WorldWideScience

Sample records for neurodegenerative disorder characterized

  1. Aquatherapy for neurodegenerative disorders.

    Science.gov (United States)

    Plecash, Alyson R; Leavitt, Blair R

    2014-01-01

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

  2. Autophagy and neurodegenerative disorders

    Institute of Scientific and Technical Information of China (English)

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

    2013-01-01

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

  3. The aging brain and neurodegenerative disorders

    International Nuclear Information System (INIS)

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

    1991-01-01

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

  4. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Science.gov (United States)

    Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

    2014-11-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  5. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Yasser Iturria-Medina

    2014-11-01

    Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  6. 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.

  7. Molecular diagnostics of neurodegenerative disorders.

    Science.gov (United States)

    Agrawal, Megha; Biswas, Abhijit

    2015-01-01

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

  8. Transmission of Neurodegenerative Disorders Through Blood Transfusion

    DEFF Research Database (Denmark)

    Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus

    2016-01-01

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

  9. 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.

  10. 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...

  11. 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

  12. Comparative Incidence of Conformational, Neurodegenerative Disorders

    Science.gov (United States)

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

    2015-01-01

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

  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. 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:

  15. 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.

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

    Science.gov (United States)

    Habibi, Laleh; Perry, George; Mahmoudi, Morteza

    2014-01-01

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

  17. 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.

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

    Science.gov (United States)

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

    2013-12-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  20. 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.

  1. 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

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

    Directory of Open Access Journals (Sweden)

    Hai-yang JIANG

    2017-10-01

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

  3. Neurodegenerative Disorders Treatment: The MicroRNA Role.

    Science.gov (United States)

    Ridolfi, Barbara; Abdel-Haq, Hanin

    2017-01-01

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

  4. 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

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    Sibongile R. Sibambo

    2009-06-01

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

  7. 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...

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

    Directory of Open Access Journals (Sweden)

    Ashok Verma

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    International Nuclear Information System (INIS)

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

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Paulo Victor Sgobbi de Souza

    2015-03-01

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

  12. 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.

  13. 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.

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

    Science.gov (United States)

    Luan, Hemi; Wang, Xian; Cai, Zongwei

    2017-11-12

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2011-09-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Heeok Hong

    2016-05-01

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

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

    DEFF Research Database (Denmark)

    Winge, Kristian

    2015-01-01

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

  2. Neurodegenerative Dementia

    International Nuclear Information System (INIS)

    Allard, Michelle

    2006-01-01

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

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

    Science.gov (United States)

    Apostolakis, Sotirios; Kypraiou, Anna-Maria

    2017-11-27

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

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

    Science.gov (United States)

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

    2017-08-16

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

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

    Directory of Open Access Journals (Sweden)

    Manju Tiwari

    2017-12-01

    Full Text Available Glucose 6 phosphate dehydrogenase (G6PD is a key and rate limiting enzyme in the pentose phosphate pathway (PPP. The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH. There are preponderance research findings that demonstrate the enzyme (G6PD role in the energy balance, and it is associated with blood-related diseases and disorders, primarily the anemia resulted from G6PD deficiency. The X-linked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe. Recent advancement in biology, more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders. The neuroprotective role of the enzyme (G6PD has also been established, as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species (ROS produced in cerebral ischemia. Though G6PD deficiency remains a global health issue, however, a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics. Here, in this study, more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia, thus providing diagnostic and therapeutic opportunities.

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

    Directory of Open Access Journals (Sweden)

    Ming Li

    2015-01-01

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

  7. Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

    Science.gov (United States)

    Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

    2018-01-01

    Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

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

    International Nuclear Information System (INIS)

    Kamei, Hidekazu

    1989-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-06-01

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

  10. 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.

  11. Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders.

    Science.gov (United States)

    Saniotis, Arthur; Henneberg, Maciej; Sawalma, Abdul-Rahman

    2018-01-01

    Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

  12. Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support.

    Science.gov (United States)

    Marsh, Samuel E; Blurton-Jones, Mathew

    2017-06-01

    Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease currently affect tens of millions of people worldwide. Unfortunately, as the world's population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. In this mini-review we will discuss recent work that examines the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. We will then also discuss some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Arthur Saniotis

    2018-03-01

    Full Text Available Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an “Endomyccorhizae like interface” (ELI nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

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

    Science.gov (United States)

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

    2007-01-01

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

  15. 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.

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

    Science.gov (United States)

    Taha, Masoumeh Fakhr

    2010-03-01

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

  17. Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders.

    Science.gov (United States)

    Meldrum, B

    1993-01-01

    The possibility that some acidic amino acids occurring naturally or as additives in the diet can act as excitotoxins producing central nervous system pathology has been the subject of extensive debate in the last 20 years and is here reviewed. High doses of glutamate, aspartate or related excitatory amino acids given in isolation to neonatal rodents produce acute degeneration organs. Neuropathology resulting from consumption of glutamate or aspartate has not been described in man. Various unusual amino acids of plant origin can produce acute excitotoxic syndromes. In man domoate (consumed in mussels that have fed on (Nitschia pungens) can produce an acute syndrome associated with limbic system lesions and anterograde amnesia. Kainate and domoate produce similar syndromes in rodents; acromelate produces spinal pathology. The mechanisms and manifestations of chronic excitotoxicity are less clearly established. A combination of impaired energy metabolism or impaired buffering of calcium and free radicals and endogenous or exogenous excitotoxins may contribute to neuronal loss in human neurodegenerative disorders.

  18. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

    Directory of Open Access Journals (Sweden)

    Alisia Carnemolla

    Full Text Available The heat shock response (HSR is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.

  19. Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

    Science.gov (United States)

    Goemaere, Julie; Knoops, Bernard

    2012-02-01

    Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

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

    Science.gov (United States)

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

    2015-08-18

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

  1. 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

  2. Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

    Science.gov (United States)

    Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

    2017-03-01

    Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

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

    Science.gov (United States)

    Letra, Liliana; Santana, Isabel

    2017-01-01

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

  4. An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders.

    Science.gov (United States)

    Yang, Yang; Jiang, Shuai; Yan, Juanjuan; Li, Yue; Xin, Zhenlong; Lin, Yan; Qu, Yan

    2015-02-01

    Recently, growing evidence has demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Adriana Covarrubias-Pinto

    2015-11-01

    Full Text Available Ascorbic acid is a key antioxidant of the Central Nervous System (CNS. Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders.

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

    KAUST Repository

    Bajic, Vladimir B.; Essack, Magbubah

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Maja Vulovic

    2018-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Min Li

    2018-01-01

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

  11. 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

  12. 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.

  13. Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Manuel E. Lopez

    2013-09-01

    Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

  14. 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.

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

    Science.gov (United States)

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

    2013-08-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  17. 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

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

    Science.gov (United States)

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

    2015-08-18

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

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

    Science.gov (United States)

    Ghosh, Arunava; Pahan, Kalipada

    2012-08-03

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

  20. 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.

  1. Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

    Czech Academy of Sciences Publication Activity Database

    Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 9-10 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

  2. 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.

  3. 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.

  4. 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.

  5. Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review

    Directory of Open Access Journals (Sweden)

    Fatemeh Ayoobi

    2017-06-01

    Full Text Available The Achillea millefolium L. (Yarrow is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and stroke.

  6. Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

    International Nuclear Information System (INIS)

    Yoshida, S.

    1999-01-01

    Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

  7. 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)

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

    Directory of Open Access Journals (Sweden)

    Francesca eCicchetti

    2014-07-01

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

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

    OpenAIRE

    Manju Tiwari

    2017-01-01

    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 f...

  10. Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

    OpenAIRE

    Risacher, Shannon L.; Saykin, Andrew J.

    2013-01-01

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

  11. 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. © Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society].

  12. Glutamate and Neurodegenerative Disease

    Science.gov (United States)

    Schaeffer, Eric; Duplantier, Allen

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

  13. 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.

  14. 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.

  15. Quantification of intermuscular and intramuscular adipose tissue using magnetic resonance imaging after neurodegenerative disorders

    Institute of Scientific and Technical Information of China (English)

    Madoka Ogawa; Robert Lester; Hiroshi Akima; Ashraf S. Gorgey

    2017-01-01

    Ectopic adiposity has gained considerable attention because of its tight association with metabolic and cardiovascular health in persons with spinal cord injury (SCI). Ectopic adiposity is characterized by the storage of adipose tissue in non-subcutaneous sites. Magnetic resonance imaging (MRI) has proven to be an effective tool in quantifying ectopic adiposity and provides the opportunity to measure different adipose depots including intermuscular adipose tissue (IMAT) and intramuscular adipose tissue (IntraMAT) or in-tramuscular fat (IMF). It is highly important to distinguish and clearly define these compartments, because controversy still exists on how to accurately quantify these adipose depots. Investigators have relied on separating muscle from fat pixels based on their characteristic signal intensities. A common technique is plotting a threshold histogram that clearly separates between muscle and fat peaks. The cut-offs to separate between muscle and fat peaks are still not clearly defined and different cut-offs have been identified. This review will outline and compare the Midpoint and Otsu techniques, two methods used to determine the threshold between muscle and fat pixels on T1 weighted MRI. The process of water/fat segmentation using the Dixon method will also be outlined. We are hopeful that this review will trigger more research towards accurately quantifying ectopic adiposity due to its high relevance to cardiometabolic health after SCI.

  16. Neuroregeneration in neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Mureşanu Dafin F

    2011-06-01

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

  17. 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

    2017-01-01

    Abstract 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 gene (Padjusted = 4.2 × 10−9, Padjusted = 4.7 × 10–9) at 14q22. The next best signal was in RELN gene (rs155333, Padjusted = 1.3 × 10–8) at 7q22, while the other variants at rs17458357 (Padjusted = 3.98 × 10–8), rs2572683 (Padjusted = 8.9 × 10–8), rs12555895 (Padjusted = 2.6 × 10–8), and rs3764030 (Padjusted = 9.4 × 10–8) were also statistically significant. The 7 SNPs were not associated with 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

  18. 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

  19. 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.

  20. 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.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

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

    OpenAIRE

    Silva, Juliana; Monge-Fuentes, Victoria; Gomes, Fl?via; Lopes, Kamila; dos Anjos, Lilian; Campos, Gabriel; Arenas, Claudia; Biolchi, Andr?ia; Gon?alves, Jacqueline; Galante, Priscilla; Campos, Leandro; Mortari, M?rcia

    2015-01-01

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for...

  3. 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.

  4. 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

  5. DNA damage in neurodegenerative diseases

    International Nuclear Information System (INIS)

    Coppedè, Fabio; Migliore, Lucia

    2015-01-01

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

  6. Curcumin and neurodegenerative diseases

    Science.gov (United States)

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

    2013-01-01

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

  7. 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.

  8. 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

  9. 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),

  10. Aptamer and its applications in neurodegenerative diseases.

    Science.gov (United States)

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

    2017-02-01

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

  11. The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis.

    Science.gov (United States)

    Leveugle, B; Spik, G; Perl, D P; Bouras, C; Fillit, H M; Hof, P R

    1994-07-04

    Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these

  12. 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.

  13. Essential Tremor: A Neurodegenerative Disease?

    Directory of Open Access Journals (Sweden)

    Julian Benito-Leon

    2014-07-01

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

  14. 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.

