenerative disease.

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    Josephs, Keith A

    2007-12-01

    Capgras syndrome is characterized by a delusional belief that a person has been replaced by an imposter. It has been described in psychiatric and neurological (neurodegenerative and nonneurodegenerative) diseases. To determine whether the clinical and demographic features of subjects with Capgras syndrome differ when the syndrome is associated with neurodegenerative compared with nonneurodegenerative diseases, and whether features differ across different neurodegenerative diseases. Retrospective study. Tertiary care medical center. Patients Forty-seven subjects with Capgras syndrome. Thirty-eight of the subjects with Capgras syndrome (81%) had a neurodegenerative disease, most commonly Lewy body disease. Capgras syndrome occurred at a younger age of onset in those with a nonneurodegenerative disease (51 vs 72 years) (P Capgras syndrome and Lewy body disease, 100% had visual hallucinations compared with only one of those with Alzheimer disease (14%). Capgras syndrome is more commonly associated with neurodegenerative diseases, especially Lewy body disease, where visual hallucinations always coexist. In the absence of a neurodegenerative disease, the onset of Capgras syndrome occurs at a significantly younger age and can be associated with psychiatric disease, cerebrovascular events, and illicit drug use.

  6. Transcranial Direct Current Stimulation in Neurodegenerative Disease

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    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

  7. Tool use in neurodegenerative diseases: Planning or technical reasoning?

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    Baumard, Josselin; Lesourd, Mathieu; Remigereau, Chrystelle; Jarry, Christophe; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Osiurak, François; Le Gall, Didier

    2017-04-29

    Recent works showed that tool use can be impaired in stroke patients because of either planning or technical reasoning deficits, but these two hypotheses have not yet been compared in the field of neurodegenerative diseases. The aim of this study was to address the relationships between real tool use, mechanical problem-solving, and planning skills in patients with Alzheimer's disease (AD, n = 32), semantic dementia (SD, n = 16), and corticobasal syndrome (CBS, n = 9). Patients were asked to select and use ten common tools, to solve three mechanical problems, and to complete the Tower of London test. Motor function and episodic memory were controlled using the Purdue Pegboard Test and the BEC96 questionnaire, respectively. A data-transformation method was applied to avoid ceiling effects, and single-case analysis was performed based on raw scores and completion time. All groups demonstrated either impaired or slowed tool use. Planning deficits were found only in the AD group. Mechanical problem-solving deficits were observed only in the AD and CBS groups. Performance in the Tower of London test was the best predictor of tool use skills in the AD group, suggesting these patients had general rather than mechanical problem-solving deficits. Episodic memory seemed to play little role in performance. Motor dysfunction tended to be associated with tool use skills in CBS patients, while tool use disorders are interpreted as a consequence of the semantic loss in SD in line with previous works. These findings may encourage caregivers to set up disease-centred interventions. © 2017 The British Psychological Society.

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

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    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.

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

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    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.

  10. Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.

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    Marcelina Malinowska

    Full Text Available BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.

  11. Epigenetic mechanisms in neurological and neurodegenerative diseases.

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    Jorge eLandgrave-Gómez

    2015-02-01

    Full Text Available The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS´s regulation and neurological disorders are mediated via modulation of chromatin structure.Epigenetics, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA, nicotinamide adenine dinucleotide (NAD+ and beta hydroxybutyrate (β-HB, regulates some of these epigenetic modifications, linking in a precise way environment with gene expression.This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of

  12. Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders

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    Roberta eZanardini

    2016-02-01

    Full Text Available The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD, which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia, can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.

  13. Induced Pluripotent Stem Cell Neuronal Models for the Study of Autophagy Pathways in Human Neurodegenerative Disease.

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    Jiménez-Moreno, Natalia; Stathakos, Petros; Caldwell, Maeve A; Lane, Jon D

    2017-08-11

    Human induced pluripotent stem cells (hiPSCs) are invaluable tools for research into the causes of diverse human diseases, and have enormous potential in the emerging field of regenerative medicine. Our ability to reprogramme patient cells to become hiPSCs, and to subsequently direct their differentiation towards those classes of neurons that are vulnerable to stress, is revealing how genetic mutations cause changes at the molecular level that drive the complex pathogeneses of human neurodegenerative diseases. Autophagy dysregulation is considered to be a major contributor in neural decline during the onset and progression of many human neurodegenerative diseases, meaning that a better understanding of the control of non-selective and selective autophagy pathways (including mitophagy) in disease-affected classes of neurons is needed. To achieve this, it is essential that the methodologies commonly used to study autophagy regulation under basal and stressed conditions in standard cell-line models are accurately applied when using hiPSC-derived neuronal cultures. Here, we discuss the roles and control of autophagy in human stem cells, and how autophagy contributes to neural differentiation in vitro. We also describe how autophagy-monitoring tools can be applied to hiPSC-derived neurons for the study of human neurodegenerative disease in vitro.