  15. 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

    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......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....... Conclusion: The developed algorithm was capable of scoring normal sleep with an accuracy around the manual inter-scorer reliability, it failed in accurately scoring abnormal sleep as encountered for the PD/MSA patients, which is due to the abnormal micro- and macrostructure pattern in these patients....

  16. When cytokinin, a plant hormone, meets the adenosine A2A receptor: a novel neuroprotectant and lead for treating neurodegenerative disorders?

    Directory of Open Access Journals (Sweden)

    Yi-Chao Lee

    Full Text Available 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 A(2A receptor (A(2A-R, which was blocked by an A(2A-R antagonist and a protein kinase A (PKA inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A(2A-R signaling event. Since the A(2A-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 A(2A-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 A(2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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

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

    Science.gov (United States)

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

    2013-01-01

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

  4. Excitatory amino acid neurotoxicity and neurodegenerative disease.

    Science.gov (United States)

    Meldrum, B; Garthwaite, J

    1990-09-01

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

  5. Olfactory memory impairment in neurodegenerative diseases.

    Science.gov (United States)

    Bahuleyan, Biju; Singh, Satendra

    2012-10-01

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

  6. Assisted delivery of antisense therapeutics in animal models of heritable neurodegenerative and neuromuscular disorders: a systematic review and meta-analysis.

    Science.gov (United States)

    van der Bent, M Leontien; Paulino da Silva Filho, Omar; van Luijk, Judith; Brock, Roland; Wansink, Derick G

    2018-03-08

    Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and patients. Success in the clinic is nevertheless still limited, due to unfavourable biodistribution and poor cellular uptake of AONs. Extensive research is currently being conducted into the formulation of AONs to improve delivery, but thus far there is no consensus on which of those strategies will be the most effective. This systematic review was designed to answer in an unbiased manner which delivery strategies most strongly enhance the efficacy of AONs in animal models of heritable neurodegenerative and neuromuscular diseases. In total, 95 primary studies met the predefined inclusion criteria. Study characteristics and data on biodistribution and toxicity were extracted and reporting quality and risk of bias were assessed. Twenty studies were eligible for meta-analysis. We found that even though the use of delivery systems provides an advantage over naked AONs, it is not yet possible to select the most promising strategies. Importantly, standardisation of experimental procedures is warranted in order to reach conclusions about the most efficient delivery strategies. Our best practice guidelines for future experiments serve as a step in that direction.

  7. Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection.

    Science.gov (United States)

    Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali

    2017-04-15

    Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression. Copyright © 2016. Published by Elsevier B.V.

  8. Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.

    Science.gov (United States)

    Niewiadomska-Cimicka, Anna; Krzyżosiak, Agnieszka; Ye, Tao; Podleśny-Drabiniok, Anna; Dembélé, Doulaye; Dollé, Pascal; Krężel, Wojciech

    2017-07-01

    Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e -5 ), cAMP (p = 4.5e -4 ), and calcium signaling (p = 3.4e -3 ). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

  9. Olfactory Memory Impairment in Neurodegenerative Diseases

    OpenAIRE

    Bahuleyan, Biju; Singh, Satendra

    2012-01-01

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

  10. 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.

  11. Progranulin in neurodegenerative disease.

    Science.gov (United States)

    Petkau, Terri L; Leavitt, Blair R

    2014-07-01

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

  12. 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

  13. Molecular characterization of WFS1 in patients with Wolfram syndrome

    NARCIS (Netherlands)

    Van den Ouweland, JMW; Cryns, K; Pennings, RJE; Walraven, [No Value; Janssen, GMC; Maassen, JA; Veldhuijzen, BFE; Arntzenius, AB; Lindhout, D; Cremers, CWRJ; Van Camp, G; Dikkeschei, LD

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  14. Molecular characterization of WFS1 in patients with Wolfram syndrome.

    NARCIS (Netherlands)

    Ouweland, J.M.W. van den; Cryns, K.; Pennings, R.J.E.; Walraven, I.; Janssen, G.M.; Maassen, J.A.; Veldhuijzen, B.F.; Arntzenius, A.B.; Lindhout, D.; Cremers, C.W.R.J.; Camp, G. van; Dikkeschei, L.D.

    2003-01-01

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  15. Nutraceutical Potential of Phenolics from ′Brava′ and ′Mansa′ Extra-Virgin Olive Oils on the Inhibition of Enzymes Associated to Neurodegenerative Disorders in Comparison with Those of ′Picual′ and ′Cornicabra′

    Directory of Open Access Journals (Sweden)

    María Figueiredo-González

    2018-03-01

    Full Text Available The increasing interest in the Mediterranean diet is based on the protective effects against several diseases, including neurodegenerative disorders. Polyphenol-rich functional foods have been proposed to be unique supplementary and nutraceutical treatments for these disorders. Extra-virgin olive oils (EVOOs obtained from ′Brava′ and ′Mansa′, varieties recently identified from Galicia (northwestern Spain, were selected for in vitro screening to evaluate their capacity to inhibit key enzymes involved in Alzheimer′s disease (AD (acetylcholinesterase (AChE, butyrylcholinesterase (BuChE and 5-lipoxygenase (5-LOX, major depressive disorder (MDD and Parkinson′s disease (PD (monoamine oxidases: hMAO-A and hMAO-B respectively. ′Brava′ oil exhibited the best inhibitory activity against all enzymes, when they are compared to ′Mansa′ oil: BuChE (IC50 = 245 ± 5 and 591 ± 23 mg·mL−1, 5-LOX (IC50 = 45 ± 7 and 106 ± 14 mg·mL−1, hMAO-A (IC50 = 30 ± 1 and 72 ± 10 mg·mL−1 and hMAO-B (IC50 = 191 ± 8 and 208 ± 14 mg·mL−1, respectively. The inhibitory capacity of the phenolic extracts could be associated with the content of secoiridoids, lignans and phenolic acids.

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

    Science.gov (United States)

    Liu, Ying; Deng, Wenbin

    2016-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Elżbieta Miller

    2014-01-01

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

  18. 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.

  19. Control and characterization of spatio-temporal disorder in ...

    Indian Academy of Sciences (India)

    characterizing the type of spatio-temporal disorder that is embodied in this disordered ... The results from this experiment will shed light on the more general questions ... sponds to only odd or even multiples of the common frequency, ω0. Thus ...

  20. Convergent molecular defects underpin diverse neurodegenerative diseases.

    Science.gov (United States)

    Tofaris, George K; Buckley, Noel J

    2018-02-19

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

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

    Science.gov (United States)

    Fusari, A; Molina, J A

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

  2. 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.

  3. Amyloid PET in neurodegenerative diseases with dementia.

    Science.gov (United States)

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

    2018-05-15

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

  4. 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

  5. Role of sigma-1 receptors in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Linda Nguyen

    2015-01-01

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

  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. Comorbidity between obsessive-compulsive disorder and body dysmorphic disorder: prevalence, explanatory theories, and clinical characterization

    Directory of Open Access Journals (Sweden)

    Frías Á

    2015-08-01

    Full Text Available Álvaro Frías,1,2 Carol Palma,1,2 Núria Farriols,1,2 Laura González2 1FPCEE Blanquerna, Universitat Ramon Llull, Barcelona, 2Adult Outpatient Mental Health Center, Hospital de Mataró – CSdM, Mataró, Spain Background: With the advent of the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, body dysmorphic disorder (BDD has been subsumed into the obsessive-compulsive disorders and related disorders (OCDRD category. Objective: We aimed to determine the empirical evidence regarding the potential relationship between BDD and obsessive-compulsive disorder (OCD based on the prevalence data, etiopathogenic pathways, and clinical characterization of patients with both disorders. Method: A comprehensive search of databases (PubMed and PsycINFO was performed. Published manuscripts between 1985 and May 2015 were identified. Overall, 53 studies fulfilled inclusion criteria. Results: Lifetime comorbidity rates of BDD–OCD are almost three times higher in samples with a primary diagnosis of BDD than those with primary OCD (27.5% vs 10.4%. However, other mental disorders, such as social phobia or major mood depression, are more likely among both types of psychiatric samples. Empirical evidence regarding the etiopathogenic pathways for BDD–OCD comorbidity is still inconclusive, whether concerning common shared features or one disorder as a risk factor for the other. Specifically, current findings concerning third variables show more divergences than similarities when comparing both disorders. Preliminary data on the clinical characterization of the patients with BDD and OCD indicate that the deleterious clinical impact of BDD in OCD patients is greater than vice versa. Conclusion: Despite the recent inclusion of BDD within the OCDRD, data from comparative studies between BDD and OCD need further evidence for supporting this nosological approach. To better define this issue, comparative studies between BDD, OCD, and social phobia

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Indian Academy of Sciences (India)

    2012-06-25

    Jun 25, 2012 ... clearly suggests that the shape of DNA is the determining factor in the cellular function. FRDA is the only ..... SCA VII. CAG. 4–35. 28–35. 37 –200. SBMA. CAG. 15–31. –. 40–62 ... production of Frataxin (Babcock et al. 1997).

  11. Skin disorders in Parkinson's disease

    DEFF Research Database (Denmark)

    Ravn, Astrid-Helene; Thyssen, Jacob P; Egeberg, Alexander

    2017-01-01

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by a symptom triad comprising resting tremor, rigidity, and akinesia. In addition, non-motor symptoms of PD are well recognized and often precede the overt motor manifestations. Cutaneous manifestations...

  12. Comorbidity between obsessive-compulsive disorder and body dysmorphic disorder: prevalence, explanatory theories, and clinical characterization

    Science.gov (United States)

    Frías, Álvaro; Palma, Carol; Farriols, Núria; González, Laura

    2015-01-01

    Background With the advent of the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, body dysmorphic disorder (BDD) has been subsumed into the obsessive-compulsive disorders and related disorders (OCDRD) category. Objective We aimed to determine the empirical evidence regarding the potential relationship between BDD and obsessive-compulsive disorder (OCD) based on the prevalence data, etiopathogenic pathways, and clinical characterization of patients with both disorders. Method A comprehensive search of databases (PubMed and PsycINFO) was performed. Published manuscripts between 1985 and May 2015 were identified. Overall, 53 studies fulfilled inclusion criteria. Results Lifetime comorbidity rates of BDD–OCD are almost three times higher in samples with a primary diagnosis of BDD than those with primary OCD (27.5% vs 10.4%). However, other mental disorders, such as social phobia or major mood depression, are more likely among both types of psychiatric samples. Empirical evidence regarding the etiopathogenic pathways for BDD–OCD comorbidity is still inconclusive, whether concerning common shared features or one disorder as a risk factor for the other. Specifically, current findings concerning third variables show more divergences than similarities when comparing both disorders. Preliminary data on the clinical characterization of the patients with BDD and OCD indicate that the deleterious clinical impact of BDD in OCD patients is greater than vice versa. Conclusion Despite the recent inclusion of BDD within the OCDRD, data from comparative studies between BDD and OCD need further evidence for supporting this nosological approach. To better define this issue, comparative studies between BDD, OCD, and social phobia should be carried out. PMID:26345330

  13. 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.

  14. [How to characterize and treat sleep complaints in bipolar disorders?