  14. 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.

  15. Parent Beliefs about the Causes of Learning and Developmental Problems among Children with Autism Spectrum Disorder: Results from a National Survey

    OpenAIRE

    Zuckerman, Katharine E.; Lindly, Olivia J.; Sinche, Brianna

    2016-01-01

    This study aimed to assess variation in parent beliefs about causes of learning and developmental problems in U.S. children with autism spectrum disorder, using data from a nationally-representative survey. Results showed that beliefs about a genetic/hereditary cause of learning/developmental problems were most common, but nearly as many parents believed in exposure causes. 40% of parents had no definite causal beliefs. On multivariate analysis, parents who were non-white, p...

  16. Nano-antioxidants: An emerging strategy for intervention against neurodegenerative conditions.

    Science.gov (United States)

    Sandhir, Rajat; Yadav, Aarti; Sunkaria, Aditya; Singhal, Nitin

    2015-10-01

    Oxidative stress has for long been linked to the neuronal cell death in many neurodegenerative conditions. Conventional antioxidant therapies have been less effective in preventing neuronal damage caused by oxidative stress due to their inability to cross the blood brain barrier. Nanoparticle antioxidants constitute a new wave of antioxidant therapies for prevention and treatment of diseases involving oxidative stress. It is believed that nanoparticle antioxidants have strong and persistent interactions with biomolecules and would be more effective against free radical induced damage. Nanoantioxidants include inorganic nanoparticles possessing intrinsic antioxidant properties, nanoparticles functionalized with antioxidants or antioxidant enzymes to function as an antioxidant delivery system. Nanoparticles containing antioxidants have shown promise as high-performance therapeutic nanomedicine in attenuating oxidative stress with potential applications in treating and preventing neurodegenerative conditions. However, to realize the full potential of nanoantioxidants, negative aspects associated with the use of nanoparticles need to be overcome to validate their long term applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Role of Sigma-1 Receptor in Cocaine Abuse and Neurodegenerative Disease.

    Science.gov (United States)

    Cai, Yu; Yang, Lu; Niu, Fang; Liao, Ke; Buch, Shilpa

    2017-01-01

    Sigma-1 receptors (Sig-1R) are recognized as a unique class of non-G protein-coupled intracellular protein. Sig-1R binds to its ligand such as cocaine , resulting in dissociation of Sig-1R from mitochondrion-associated ER membrane (MAM) to the endoplasmic reticulum (ER), plasma membrane, and nuclear membrane, regulating function of various proteins. Sig-1R has diverse roles in both physiological as well as in pathogenic processes. The disruption of Sig-1R pathways has been implicated as causative mechanism(s) in the development of both neurodegenerative disorders such as Alzheimer disease (AD ), Parkinson disease (PD ), amyotrophic lateral sclerosis (ALS ) and Huntington Disease (HD ) . Additionally, the interaction of cocaine and Sig-1R has more recently been implicated in potentiating the pathogenesis of HIV-associated neurocognitive disorders (HAND) through impairment of blood-brain barrier (BBB), microglial activation and astrogliosis. On the other hand, restoration of Sig-1R homeostasis has been shown to exert neuroprotective effects. In this review, we provide an overview of how Sig-1R plays a role in the pathogenesis of neurodegenerative disorders and cocaine and implications for future development of therapeutic strategies.

  18. Anti-aging herbal medicine--how and why can they be used in aging-associated neurodegenerative diseases?

    Science.gov (United States)

    Ho, Yuen-Shan; So, Kwok-Fai; Chang, Raymond Chuen-Chung

    2010-07-01

    Aging is a universal biological process that leads to progressive and deleterious changes in organisms. From ancient time, mankind has already interested in preventing and keeping ourselves young. Anti-aging study is certainly not a new research area. Nowadays, the meaning of anti-aging has been changed from simply prolonging lifespan to increasing health span, which emphasizes more on the quality of life. This is the concept of healthy aging and prevention of pathological aging, which is associated with diseases. Keeping our brain functions as in young age is an important task for neuroscientists to prevent aging-associated neurological disorders, such as Alzheimer's diseases (AD) and Parkinson's disease (PD). The causes of these diseases are not fully understood, but it is believed that these diseases are affected by multiple factors. Neurodegenerative diseases can be cross-linked with a number of aging-associated conditions. Based on this, a holistic approach in anti-aging research seems to be more reasonable. Herbal medicine has a long history in Asian countries. It is believed that many of the medicinal herbs have anti-aging properties. Recent studies have shown that some medicinal herbs are effective in intervention or prevention of aging-associated neurological disorders. In this review, we use wolfberry and ginseng as examples to elaborate the properties of anti-aging herbs. The characteristics of medicinal herbs, especially their applications in different disease stages (prevention and intervention) and multi-targets properties, allow them to be potential anti-aging intervention in prevention and treatment of the aging-associated neurological disorders. 2009 Elsevier Ireland Ltd. All rights reserved.

  19. Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

    Directory of Open Access Journals (Sweden)

    Cali E Willet

    Full Text Available Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant. Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

  20. The Relationship between the Expression of Ethylene-Related Genes and Papaya Fruit Ripening Disorder Caused by Chilling Injury

    Science.gov (United States)

    Zou, Yuan; Zhang, Lin; Rao, Shen; Zhu, Xiaoyang; Ye, Lanlan; Chen, Weixin; Li, Xueping

    2014-01-01

    Papaya (Carica papaya L.) is sensitive to low temperature and easy to be subjected to chilling injury, which causes fruit ripening disorder. This study aimed to investigate the relationship between the expression of genes related to ethylene and fruit ripening disorder caused by chilling injury. Papaya fruits were firstly stored at 7°C and 12°C for 25 and 30 days, respectively, then treated with exogenous ethylene and followed by ripening at 25°C for 5 days. Chilling injury symptoms such as pulp water soaking were observed in fruit stored at 7°C on 20 days, whereas the coloration and softening were completely blocked after 25 days, Large differences in the changes in the expression levels of twenty two genes involved in ethylene were seen during 7°C-storage with chilling injury. Those genes with altered expression could be divided into three groups: the group of genes that were up-regulated, including ACS1/2/3, EIN2, EIN3s/EIL1, CTR1/2/3, and ERF1/3/4; the group of genes that were down-regulated, including ACO3, ETR1, CTR4, EBF2, and ERF2; and the group of genes that were un-regulated, including ACO1/2, ERS, and EBF1. The results also showed that pulp firmness had a significantly positive correlation with the expression of ACS2, ACO1, CTR1/4, EIN3a/b, and EBF1/2 in fruit without chilling injury. This positive correlation was changed to negative one in fruit after storage at 7°C for 25 days with chilling injury. The coloring index displayed significantly negative correlations with the expression levels of ACS2, ACO1/2, CTR4, EIN3a/b, ERF3 in fruit without chilling injury, but these correlations were changed into the positive ones in fruit after storage at 7°C for 25 days with chilling injury. All together, these results indicate that these genes may play important roles in the abnormal softening and coloration with chilling injury in papaya. PMID:25542021

  1. The relationship between the expression of ethylene-related genes and papaya fruit ripening disorder caused by chilling injury.

    Science.gov (United States)

    Zou, Yuan; Zhang, Lin; Rao, Shen; Zhu, Xiaoyang; Ye, Lanlan; Chen, Weixin; Li, Xueping