    Science.gov (United States)

    Geoffroy, P A; Micoulaud Franchi, J-A; Lopez, R; Poirot, I; Brion, A; Royant-Parola, S; Etain, B

    2017-08-01

    Sleep complaints are very common in bipolar disorders (BD) both during acute phases (manic and depressive episodes) and remission (about 80 % of patients with remitted BD have poor sleep quality). Sleep complaints during remission are of particular importance since they are associated with more mood relapses and worse outcomes. In this context, this review discusses the characterization and treatment of sleep complaints in BD. We examined the international scientific literature in June 2016 and performed a literature search with PubMed electronic database using the following headings: "bipolar disorder" and ("sleep" or "insomnia" or "hypersomnia" or "circadian" or "apnoea" or "apnea" or "restless legs"). Patients with BD suffer from sleep and circadian rhythm abnormalities during major depressive episodes (insomnia or hypersomnia, nightmares, nocturnal and/or early awakenings, non-restorative sleep) and manic episodes (insomnia, decreased need for sleep without fatigue), but also some of these abnormalities may persist during remission. These remission phases are characterized by a reduced quality and quantity of sleep, with a longer sleep duration, increased sleep latency, a lengthening of the wake time after sleep onset (WASO), a decrease of sleep efficiency, and greater variability in sleep/wake rhythms. Patients also present frequent sleep comorbidities: chronic insomnia, sleepiness, sleep phase delay syndrome, obstructive sleep apnea/hypopnea syndrome (OSAHS), and restless legs syndrome (RLS). These disorders are insufficiently diagnosed and treated whereas they are associated with mood relapses, treatment resistance, affect cognitive global functioning, reduce the quality of life, and contribute to weight gain or metabolic syndrome. Sleep and circadian rhythm abnormalities have been also associated with suicidal behaviors. Therefore, a clinical exploration with characterization of these abnormalities and disorders is essential. This exploration should be

  15. Characterizing somatization, hypochondriasis, and hysteria in the borderline personality disorder.

    Science.gov (United States)

    Snyder, S; Pitts, W M

    1986-03-01

    Somatization, hypochondriasis, and hysteria have often been considered as associated features of the borderline personality disorder. This study was designed to characterize these three syndromes in the borderline patient. Inpatients with DSM-III borderline personality disorder were compared with controls with dysthymic disorder. Scales and items from standardized rating instruments which measured the three syndromes were scored and compared between groups. Although the hysteria-obvious and hypochondriasis scales of the MMPI and the Hamilton Depression Scale item measuring hypochondriasis were elevated in the borderline group, there were no significant differences between groups. Scores of dysthymic patients significantly exceeded those of borderline patients on four of five MMPI codetypes measuring the three syndromes. Findings are discussed in light of previous psychodynamic, empirical, and research literature.

  16. 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

  17. 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.

  18. Chameleon sequences in neurodegenerative diseases

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  19. 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.

  20. 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.)

  1. 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.

  2. REM sleep behavior disorder in Parkinson′s disease: A case from India confirmed with polysomnographic data

    Directory of Open Access Journals (Sweden)

    Ravi Gupta

    2013-01-01

    Full Text Available Rapid eye movement (REM sleep behavior disorder is a condition characterized by dream enactment. This condition may accompany neurodegenerative disorders. However, only a few reports from India are available, that too, without any polysomnographic evidence. We are reporting a case of REM sleep behavior disorder with polysomnographic evidence.

  3. 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.

  4. [Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal].

    Science.gov (United States)

    Gomes, Tiago; Guimaraes, Joana; Leão, Miguel

    2017-06-30

    In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

  5. Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal

    Directory of Open Access Journals (Sweden)

    Tiago Gomes

    2017-06-01

    Full Text Available In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

  6. LSTM for diagnosis of neurodegenerative diseases using gait data

    Science.gov (United States)

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

    2018-04-01

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

  7. Cerebral correlates of psychotic syndromes in neurodegenerative diseases

    OpenAIRE

    Jellinger, Kurt A

    2012-01-01

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

  8. Cerebral correlates of psychotic syndromes in neurodegenerative diseases.

    Science.gov (United States)

    Jellinger, Kurt A

    2012-05-01

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

  9. Role of Ionizing Radiation in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Neel K. Sharma

    2018-05-01

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

  10. Role of Ionizing Radiation in Neurodegenerative Diseases

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

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

    2007-11-01

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

  12. Protection against neurodegenerative disease on Earth and in space

    Science.gov (United States)

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

    2016-01-01

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

  13. Electroencephalographic characterization of subgroups of children with learning disorders.

    Directory of Open Access Journals (Sweden)

    Milene Roca-Stappung

    Full Text Available Electroencephalographic alterations have been reported in subjects with learning disorders, but there is no consensus on what characterizes their electroencephalogram findings. Our objective was to determine if there were subgroups within a group of scholars with not otherwise specified learning disorders and if they had specific electroencephalographic patterns. Eighty-five subjects (31 female, 8-11 years who scored low in at least two subscales -reading, writing and arithmetic- of the Infant Neuropsychological Evaluation were included. Electroencephalograms were recorded in 19 leads during rest with eyes closed; absolute power was obtained every 0.39 Hz. Three subgroups were formed according to children's performance: Group 1 (G1, higher scores than Group 2 in reading speed and reading and writing accuracy, Group 2 (G2, better performance than G1 in composition and Group 3 (G3, lower scores than Groups 1 and 2 in the three subscales. G3 had higher absolute power in frequencies in the delta and theta range at left frontotemporal sites than G1 and G2. G2 had higher absolute power within alpha frequencies than G3 and G1 at the left occipital site. G3 had higher absolute power in frequencies in the beta range than G1 in parietotemporal areas and than G2 in left frontopolar and temporal sites. G1 had higher absolute power within beta frequencies than G2 in the left frontopolar site. G3 had lower gamma absolute power values than the other groups in the left hemisphere, and gamma activity was higher in G1 than in G2 in frontopolar and temporal areas. This group of children with learning disorders is very heterogeneous. Three subgroups were found with different cognitive profiles, as well as a different electroencephalographic pattern. It is important to consider these differences when planning interventions for children with learning disorders.

  14. Nanobiomaterials' applications in neurodegenerative diseases.

    Science.gov (United States)

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

    2017-02-01

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

  15. Mapping Neurodegenerative Disease Onset and Progression.

    Science.gov (United States)

    Seeley, William W

    2017-08-01

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

  16. Computed tomography of neurodegenerative disease in childhood

    International Nuclear Information System (INIS)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jocelyn M Madeira

    2015-01-01

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

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

    Science.gov (United States)

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

    2017-12-10

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

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

    OpenAIRE

    Melki, Ronald

    2015-01-01

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

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

    Science.gov (United States)

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

    2018-04-03

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

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

    Science.gov (United States)

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

    2018-01-01

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

  2. 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

  3. Mechanical characterization of disordered and anisotropic cellular monolayers

    Science.gov (United States)

    Nestor-Bergmann, Alexander; Johns, Emma; Woolner, Sarah; Jensen, Oliver E.

    2018-05-01

    We consider a cellular monolayer, described using a vertex-based model, for which cells form a spatially disordered array of convex polygons that tile the plane. Equilibrium cell configurations are assumed to minimize a global energy defined in terms of cell areas and perimeters; energy is dissipated via dynamic area and length changes, as well as cell neighbor exchanges. The model captures our observations of an epithelium from a Xenopus embryo showing that uniaxial stretching induces spatial ordering, with cells under net tension (compression) tending to align with (against) the direction of stretch, but with the stress remaining heterogeneous at the single-cell level. We use the vertex model to derive the linearized relation between tissue-level stress, strain, and strain rate about a deformed base state, which can be used to characterize the tissue's anisotropic mechanical properties; expressions for viscoelastic tissue moduli are given as direct sums over cells. When the base state is isotropic, the model predicts that tissue properties can be tuned to a regime with high elastic shear resistance but low resistance to area changes, or vice versa.

  4. Implications of glial nitric oxyde in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jose Enrique eYuste

    2015-08-01

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

  5. 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:

  6. Autonomic Function in Neurodegenerative Diseases

    DEFF Research Database (Denmark)

    Sørensen, Gertrud Laura; Jennum, Poul Jørgen

    2013-01-01

    areas, which is consistent with the Braak hypothesis. In the narcolepsy patients, it was shown that a reduced HRR to arousals was primarily predicted by hypocretin deficiency in both rapid-eye-movement (REM) and non-REM sleep, independent of cataplexy and other factors. The results confirm...... that hypocretin deficiency affects the autonomic nervous system of patients with narcolepsy and that the hypocretin system is important for proper heart rate modulation at rest.Furthermore, it was shown that hypocretin deficiency and cataplexy are associated with signs of destabilized sleep-wake and REM sleep...... 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...

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

    Science.gov (United States)

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

    2017-01-01

    neurodegenerative diseases and neurotrauma. However, other applications in proteomics such as "individual" proteome sequencing with its signature PTMs, have not been fully investigated as compared to the achievements in the genomics discipline This infers that proteomics research work has promising potential, yet to be discovered, in the precision medicine and comprises a major component of the personalized medicine infrastructure as it allows individual characterization of disease at the protein level. To conclude, the field of proteomics-based personalized medicine is still in its infancy compared to genomics field due to several technical and instrumentation-based obstacles; however, we anticipate to have this initiative leading in the coming future. This chapter will discuss briefly how neuroproteomics can impact personalized medicine in the fields of neurodegenerative disorders particularly in Alzheimer's disease and brain injury .

  8. A novel NREM and REM parasomnia with sleep breathing disorder associated with antibodies against IgLON5: a case series, pathological features, and characterization of the antigen

    Science.gov (United States)

    Sabater, Lidia; Gaig, Carles; Gelpi, Ellen; Bataller, Luis; Lewerenz, Jan; Torres-Vega, Estefanía; Contreras, Angeles; Giometto, Bruno; Compta, Yaroslau; Embid, Cristina; Vilaseca, Isabel; Iranzo, Alex; Santamaría, Joan; Dalmau, Josep; Graus, Francesc

    2014-01-01

    Summary Background Autoimmunity may be involved in sleep and neurodegenerative disorders. We aimed to describe a neurological syndrome with prominent sleep dysfunction and antibodies to a previously unknown neuronal antigen. Methods In this observational study, clinical and video-polysomnography (V- PSG) investigations identified a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic University of Barcelona for abnormal sleep behaviors and obstructive sleep apnea(OSA). They had antibodies against a neuronal surface antigen also present in five additional patients referred to our laboratory for antibody studies. These five patients had been evaluated with PSG and in two, the study was done or reviewed in our Sleep Unit. Two patients underwent postmortem brain examination. Immunoprecipitation and mass spectrometry were used to characterize the antigen and to develop a diagnostic test. Serum or CSF from 285 patients with neurodegenerative, sleep, or autoimmune disorders served as controls. Findings All eight patients (five women; range: 52–76 years, median 59) had abnormal sleep movements and behaviors and OSA confirmed by PSG. Six patients had a chronic evolution (range 2–12 years, median 5.5); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability, and followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid evolution with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died two and six months after symptom onset. In 5/5 patients, the V-PSG reviewed in our Unit disclosed OSA, stridor, and abnormal sleep architecture with undifferentiated NREM sleep or poorly structured stage N2 with simple movements and finalistic behaviors, normalization of NREM sleep by the end of the night, and REM sleep behavior disorder. Four/4 patients carried the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4

  9. 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.