    2014-01-01

    Papaya (Carica papaya L.) is sensitive to low temperature and easy to be subjected to chilling injury, which causes fruit ripening disorder. This study aimed to investigate the relationship between the expression of genes related to ethylene and fruit ripening disorder caused by chilling injury. Papaya fruits were firstly stored at 7°C and 12°C for 25 and 30 days, respectively, then treated with exogenous ethylene and followed by ripening at 25°C for 5 days. Chilling injury symptoms such as pulp water soaking were observed in fruit stored at 7°C on 20 days, whereas the coloration and softening were completely blocked after 25 days, Large differences in the changes in the expression levels of twenty two genes involved in ethylene were seen during 7°C-storage with chilling injury. Those genes with altered expression could be divided into three groups: the group of genes that were up-regulated, including ACS1/2/3, EIN2, EIN3s/EIL1, CTR1/2/3, and ERF1/3/4; the group of genes that were down-regulated, including ACO3, ETR1, CTR4, EBF2, and ERF2; and the group of genes that were un-regulated, including ACO1/2, ERS, and EBF1. The results also showed that pulp firmness had a significantly positive correlation with the expression of ACS2, ACO1, CTR1/4, EIN3a/b, and EBF1/2 in fruit without chilling injury. This positive correlation was changed to negative one in fruit after storage at 7°C for 25 days with chilling injury. The coloring index displayed significantly negative correlations with the expression levels of ACS2, ACO1/2, CTR4, EIN3a/b, ERF3 in fruit without chilling injury, but these correlations were changed into the positive ones in fruit after storage at 7°C for 25 days with chilling injury. All together, these results indicate that these genes may play important roles in the abnormal softening and coloration with chilling injury in papaya.

  2. Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose.

    Science.gov (United States)

    Chavushyan, V A; Simonyan, K V; Simonyan, R M; Isoyan, A S; Simonyan, G M; Babakhanyan, M A; Hovhannisyian, L E; Nahapetyan, Kh H; Avetisyan, L G; Simonyan, M A

    2017-12-19

    Excess dietary fructose intake associated with metabolic syndrome and insulin resistance and increased risk of developing type 2 diabetes. Previous animal studies have reported that diabetic animals have significantly impaired behavioural and cognitive functions, pathological synaptic function and impaired expression of glutamate receptors. Correction of the antioxidant status of laboratory rodents largely prevents the development of fructose-induced plurimetabolic changes in the nervous system. We suggest a novel concept of efficiency of Stevia leaves for treatment of central diabetic neuropathy. By in vivo extracellular studies induced spike activity of hippocampal neurons during high frequency stimulation of entorhinal cortex, as well as neurons of basolateral amygdala to high-frequency stimulation of the hippocampus effects of Stevia rebaudiana Bertoni plant evaluated in synaptic activity in the brain of fructose-enriched diet rats. In the conditions of metabolic disorders caused by fructose, antioxidant activity of Stevia rebaudiana was assessed by measuring the NOX activity of the hippocampus, amygdala and spinal cord. In this study, the characteristic features of the metabolic effects of dietary fructose on synaptic plasticity in hippocampal neurons and basolateral amygdala and the state of the NADPH oxidase (NOX) oxidative system of these brain formations are revealed, as well as the prospects for development of multitarget and polyfunctional phytopreparations (with adaptogenic, antioxidant, antidiabetic, nootropic activity) from native raw material of Stevia rebaudiana. Stevia modulates degree of expressiveness of potentiation/depression (approaches but fails to achieve the norm) by shifting the percentage balance in favor of depressor type of responses during high-frequency stimulation, indicating its adaptogenic role in plasticity of neural networks. Under the action of fructose an increase (3-5 times) in specific quantity of total fraction of NOX

  3. 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.

  4. Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases.

    Science.gov (United States)

    Moretti, Morgana; Fraga, Daiane Bittencourt; Rodrigues, Ana Lúcia S

    2017-12-01

    In this review, we summarize the involvement of ascorbic acid in neurodegenerative diseases by presenting available evidence on the behavioral and biochemical effects of this compound in animal models of neurodegeneration as well as the use of ascorbic acid as a therapeutic approach to alleviate neurodegenerative progression in clinical studies. Ascorbate, a reduced form of vitamin C, has gained interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. In the brain, ascorbate exerts neuromodulatory functions and scavenges reactive oxygen species generated during synaptic activity and neuronal metabolism. These are important properties as redox imbalance and abnormal protein aggregation constitute central mechanisms implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Indeed, several studies have indicated an association between low serum ascorbate concentrations and neurodegeneration. Moreover, ascorbic acid is a suitable candidate for supplying either antioxidant defense or modulation of neuronal and astrocytic metabolism under neurodegenerative conditions. Ascorbic acid acts mainly by decreasing oxidative stress and reducing the formation of protein aggregates, which may contribute to the reduction of cognitive and/or motor impairments observed in neurodegenerative processes. Although several studies support a possible role of ascorbic acid administration against neurodegeneration, more researches ar