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

    Science.gov (United States)

    Ita, Kevin

    2017-06-01

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

  11. Role of agmatine in neurodegenerative diseases and epilepsy.

    Science.gov (United States)

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

    2014-06-01

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

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Science.gov (United States)

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

    2018-03-01

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

  14. Characterizing Sleep in Adolescents and Adults with Autism Spectrum Disorders

    Science.gov (United States)

    Goldman, S. E.; Alder, M. L.; Burgess, H. J.; Corbett, B. A.; Hundley, R.; Wofford, D.; Fawkes, D. B.; Wang, L.; Laudenslager, M. L.; Malow, B. A.

    2017-01-01

    We studied 28 adolescents/young adults with autism spectrum disorders (ASD) and 13 age/sex matched individuals of typical development (TD). Structured sleep histories, validated questionnaires, actigraphy (4 weeks), and salivary cortisol and melatonin (4 days each) were collected. Compared to those with TD, adolescents/young adults with ASD had…

  15. Congo red and protein aggregation in neurodegenerative diseases.

    Science.gov (United States)

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

    2007-01-01

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

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

    Science.gov (United States)

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

    2016-11-01

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

  17. The role of lipid nanoparticles and its surface modification in reaching the brain: an approach for neurodegenerative diseases treatment.

    Science.gov (United States)

    Pedraz, Jose Luis; Igartua, Manoli; Maria, Rosa; Hernando, Sara

    2018-05-09

    Nanomedicine is a field of science that employs materials in the nanometer scale. Specifically, the use of nanoparticles (NPs) has some medical applications due to their structure, for example, the ability to cross the biological barriers, and their effectiveness avoiding some drug delivery problems. Because of that, in the last years, the use of NPs has been raised as a workable solution for neurodegenerative diseases (ND) treatment [1,2]. NDs are characterized by a continuous structural and functional neuronal loss, usually correlated with neuronal death. Between NDs, Alzheimer disease (AD) and Parkinson's disease (PD) are the most common disorders worldwide, becoming a serious economic burden and public health problem [3]. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. 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.

  19. SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling.

    Science.gov (United States)

    Shahid, Mohammad; Shahzad Cheema, Muhammad; Klenner, Alexander; Younesi, Erfan; Hofmann-Apitius, Martin

    2013-03-01

    Systems pharmacological modeling of drug mode of action for the next generation of multitarget drugs may open new routes for drug design and discovery. Computational methods are widely used in this context amongst which support vector machines (SVM) have proven successful in addressing the challenge of classifying drugs with similar features. We have applied a variety of such SVM-based approaches, namely SVM-based recursive feature elimination (SVM-RFE). We use the approach to predict the pharmacological properties of drugs widely used against complex neurodegenerative disorders (NDD) and to build an in-silico computational model for the binary classification of NDD drugs from other drugs. Application of an SVM-RFE model to a set of drugs successfully classified NDD drugs from non-NDD drugs and resulted in overall accuracy of ∼80 % with 10 fold cross validation using 40 top ranked molecular descriptors selected out of total 314 descriptors. Moreover, SVM-RFE method outperformed linear discriminant analysis (LDA) based feature selection and classification. The model reduced the multidimensional descriptors space of drugs dramatically and predicted NDD drugs with high accuracy, while avoiding over fitting. Based on these results, NDD-specific focused libraries of drug-like compounds can be designed and existing NDD-specific drugs can be characterized by a well-characterized set of molecular descriptors. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum.

    Science.gov (United States)

    Van Rheenen, T E; Lewandowski, K E; Tan, E J; Ospina, L H; Ongur, D; Neill, E; Gurvich, C; Pantelis, C; Malhotra, A K; Rossell, S L; Burdick, K E

    2017-07-01

    Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive subgroups emerging from within each of these nosological categories uphold group-average findings. We addressed this by identifying cognitive subgroups in large samples of SZ and BD patients independently, and comparing their cognitive profiles. The utility of a cross-diagnostic clustering approach to understanding cognitive heterogeneity in these patients was also explored. Hierarchical clustering analyses were conducted using cognitive data from 1541 participants (SZ n = 564, BD n = 402, healthy control n = 575). Three qualitatively and quantitatively similar clusters emerged within each clinical group: a severely impaired cluster, a mild-moderately impaired cluster and a relatively intact cognitive cluster. A cross-diagnostic clustering solution also resulted in three subgroups and was superior in reducing cognitive heterogeneity compared with disorder clustering independently. Quantitative SZ-BD cognitive differences commonly seen using group averages did not hold when cognitive heterogeneity was factored into our sample. Members of each corresponding subgroup, irrespective of diagnosis, might be manifesting the outcome of differences in shared cognitive risk factors.

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

    Directory of Open Access Journals (Sweden)

    Antonio Martin

    2011-01-01

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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    Masaaki Akagi

    2015-02-01

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

  4. Methods for the prognosus and suagnosis of neurodegenerative diseases

    OpenAIRE

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2018-02-12

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

  6. Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Tarozzi

    2013-01-01

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

  7. Characterization of primary cutaneous CD8+/CD30+ lymphoproliferative disorders.

    Science.gov (United States)

    Martires, Kathryn J; Ra, Seong; Abdulla, Farah; Cassarino, David S

    2015-11-01

    CD30 primary cutaneous lymphoproliferative diseases include both lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (PCALCL). The neoplastic cell of most primary CD30 lymphoproliferative disorders is CD4 positive. The terminology LyP "type D" has been used to describe a growing number of cases of LyP with a predominantly CD8 infiltrate. PCALCL with a CD8 phenotype has also been described, which presents a particularly difficult diagnostic and management challenge, given the difficulty in distinguishing it histologically from other cytotoxic lymphomas such as primary cutaneous aggressive epidermotropic CD8 cytotoxic T-cell lymphoma and CD8 gamma/delta and natural killer/T-cell lymphoma. We report 7 additional cases of these rare cutaneous CD8/CD30 lymphoproliferative disorders. We also present a unique case of CD8/CD30 LyP with histologic similarities to LyP type B. In all 7 of our cases of CD8 LyP and CD8 anaplastic large cell lymphoma, we found focal to diffuse MUM-1 positivity. We propose that MUM-1 may represent an adjunctive marker for CD8 lymphoproliferative disease. Finally, we review the current literature on cases of CD8 LyP and PCALCL. For the 106 cases examined, we found similar clinical and histologic features to those reported for traditional CD4CD30 LyP and PCALCL.

  8. Growth and characterization of GaInP unicompositional disorder-order-disorder quantum wells

    International Nuclear Information System (INIS)

    Schneider, R.P. Jr.; Jones, E.D.; Follstaedt, D.M.

    1994-01-01

    Metalorganic vapor phase epitaxy (MOVPE) is used to grow unicompositional quantum-well (QW) structures, in which the QW and barrier layers are composed of ordered and disordered GaInP, respectively. Transmission electron dark-field micrographs reveal abrupt interfaces between highly ordered QWs and disordered barriers, with no evidence of defect formation. Low-temperature photoluminescence from the structures exhibits relatively broad emission peaks, with emission energy increasing with decreasing QW thickness. The dependence of emission energy on well thickness can be described by a finite square well model only when a type-II band alignment is taken for the heterostructure, in which the conduction band edge of the ordered GaInP QW lies about 135--150 meV below that of the disordered barrier material. These results demonstrate a high degree of control over the ordering process in MOVPE, such that quantum size effects can be realized solely through disorder-order phenomena. Further, the data provide strong support for a type-II (spatially indirect) recombination transition between ordered and disordered GaInP

  9. Higher-level gait disorders: an open frontier.

    Science.gov (United States)

    Nutt, John G

    2013-09-15

    The term higher-level gait disorders (HLGD) defines a category of balance and gait disorders that are not explained by deficits in strength, tone, sensation, or coordination. HLGD are characterized by various combinations of disequilibrium and impaired locomotion. A plethora of new imaging techniques are beginning to determine the neural circuits that are the basis of these disorders. Although a variety of neurodegenerative and other pathologies can produce HLGD, the most common cause appears to be microvascular disease that causes white-matter lesions and thereby disrupts balance/locomotor circuits. © 2013 Movement Disorder Society.

  10. 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.

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  12. Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders.

    Science.gov (United States)

    Parker, E I; Xing, M; Moreno-De-Luca, A; Harmouche, E; Terk, M R

    2014-01-01

    Lysosomal storage diseases (LSDs) are a large group of genetic metabolic disorders that result in the accumulation of abnormal material, such as mucopolysaccharides, glycoproteins, amino acids and lipids, within cells. Since many LSDs manifest during infancy or early childhood, with potentially devastating consequences if left untreated, timely identification is imperative to prevent irreversible damage and early death. In this review, the key imaging features of the non-lipid or extralipid LSDs are examined and correlated with salient clinical manifestations and genetic information. Disorders are stratified based on the type of excess material causing tissue or organ dysfunction, with descriptions of the mucopolysaccharidoses, mucolipidoses, alpha-mannosidosis, glycogen storage disorder II and cystinosis. In addition, similarities and differences in radiological findings between each of these LSDs are highlighted to facilitate further recognition. Given the rare and extensive nature of the LSDs, mastery of their multiple clinical and radiological traits may seem challenging. However, an understanding of the distinguishing imaging characteristics of LSDs and their clinical correlates may allow radiologists to play a key role in the early diagnosis of these progressive and potentially fatal disorders.

  13. Characterizing the Use of Telepsychiatry for Patients with Opioid Use Disorder and Cooccurring Mental Health Disorders in Ontario, Canada

    Directory of Open Access Journals (Sweden)

    Brittanie LaBelle

    2018-01-01

    Full Text Available Rural patients with opioid use disorder (OUD face a variety of barriers when accessing opioid agonist therapy (OAT and psychiatric services, due to the limited supply of physicians and the vast geographic area. The telemedicine allows for contact between patients and their physician—regardless of physical distance. Objective. We characterize the usage of telemedicine to deliver psychiatric services to patients with OUD in Ontario, as well as traits of treatment-seeking patients with opioid dependence and concurrent psychiatric disorders. Methodology. A retrospective cohort study was conducted using an administrative database for patients who received psychiatric services via telemedicine between 2008 and 2014 and who also had OUD. Results. We identified 9,077 patients with concurrent opioid use and other mental health disorders who had received psychiatric services via telemedicine from 2008 to 2014; 7,109 (78.3% patients lived in Southern Ontario and 1,968 (21.7% in Northern Ontario. Telemedicine was used more frequently to provide mental health services to patients residing in Northern Ontario than Southern Ontario. Conclusion. Telemedicine is increasingly being utilized throughout Ontario for delivering mental health treatment. There is an opportunity to increase access to psychiatric services for patients with opioid dependence and concurrent psychiatric disorders through the use of the telemedicine.

  14. Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

    Science.gov (United States)

    Thurm, Audrey; Himelstein, Daniel; DʼSouza, Precilla; Rennert, Owen; Jiang, Susanqi; Olatunji, Damilola; Longo, Nicola; Pasquali, Marzia; Swedo, Susan; Salomons, Gajja S; Carrillo, Nuria

    2016-05-01

    Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders. Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability. We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD. Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

  15. Posttraumatic Stress Disorder: Structural Characterization with 3-T MR Imaging.

    Science.gov (United States)

    Li, Shiguang; Huang, Xiaoqi; Li, Lingjiang; Du, Fei; Li, Jing; Bi, Feng; Lui, Su; Turner, Jessica A; Sweeney, John A; Gong, Qiyong

    2016-08-01

    Purpose To explore cerebral alterations related to the emergence of posttraumatic stress disorder (PTSD) by using three-dimensional T1-weighted imaging and also to explore the relationship of gray and white matter abnormalities and the anatomic changes with clinical severity and duration of time since the trauma. Materials and Methods Informed consent was provided, and the prospective study was approved by the ethics committee of the West China Hospital. Recruited were 67 patients with PTSD and 78 adult survivors without PTSD 7-15 months after a devastating earthquake in western China. All participants underwent magnetic resonance (MR) imaging with a 3-T imager to obtain anatomic images. Cortical thickness and volumes of 14 subcortical gray matter structures and five subregions of the corpus callosum were analyzed with software. Statistical differences between patients with PTSD and healthy survivors were evaluated with a general linear model. Averaged data from the regions with volumetric or cortical thickness differences between groups were extracted in each individual to examine correlations between morphometric measures and clinical profiles. Results Patients with PTSD showed greater cortical thickness in the right superior temporal gyrus, inferior parietal lobule, and left precuneus (P PTSD severity was positively correlated with cortical thickness in the left precuneus (r = 0.332; P = .008). The volumes of posterior corpus callosum were negatively correlated with PTSD ratings in all survivors (r = -0.210; P = .013) and with cortical thickness of the left precuneus in patients with PTSD (r = -0.302; P = .017). Conclusion Results indicate that patients with PTSD had alterations in both cerebral gray matter and white matter compared with individuals who experienced similar psychologic trauma from the same stressor. Importantly, early in the course of PTSD, gray matter changes were in the form of increased, not decreased, cortical thickness, which may have

  16. Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications

    Science.gov (United States)

    Santamaría-García, Hernando; Santangelo, Gabriella

    2018-01-01

    Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM), emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs), most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients' management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD), or may emerge during the disease course as critical aspects, such as for Parkinson's and Alzheimer's diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients' well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits. PMID:29854017

  17. Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Foteini Christidi

    2018-01-01

    Full Text Available Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM, emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs, most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients’ management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD, or may emerge during the disease course as critical aspects, such as for Parkinson’s and Alzheimer’s diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients’ well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits.

  18. Characterization of Motor Control in Handwriting Difficulties in Children with or without Developmental Coordination Disorder

    Science.gov (United States)

    Chang, Shao-Hsia; Yu, Nan-Ying

    2010-01-01

    Aim: The purpose of this study was to characterize handwriting deficits in children with developmental coordination disorder (DCD) using computerized movement analyses. Method: Seventy-two children (40 females, 32 males; mean age 7y, SD 7mo; range 6y 2mo to 7y 11mo) with handwriting deficits (33 with DCD, 39 without DCD); and 22 age- and…

  19. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Federica Ciregia

    2017-08-01

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

  20. 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.

  1. TRPM2, calcium and neurodegenerative diseases

    Science.gov (United States)

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

    2010-01-01

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

  2. 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.

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

    Science.gov (United States)

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

    2014-09-15

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

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

    Science.gov (United States)

    Dodge, James C

    2017-01-01

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

  5. 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.

  6. 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.

  7. 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

    in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given...

  8. 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...

  9. Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction

    National Research Council Canada - National Science Library

    Bambrick, Linda L

    2007-01-01

    This research program will determine whether accelerated neuron death due to increased oxidative stress resulting from mitochondrial dysfunction can be compensated or corrected by neurotrophin stimulation...

  10. Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction

    National Research Council Canada - National Science Library

    Bambrick, Linda L

    2006-01-01

    This research program will determine whether accelerated neuron death due to increased oxidative stress resulting from mitochondrial dysfunction can be compensated or corrected by neurotrophin stimulation...

  11. Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction

    National Research Council Canada - National Science Library

    Bambrick, Linda L

    2004-01-01

    This research program will determine whether accelerated neuron death due to increased oxidative stress resulting from mitochondrial dysfunction can be compensated or corrected by neurotrophin stimulation...

  12. Neurotrophin Therapy of Neurodegenerative Disorders With Mitochondrial Dysfunction

    National Research Council Canada - National Science Library

    Bambrick, Linda L

    2005-01-01

    This research program will determine whether accelerated neuron death due to increased oxidative stress resulting from mitochondrial dysfunction can be compensated or corrected by neurotrophin stimulation...

  13. Characterizing adult attention-deficit/hyperactivity-disorder and comorbid borderline personality disorder: ADHD symptoms, psychopathology, cognitive functioning and psychosocial factors.

    Science.gov (United States)

    O'Malley, G K; McHugh, L; Mac Giollabhui, N; Bramham, J

    2016-01-01

    To characterize adults with comorbid attention-deficit/hyperactivity-disorder (ADHD) and borderline personality disorder (BPD) with regard to ADHD symptoms, psychopathology, cognitive functioning and psychosocial factors. A between-group design compared a group of individuals diagnosed with ADHD (n=40) with a group diagnosed with BPD and who also met the criteria for ADHD (ADHD+BPD) (n=20). Significant differences were observed for both childhood and current impulsivity symptoms, whereby ADHD+BPD exhibited increased impulsivity; no differences on self-report and cognitive measures of impulsivity were reported. The ADHD+BPD group scored significantly higher on measures of depression, anxiety and numerous other axis I and II conditions. The ADHD+BPD group scored significantly lower on most measures of intellectual functioning and attention, however largely not on those relating to response inhibition. Furthermore, group differences were observed for psychosocial factors, including education, substance use and criminal record. Comorbid ADHD and BPD is characterized by more symptoms of impulsivity, additional psychopathology, comparatively lower intellectual and attentional functioning and increased psychosocial difficulties. Copyright © 2015. Published by Elsevier Masson SAS.

  14. 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.

  15. Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases

    Science.gov (United States)

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

    2018-01-01

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

  16. Motor learning characterization in people with autism spectrum disorder: A systematic review.

    Science.gov (United States)

    de Moraes, Íbis Ariana Peña; Massetti, Thais; Crocetta, Tânia Brusque; da Silva, Talita Dias; de Menezes, Lilian Del Ciello; Monteiro, Carlos Bandeira de Mello; Magalhães, Fernando Henrique

    2017-01-01

    Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder primarily characterized by deficits in social interaction, communication and implicit skill learning. To analyse the results of research on "motor learning" and the means used for measuring "autistic disorder". A systematic literature search was done using Medline/PubMed, Web of Science, BVS (virtual health library), and PsycINFO. We included articles that contained the keywords "autism" and "motor learning". The variables considered were the methodological aspects; results presented, and the methodological quality of the studies. A total of 42 studies were identified; 33 articles were excluded because they did not meet the inclusion criteria. Data were extracted from nine eligible studies and summarized. We concluded that although individuals with ASD showed performance difficulties in different memory and motor learning tasks, acquisition of skills still takes place in this population; however, this skill acquisition is related to heterogeneous events, occurring without the awareness of the individual.

  17. From Narcissistic Personality Disorder to Frontotemporal Dementia: A Case Report

    OpenAIRE

    Michele Poletti; Ubaldo Bonuccelli

    2011-01-01

    Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disord...

  18. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  19. 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

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

    Institute of Scientific and Technical Information of China (English)

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

    2000-01-01

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

  1. Neurodegenerative diseases of the central motor system in MRI

    International Nuclear Information System (INIS)

    Alfke, K.

    2005-01-01

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

  2. 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.

  3. Expression of Nrf2 in neurodegenerative diseases.

    Science.gov (United States)

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

    2007-01-01

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

  4. 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.

  5. Folic acid, neurodegenerative and neuropsychiatric disease.

    Science.gov (United States)

    Kronenberg, Golo; Colla, Michael; Endres, Matthias

    2009-04-01

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

  6. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

  8. 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.

  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. Association between environmental exposure to pesticides and neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-11-15

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

  11. Patient Characterization Protocols for Psychophysiological Studies of Traumatic Brain Injury and Post-TBI Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Paul E. Rapp

    2013-07-01

    Full Text Available Psychophysiological investigations of traumatic brain injury (TBI are being conducted for several reasons, including the objective of learning more about the underlying physiological mechanisms of the pathological processes that can be initiated by a head injury. Additional goals include the development of objective physiologically based measures that can be used to monitor the response to treatment and to identify minimally symptomatic individuals who are at risk of delayed onset neuropsychiatric disorders following injury. Research programs studying TBI search for relationships between psychophysiological measures, particularly ERP component properties (e.g. timing, amplitude, scalp distribution, and a participant’s clinical condition. Moreover, the complex relationships between brain injury and psychiatric disorders are receiving increased research attention, and ERP technologies are making contributions to this effort. This review has two objectives supporting such research efforts. The first is to review evidence indicating that traumatic brain injury is a significant risk factor for post-injury neuropsychiatric disorders. The second objective is to introduce ERP researchers who are not familiar with neuropsychiatric assessment to the instruments that are available for characterizing traumatic brain injury, post-concussion syndrome, and psychiatric disorders. Specific recommendations within this very large literature are made. We have proceeded on the assumption that, as is typically the case in an ERP laboratory, the investigators are not clinically qualified and that they will not have access to participant medical records.

  12. Characterization of Esophageal Motility Disorders in Children Presenting With Dysphagia Using High-Resolution Manometry.

    Science.gov (United States)

    Edeani, Francis; Malik, Adeel; Kaul, Ajay

    2017-03-01

    The Chicago classification was based on metrics derived from studies in asymptomatic adult subjects. Our objectives were to characterize esophageal motility disorders in children and to determine whether the spectrum of manometric findings is similar between the pediatric and adult populations. Studies have suggested that the metrics utilized in manometric diagnosis depend on age, size, and manometric assembly. This would imply that a different set of metrics should be used for the pediatric population. There are no standardized and generally accepted metrics for use in the pediatric population, though there have been attempts to establish metrics specific to this population. Overall, we found that the distribution of esophageal motility disorders in children was like that described in adults using the Chicago classification. This analysis will serve as a prequel to follow-up studies exploring the individual metrics for variability among patients, with the objective of establishing novel metrics for the pediatric population.

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Santa Cirmi

    2016-09-01

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

  15. Improving drug delivery technology for treating neurodegenerative diseases.

    Science.gov (United States)

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

    2016-07-01

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

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

    Science.gov (United States)

    Kovacs, Gabor G

    2016-02-02

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

  17. Salt-bridge networks within globular and disordered proteins: characterizing trends for designable interactions.

    Science.gov (United States)

    Basu, Sankar; Mukharjee, Debasish

    2017-07-01

    There has been considerable debate about the contribution of salt bridges to the stabilization of protein folds, in spite of their participation in crucial protein functions. Salt bridges appear to contribute to the activity-stability trade-off within proteins by bringing high-entropy charged amino acids into close contacts during the course of their functions. The current study analyzes the modes of association of salt bridges (in terms of networks) within globular proteins and at protein-protein interfaces. While the most common and trivial type of salt bridge is the isolated salt bridge, bifurcated salt bridge appears to be a distinct salt-bridge motif having a special topology and geometry. Bifurcated salt bridges are found ubiquitously in proteins and interprotein complexes. Interesting and attractive examples presenting different modes of interaction are highlighted. Bifurcated salt bridges appear to function as molecular clips that are used to stitch together large surface contours at interacting protein interfaces. The present work also emphasizes the key role of salt-bridge-mediated interactions in the partial folding of proteins containing long stretches of disordered regions. Salt-bridge-mediated interactions seem to be pivotal to the promotion of "disorder-to-order" transitions in small disordered protein fragments and their stabilization upon binding. The results obtained in this work should help to guide efforts to elucidate the modus operandi of these partially disordered proteins, and to conceptualize how these proteins manage to maintain the required amount of disorder even in their bound forms. This work could also potentially facilitate explorations of geometrically specific designable salt bridges through the characterization of composite salt-bridge networks. Graphical abstract ᅟ.

  18. Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India.

    Science.gov (United States)

    Bindu, Parayil Sankaran; Govindaraju, Chikanna; Sonam, Kothari; Nagappa, Madhu; Chiplunkar, Shwetha; Kumar, Rakesh; Gayathri, Narayanappa; Bharath, M M Srinivas; Arvinda, Hanumanthapura R; Sinha, Sanjib; Khan, Nahid Akthar; Govindaraj, Periyasamy; Nunia, Vandana; Paramasivam, Arumugam; Thangaraj, Kumarasamy; Taly, Arun B

    2016-03-01

    There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder. Copyright © 2015. Published by Elsevier B.V.

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

    Directory of Open Access Journals (Sweden)

    Manuel J. Rodríguez

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Carol A Lazzara

    2015-10-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  2. Characterizing Time Irreversibility in Disordered Fermionic Systems by the Effect of Local Perturbations

    Science.gov (United States)

    Vardhan, Shreya; De Tomasi, Giuseppe; Heyl, Markus; Heller, Eric J.; Pollmann, Frank

    2017-07-01

    We study the effects of local perturbations on the dynamics of disordered fermionic systems in order to characterize time irreversibility. We focus on three different systems: the noninteracting Anderson and Aubry-André-Harper (AAH) models and the interacting spinless disordered t -V chain. First, we consider the effect on the full many-body wave functions by measuring the Loschmidt echo (LE). We show that in the extended or ergodic phase the LE decays exponentially fast with time, while in the localized phase the decay is algebraic. We demonstrate that the exponent of the decay of the LE in the localized phase diverges proportionally to the single-particle localization length as we approach the metal-insulator transition in the AAH model. Second, we probe different phases of disordered systems by studying the time expectation value of local observables evolved with two Hamiltonians that differ by a spatially local perturbation. Remarkably, we find that many-body localized systems could lose memory of the initial state in the long-time limit, in contrast to the noninteracting localized phase where some memory is always preserved.

  3. Motor learning characterization in people with autism spectrum disorder: A systematic review

    Directory of Open Access Journals (Sweden)

    Íbis Ariana Peña de Moraes

    Full Text Available ABSTRACT Autism Spectrum Disorder (ASD is a neurodevelopmental disorder primarily characterized by deficits in social interaction, communication and implicit skill learning. OBJECTIVE: To analyse the results of research on "motor learning" and the means used for measuring "autistic disorder". METHODS: A systematic literature search was done using Medline/PubMed, Web of Science, BVS (virtual health library, and PsycINFO. We included articles that contained the keywords "autism" and "motor learning". The variables considered were the methodological aspects; results presented, and the methodological quality of the studies. RESULTS: A total of 42 studies were identified; 33 articles were excluded because they did not meet the inclusion criteria. Data were extracted from nine eligible studies and summarized. CONCLUSION: We concluded that although individuals with ASD showed performance difficulties in different memory and motor learning tasks, acquisition of skills still takes place in this population; however, this skill acquisition is related to heterogeneous events, occurring without the awareness of the individual.

  4. Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?

    Science.gov (United States)

    Pellegrini, Carolina; Antonioli, Luca; Colucci, Rocchina; Blandizzi, Corrado; Fornai, Matteo

    2018-05-24

    Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.

  5. Transcranial Direct Current Stimulation in Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Argye E. Hillis

    2014-04-01

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

  6. Venlafaxine-induced REM sleep behavioral disorder presenting as two fractures

    Directory of Open Access Journals (Sweden)

    R. Ryan Williams

    2017-10-01

    Full Text Available Rapid eye movement (REM sleep behavioral disorder is characterized by the absence of muscular atonia during REM sleep. In this disorder, patients can violently act out their dreams, placing them at risk for traumatic fractures during these episodes. REM sleep behavioral disorder (RBD can be a sign of future neurodegenerative disease and has also been found to be a side effect of certain psychiatric medications. We present a case of venlafaxine-induced RBD in a 55 year old female who presented with a 13 year history of intermittent parasomnia and dream enactment in addition to a recent history of two fractures requiring intervention.

  7. Venlafaxine-induced REM sleep behavioral disorder presenting as two fractures.

    Science.gov (United States)

    Ryan Williams, R; Sandigo, Gustavo

    2017-10-01

    Rapid eye movement (REM) sleep behavioral disorder is characterized by the absence of muscular atonia during REM sleep. In this disorder, patients can violently act out their dreams, placing them at risk for traumatic fractures during these episodes. REM sleep behavioral disorder (RBD) can be a sign of future neurodegenerative disease and has also been found to be a side effect of certain psychiatric medications. We present a case of venlafaxine-induced RBD in a 55 year old female who presented with a 13 year history of intermittent parasomnia and dream enactment in addition to a recent history of two fractures requiring intervention.

  8. Early stages of bipolar disorder: characterization and strategies for early intervention

    Directory of Open Access Journals (Sweden)

    Adiel C. Rios

    2015-12-01

    Full Text Available Objective: To characterize the early stages of bipolar disorder (BD, defined as the clinical prodrome/subsyndromal stage and first-episode phase, and strategies for their respective treatment. Methods: A selective literature search of the PubMed, Embase, PsycINFO, and ISI databases from inception until March 2014 was performed. Included in this review were articles that a characterized prodromal and first-episode stages of BD or b detailed efficacy and safety/tolerability of interventions in patients considered prodromal for BD or those with only one episode of mania/hypomania. Results: As research has only recently focused on characterization of the early phase of BD, there is little evidence for the effectiveness of any treatment option in the early phase of BD. Case management; individual, group, and family therapy; supportive therapy; and group psychoeducation programs have been proposed. Most evidence-based treatment guidelines for BD do not address treatment specifically in the context of the early stages of illness. Evidence for pharmacotherapy is usually presented in relation to illness polarity (i.e., manic/mixed or depressed or treatment phase. Conclusions: Although early recognition and treatment are critical to preventing unfavorable outcomes, there is currently little evidence for interventions in these stages of BD.

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

    Science.gov (United States)

    Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Luisa Benussi

    2017-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Laura Foucault-Fruchard

    2017-01-01

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

  12. Differential diagnosis of neurodegenerative dementias with nuclear medicine methods

    International Nuclear Information System (INIS)

    Kluge, R.

    2015-01-01

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

  13. 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.

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

    Directory of Open Access Journals (Sweden)

    Silvia Vanni

    2018-01-01

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

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

    Science.gov (United States)

    Vanni, Silvia; Zattoni, Marco; Moda, Fabio; Giaccone, Giorgio; Tagliavini, Fabrizio; Haïk, Stéphane; Deslys, Jean-Philippe; Zanusso, Gianluigi; Ironside, James W; Carmona, Margarita; Ferrer, Isidre; Kovacs, Gabor G; Legname, Giuseppe

    2018-01-01

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

  16. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency

    DEFF Research Database (Denmark)

    Knudsen, Stine; Gammeltoft, Steen; Jennum, Poul J

    2010-01-01

    Rapid eye movement sleep behaviour disorder is characterized by dream-enacting behaviour and impaired motor inhibition during rapid eye movement sleep. Rapid eye movement sleep behaviour disorder is commonly associated with neurodegenerative disorders, but also reported in narcolepsy with cataplexy....... Most narcolepsy with cataplexy patients lack the sleep-wake, and rapid eye movement sleep, motor-regulating hypocretin neurons in the lateral hypothalamus. In contrast, rapid eye movement sleep behaviour disorder and hypocretin deficiency are rare in narcolepsy without cataplexy. We hypothesized...... that rapid eye movement sleep behaviour disorder coexists with cataplexy in narcolepsy due to hypocretin deficiency. In our study, rapid eye movement sleep behaviour disorder was diagnosed by the International Classification of Sleep Disorders (2nd edition) criteria in 63 narcolepsy patients with or without...

  17. From bench to bed: putative animal models of REM sleep behavior disorder (RBD).

    Science.gov (United States)

    Krenzer, Martina; Lu, Jun; Mayer, Geert; Oertel, Wolfgang

    2013-04-01

    REM behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia, leading to abnormal and potentially injurious behavior during REM sleep. It is considered one of the most specific predictors of neurodegenerative disorders, such as Parkinson's disease. In this paper, we provide an overview of animal models contributing to our current understanding of REM-associated atonia, and, as a consequence, the pathophysiology of RBD. The generator of REM-associated atonia is located in glutamatergic neurons of the pontine sublaterodorsal nucleus (SLD), as shown in cats, rats and mice. These findings are supported by clinical cases of patients with lesions of the homologous structure in humans. Glutamatergic SLD neurons, presumably in conjunction with others, project to (a) the ventromedial medulla, where they either directly target inhibitory interneurons to alpha motor neurons or are relayed, and (b) the spinal cord directly. At the spinal level, alpha motor neurons are inhibited by GABAergic and glycinergic interneurons. Our current understanding is that lesions of the glutamatergic SLD are the key factor for REM sleep behavior disorder. However, open questions remain, e.g. other features of RBD (such as the typically aggressive dream content) or the frequent progression from idiopathic RBD to neurodegenerative disorders, to name only a few. In order to elucidate these questions, a constant interaction between basic and clinical researchers is required, which might, ultimately, create an early therapeutic window for neurodegenerative disorders.

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

    Science.gov (United States)

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

    2018-04-03

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

  19. Beer and bread to brains and beyond: can yeast cells teach us about neurodegenerative disease?

    Science.gov (United States)

    Gitler, Aaron D

    2008-01-01

    For millennia, humans have harnessed the astonishing power of yeast, producing such culinary masterpieces as bread, beer and wine. Therefore, in this new millennium, is it very farfetched to ask if we can also use yeast to unlock some of the modern day mysteries of human disease? Remarkably, these seemingly simple cells possess most of the same basic cellular machinery as the neurons in the brain. We and others have been using the baker's yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms of devastating neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's and amyotrophic lateral sclerosis. While very different in their pathophysiology, they are collectively referred to as protein-misfolding disorders because of the presence of misfolded and aggregated forms of various proteins in the brains of affected individuals. Using yeast genetics and the latest high-throughput screening technologies, we have identified some of the potential causes underpinning these disorders and discovered conserved genes that have proven effective in preventing neuron loss in animal models. Thus, these genes represent new potential drug targets. In this review, I highlight recent work investigating mechanisms of cellular toxicity in a yeast Parkinson's disease model and discuss how similar approaches are being applied to additional neurodegenerative diseases.

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

    Science.gov (United States)

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

    2015-01-01

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

  1. Advancing biomarker research: utilizing 'Big Data' approaches for the characterization and prevention of bipolar disorder.

    Science.gov (United States)

    McIntyre, Roger S; Cha, Danielle S; Jerrell, Jeanette M; Swardfager, Walter; Kim, Rachael D; Costa, Leonardo G; Baskaran, Anusha; Soczynska, Joanna K; Woldeyohannes, Hanna O; Mansur, Rodrigo B; Brietzke, Elisa; Powell, Alissa M; Gallaugher, Ashley; Kudlow, Paul; Kaidanovich-Beilin, Oksana; Alsuwaidan, Mohammad

    2014-08-01

    To provide a strategic framework for the prevention of bipolar disorder (BD) that incorporates a 'Big Data' approach to risk assessment for BD. Computerized databases (e.g., Pubmed, PsychInfo, and MedlinePlus) were used to access English-language articles published between 1966 and 2012 with the search terms bipolar disorder, prodrome, 'Big Data', and biomarkers cross-referenced with genomics/genetics, transcriptomics, proteomics, metabolomics, inflammation, oxidative stress, neurotrophic factors, cytokines, cognition, neurocognition, and neuroimaging. Papers were selected from the initial search if the primary outcome(s) of interest was (were) categorized in any of the following domains: (i) 'omics' (e.g., genomics), (ii) molecular, (iii) neuroimaging, and (iv) neurocognitive. The current strategic approach to identifying individuals at risk for BD, with an emphasis on phenotypic information and family history, has insufficient predictive validity and is clinically inadequate. The heterogeneous clinical presentation of BD, as well as its pathoetiological complexity, suggests that it is unlikely that a single biomarker (or an exclusive biomarker approach) will sufficiently augment currently inadequate phenotypic-centric prediction models. We propose a 'Big Data'- bioinformatics approach that integrates vast and complex phenotypic, anamnestic, behavioral, family, and personal 'omics' profiling. Bioinformatic processing approaches, utilizing cloud- and grid-enabled computing, are now capable of analyzing data on the order of tera-, peta-, and exabytes, providing hitherto unheard of opportunities to fundamentally revolutionize how psychiatric disorders are predicted, prevented, and treated. High-throughput networks dedicated to research on, and the treatment of, BD, integrating both adult and younger populations, will be essential to sufficiently enroll adequate samples of individuals across the neurodevelopmental trajectory in studies to enable the characterization

  2. Characterizing Positive and Negative Emotional Experiences in Young Adults With Borderline Personality Disorder Symptoms.

    Science.gov (United States)

    Chu, Carol; Victor, Sarah E; Klonsky, E David

    2016-09-01

    Some researchers suggest that borderline personality disorder (BPD) is characterized by elevated negative emotion; others argue that BPD involves both reduced positive and increased negative emotion. This study characterizes the emotional experiences of individuals with BPD symptoms in a combined university and community sample. Participants (N = 150) completed a clinical interview assessing BPD symptoms and self-report measures of positive and negative emotion. A subset (n = 106) completed a measure of emotion daily for 2 weeks. Pearson's correlations and multilevel modeling were used to examine the cross-sectional and longitudinal relationships between BPD symptoms and emotions. BPD symptoms were robustly related to increased negative emotion; this relationship remained after accounting for positive emotion. BPD symptoms were weakly related to decreased positive emotion; this relationship was no longer significant after accounting for negative emotion. BPD symptoms predicted higher levels of negative and not positive emotion over 14 days. These patterns held for subscales assessing intensity, frequency, and duration of negative and positive emotions. Findings suggest that individuals with BPD features are chiefly distinguished by elevated negative emotional experience. © 2016 Wiley Periodicals, Inc.

  3. Mismanagement of Wilson's disease as psychotic disorder.

    Science.gov (United States)

    Bidaki, Reza; Zarei, Mina; Mirhosseini, S M Mahdy; Moghadami, Samar; Hejrati, Maral; Kohnavard, Marjan; Shariati, Behnam

    2012-01-01

    Wilson's disease (WD) or hepatolenticular degeneration is an inherited neurodegenerative disorder of copper metabolism (autosomal recessive, chromosome13). Psychiatric disorders in WD include dementia, characterized by mental slowness, poor concentration, and memory impairment. Symptoms may progress rapidly, especially in younger patients, but are more often gradual in development with periods of remission and exacerbation. Delusional disorder and schizophrenia-like psychosis are rare forms of psychiatric presentation. In this report, the patient with WD presented by psychosis symptoms and treated mistaken as schizophrenia for almost ten years. Although he has treated with antipsychotics, he had periods of remissions and relapses and never was symptoms free. Since psychosis can be the manifestation of medical diseases such as WD, overall view of these patients is necessary and medical diseases should be considered as a differential diagnosis.

  4. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

    Science.gov (United States)

    Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

    2013-06-01

    Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds.

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

    Directory of Open Access Journals (Sweden)

    Maurizio Giorelli

    2014-06-01

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

  6. Social skills training versus cognitive therapy for social anxiety disorder characterized by fear of blushing, trembling, or sweating

    NARCIS (Netherlands)

    Bögels, S.M.; Voncken, M.

    2008-01-01

    Current interpersonal models suggest that social anxiety disorder (SAD) is characterized by interpersonal difficulties. Individuals with SAD and fear of showing bodily symptoms also suffer from interpersonal problems, such as not being open and avoidance of expressing insecurity. Training in social

  7. Characterizing Community-Based Mental Health Services for Children with Autism Spectrum Disorders and Disruptive Behavior Problems

    Science.gov (United States)

    Brookman-Frazee, Lauren I.; Taylor, Robin; Garland, Ann F.

    2010-01-01

    This study describes the characteristics of children with autism spectrum disorders (ASD) with disruptive behavior problems served in community-based mental health clinics, characterizes psychotherapy process and outcome, and examines differences between children with ASD and a non-ASD comparison group. Results indicate that children with ASD…

  8. The Presence of Periodic Limb Movement Disorder in a Patient with Diabetes Mellitus and Optic Atrophy (Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Bo Seong Kwon

    2014-12-01

    Full Text Available Wolfram syndrome (WFS is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD, together known as DIDMOAD. This syndrome is a rare autosomal recessive neurodegenerative disorder and typically begins wtih insulin-dependent diabetes mellitus. Periodic limb movement disorder (PLMD is characterized by periodic episodes of repetitive, highly stereotyped, limb movement during sleep, which results in disturbed sleep. Its pathophysiology is unclear. It is associated with many conditions, but we were unable to find a previous report regarding WFS accompanied by PLMD. We therefore report, for the first time, about a patient with WFS presenting with PLMD and discuss its pathomechanism with a literature review.

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

    Science.gov (United States)

    Ramalingam, Mahesh; Kim, Sung-Jin

    2014-06-01

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

  10. Prediction of neurodegenerative diseases from functional brain imaging data

    NARCIS (Netherlands)

    Mudali, Deborah

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Panchanan Maiti

    2014-01-01

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

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

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-04-01

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

  13. X-ray imaging characterization of femoral bones in aging mice with osteopetrotic disorder.

    Science.gov (United States)

    Tu, Shu-Ju; Huang, Hong-Wen; Chang, Wei-Jeng

    2015-04-01

    Aging mice with a rare osteopetrotic disorder in which the entire space of femoral bones are filled with trabecular bones are used as our research platform. A complete study is conducted with a micro computed tomography (CT) system to characterize the bone abnormality. Technical assessment of femoral bones includes geometric structure, biomechanical strength, bone mineral density (BMD), and bone mineral content (BMC). Normal aging mice of similar ages are included for comparisons. In our imaging work, we model the trabecular bone as a cylindrical rod and new quantitative which are not previously discussed are developed for advanced analysis, including trabecular segment length, trabecular segment radius, connecting node number, and distribution of trabecular segment radius. We then identified a geometric characteristic in which there are local maximums (0.0049, 0.0119, and 0.0147 mm) in the structure of trabecular segment radius. Our calculations show 343% higher in percent trabecular bone volume at distal-metaphysis; 38% higher in cortical thickness at mid-diaphysis; 11% higher in cortical cross-sectional moment of inertia at mid-diaphysis; 42% higher in cortical thickness at femur neck; 26% higher in cortical cross-sectional moment of inertia at femur neck; 31% and 395% higher in trabecular BMD and BMC at distal-metaphysis; 17% and 27% higher in cortical BMD and BMC at distal-metaphysis; 9% and 53% higher in cortical BMD and BMC at mid-diaphysis; 25% and 64% higher in cortical BMD and BMC at femur neck. Our new quantitative parameters and findings may be extended to evaluate the treatment response for other similar bone disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Regulatory Role of Circular RNAs and Neurological Disorders.

    Science.gov (United States)

    Floris, Gabriele; Zhang, Longbin; Follesa, Paolo; Sun, Tao

    2017-09-01

    Circular RNAs (circRNAs) are a class of long noncoding RNAs that are characterized by the presence of covalently linked ends and have been found in all life kingdoms. Exciting studies in regulatory roles of circRNAs are emerging. Here, we summarize classification, characteristics, biogenesis, and regulatory functions of circRNAs. CircRNAs are found to be preferentially expressed along neural genes and in neural tissues. We thus highlight the association of circRNA dysregulation with neurodegenerative diseases such as Alzheimer's disease. Investigation of regulatory role of circRNAs will shed novel light in gene expression mechanisms during development and under disease conditions and may identify circRNAs as new biomarkers for aging and neurodegenerative disorders.

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

    Science.gov (United States)

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

    2015-08-01

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

  16. Characterizing psychiatric comorbidity in children with autism spectrum disorder receiving publicly funded mental health services.

    Science.gov (United States)

    Brookman-Frazee, Lauren; Stadnick, Nicole; Chlebowski, Colby; Baker-Ericzén, Mary; Ganger, William

    2017-09-01

    Publicly funded mental health programs play a significant role in serving children with autism spectrum disorder. Understanding patterns of psychiatric comorbidity for this population within mental health settings is important to implement appropriately tailored interventions. This study (1) describes patterns of psychiatric comorbidity in children with autism spectrum disorder who present to mental health services with challenging behaviors and (2) identifies child characteristics associated with comorbid conditions. Data are drawn from baseline assessments from 201 children with autism spectrum disorder who participated in a community effectiveness trial across 29 publicly funded mental health programs. Non-autism spectrum disorder diagnoses were assessed using an adapted Mini-International Neuropsychiatric Interview, parent version. Approximately 92% of children met criteria for at least one non-autism spectrum disorder diagnosis (78% attention deficit hyperactivity disorder, 58% oppositional defiant disorder, 56% anxiety, 30% mood). Logistic regression indicated that child gender and clinical characteristics were differentially associated with meeting criteria for attention deficit hyperactivity disorder, oppositional defiant disorder, an anxiety, or a mood disorder. Exploratory analyses supported a link between challenging behaviors and mood disorder symptoms and revealed high prevalence of these symptoms in this autism spectrum disorder population. Findings provide direction for tailoring intervention to address a broad range of clinical issues for youth with autism spectrum disorder served in mental health settings.

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

    Directory of Open Access Journals (Sweden)

    Sheila K. Pirooznia

    2013-03-01

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

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

    Science.gov (United States)

    Vyas, Sheela; Maatouk, Layal

    2013-12-01

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

  19. Characterization of IGF-II isoforms in binge eating disorder and its group psychological treatment.

    Directory of Open Access Journals (Sweden)

    Giorgio Tasca

    Full Text Available Binge eating disorder (BED affects 3.5% of the population and is characterized by binge eating for at least 2 days a week for 6 months. Treatment options include cognitive behavioral therapy, interpersonal psychotherapy, and pharmacotherapy which are associated with varied success. Little is known about the biology of BED. Since there is evidence that the insulin like growth factor system is implicated in regulation of body weight, insulin sensitivity and feeding behavior, we speculated it may be involved in BED.A cross-sectional comparison was made between three groups of women: overweight with BED, overweight without BED and normal weight without BED. Women were assigned to Group Psychodynamic Interpersonal Psychotherapy. Blood was collected before therapy, at completion and at 6 months follow up for evaluation of IGF-II using Western blot.97 overweight women with BED contributed to the cross-sectional comparison. The two control groups comprised 53 overweight women without BED, and 50 age matched normal weight women without BED. Obese women had significantly lower Big IGF-II than normal weight women, p = .028; Overweight women with BED had higher Mature IGF-II than normal weight women, p<.05. Big IGF-II showed a significant decreasing slope from pre- to post- to six months post-group psychological treatment, unrelated to changes in BMI (p = .008.Levels of IGF-II isoforms differed significantly between overweight and normal weight women. Overweight women with BED display abnormal levels of circulating IGF-II isoforms. BED is characterized by elevated mature IGF-II, an isoform shown to carry significant bioactivity. This finding is not related to BMI or to changes in body weight. The results also provide preliminary evidence that BIG IGF-II is sensitive to change due to group psychological treatment. We suggest that abnormalities in IGF-II processing may be involved in the neurobiology of BED.

  20. Morphometric brain characterization of refractory obsessive-compulsive disorder: diffeomorphic anatomic registration using exponentiated Lie algebra.

    Science.gov (United States)

    Tang, Wanjie; Li, Bin; Huang, Xiaoqi; Jiang, Xiaoyu; Li, Fei; Wang, Lijuan; Chen, Taolin; Wang, Jinhui; Gong, Qiyong; Yang, Yanchun

    2013-10-01

    Few studies have used neuroimaging to characterize treatment-refractory obsessive-compulsive disorder (OCD). This study sought to explore gray matter structure in patients with treatment-refractory OCD and compare it with that of healthy controls. A total of 18 subjects with treatment-refractory OCD and 26 healthy volunteers were analyzed by MRI using a 3.0-T scanner and voxel-based morphometry (VBM). Diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL) was used to identify structural changes in gray matter associated with treatment-refractory OCD. A partial correlation model was used to analyze whether morphometric changes were associated with Yale-Brown Obsessive-Compulsive Scale scores and illness duration. Gray matter volume did not differ significantly between the two groups. Treatment-refractory OCD patients showed significantly lower gray matter density than healthy subjects in the left posterior cingulate cortex (PCC) and mediodorsal thalamus (MD) and significantly higher gray matter density in the left dorsal striatum (putamen). These changes did not correlate with symptom severity or illness duration. Our findings provide new evidence of deficits in gray matter density in treatment-refractory OCD patients. These patients may show characteristic density abnormalities in the left PCC, MD and dorsal striatum (putamen), which should be verified in longitudinal studies. © 2013. Published by Elsevier Inc. All rights reserved.

  1. Impulsive behavior in adults with attention deficit/ hyperactivity disorder: characterization of attentional, motor and cognitive impulsiveness.

    Science.gov (United States)

    Malloy-Diniz, L; Fuentes, D; Leite, W Borges; Correa, H; Bechara, A

    2007-07-01

    Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention and/or hyperactivity/impulsivity. Impulsivity persists in adults with ADHD and might be the basis of much of the impairment observed in the daily lives of such individuals. The objective of this study was to address the presence, and more importantly, the three dimensions of impulsivity: attentional, non-planning and motor, in how they may relate to neuropsychological mechanisms of impulse control. We studied a sample of 50 adults with ADHD and 51 healthy comparison controls using the Barratt Impulsivity Scale Version 11 (BIS), and neuropsychological tasks, namely the Continuous Performance Task (CPT-II) and the Iowa Gambling Task (IGT). The ADHD group showed more signs of impulsivity on the three dimensions of BIS, committed more errors of omission and commission on the CPT-II, and made more disadvantageous choices on the IGT. These results support the existence of deficits related to three components of impulsivity: motor, cognitive, and attentional among adults with ADHD. Most importantly, this study also highlights the complementary nature of self-report questionnaires and neuropsychological tasks in the assessment of impulsivity in ADHD adults.

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

    Directory of Open Access Journals (Sweden)

    Natalia Fernández-Borges

    2013-01-01

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

  3. Modeling cognitive deficits following neurodegenerative diseases and traumatic brain injuries with deep convolutional neural networks.

    Science.gov (United States)

    Lusch, Bethany; Weholt, Jake; Maia, Pedro D; Kutz, J Nathan

    2018-06-01

    The accurate diagnosis and assessment of neurodegenerative disease and traumatic brain injuries (TBI) remain open challenges. Both cause cognitive and functional deficits due to focal axonal swellings (FAS), but it is difficult to deliver a prognosis due to our limited ability to assess damaged neurons at a cellular level in vivo. We simulate the effects of neurodegenerative disease and TBI using convolutional neural networks (CNNs) as our model of cognition. We utilize biophysically relevant statistical data on FAS to damage the connections in CNNs in a functionally relevant way. We incorporate energy constraints on the brain by pruning the CNNs to be less over-engineered. Qualitatively, we demonstrate that damage leads to human-like mistakes. Our experiments also provide quantitative assessments of how accuracy is affected by various types and levels of damage. The deficit resulting from a fixed amount of damage greatly depends on which connections are randomly injured, providing intuition for why it is difficult to predict impairments. There is a large degree of subjectivity when it comes to interpreting cognitive deficits from complex systems such as the human brain. However, we provide important insight and a quantitative framework for disorders in which FAS are implicated. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Ciechanover, Aaron; Kwon, Yong Tae

    2015-03-13

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

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

    Science.gov (United States)

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

    2012-01-01

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

  6. Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Ian James Martins

    2015-12-01

    Full Text Available Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

  7. Lentiviral vectors in neurodegenrative disorders - Aspects in gene therapy and disease models

    DEFF Research Database (Denmark)

    Nielsen, Troels Tolstrup

    2009-01-01

    Neurodegenerative disorders remain a complex group of diseases (i.e. Huntington's disease, HD) that are characterized by progressive loss of neurons resulting in movement disorders, cognitive decline, dementia and death. There is no cure for these diseases and treatment relies on symptomatic relief...... expression and escape transgene silencing during differentiation of neural stem cell lines. However, insulator vectors appeared to be impaired in functionality, which has importance for the future use of insulators in viral vectors. Finally, cell based models of HD was constructed to elucidate...

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

    Directory of Open Access Journals (Sweden)

    Godoy, Maria Dantas Costa Lima

    2015-01-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

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

    Science.gov (United States)

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

    2008-04-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

    National Research Council Canada - National Science Library

    Tröster, Alexander I

    1998-01-01

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

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

    OpenAIRE

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

    2013-01-01

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

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

    Science.gov (United States)

    Delzescaux, Sabine; Blondel, Frédéric

    2015-01-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    OpenAIRE

    Casini , Elisa

    2017-01-01

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

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

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2013-12-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  20. 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.

  1. Sublethal RNA Oxidation as a Mechanism for Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Mark A. Smith

    2008-05-01

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

  2. Characterization of Movement Disorder Phenomenology in Genetically Proven, Familial Frontotemporal Lobar Degeneration: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Gasca-Salas, Carmen; Masellis, Mario; Khoo, Edwin; Shah, Binit B.; Fisman, David; Lang, Anthony E.; Kleiner-Fisman, Galit

    2016-01-01

    Background Mutations in granulin (PGRN) and tau (MAPT), and hexanucleotide repeat expansions near the C9orf72 genes are the most prevalent genetic causes of frontotemporal lobar degeneration. Although behavior, language and movement presentations are common, the relationship between genetic subgroup and movement disorder phenomenology is unclear. Objective We conducted a systematic review and meta-analysis of the literature characterizing the spectrum and prevalence of movement disorders in genetic frontotemporal lobar degeneration. Methods Electronic databases were searched using terms related to frontotemporal lobar degeneration and movement disorders. Articles were included when cases had a proven genetic cause. Study-specific prevalence estimates for clinical features were transformed using Freeman-Tukey arcsine transformation, allowing for pooled estimates of prevalence to be generated using random-effects models. Results The mean age at onset was earlier in those with MAPT mutations compared to PGRN (p<0.001) and C9orf72 (p = 0.024). 66.5% of subjects had an initial non-movement presentation that was most likely a behavioral syndrome (35.7%). At any point during the disease, parkinsonism was the most common movement syndrome reported in 79.8% followed by progressive supranuclear palsy (PSPS) and corticobasal (CBS) syndromes in 12.2% and 10.7%, respectively. The prevalence of movement disorder as initial presentation was higher in MAPT subjects (35.8%) compared to PGRN subjects (10.1). In those with a non-movement presentation, language disorder was more common in PGRN subjects (18.7%) compared to MAPT subjects (5.4%). Summary This represents the first systematic review and meta-analysis of the occurrence of movement disorder phenomenology in genetic frontotemporal lobar degeneration. Standardized prospective collection of clinical information in conjunction with genetic characterization will be crucial for accurate clinico-genetic correlation. PMID:27100392

  3. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    International Nuclear Information System (INIS)

    So, Young; Kim, Hahn Young; Roh, Hong Gee; Han, Seol Heui

    2007-01-01

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr ∼ 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1∼9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI

  4. Large cerebral perfusion defects observed in brain perfusion SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients

    Energy Technology Data Exchange (ETDEWEB)

    So, Young; Kim, Hahn Young; Roh, Hong Gee; Han, Seol Heui [Konkuk University School of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    Transient global amnesia (TGA) is a memory disorder characterized by an episode of antegrade amnesia and bewilderment which persists for several hours. We analyzed brain perfusion SPECT findings and clinical outcome of patients who suffered from TGA. From September 2005 to August 2007, 12 patients underwent Tc-99m ECD brain perfusion SPECT for neuroimaging of TGA. All patients also underwent MRI and MRA including DWI (MRI). Among them, 10 patients who could be chased more than 6 months were included in this study. Their average age was 60.74.0 yrs (M: F = 2: 8) and the average duration of amnesia was 4.42.2 hrs (1 hr {approx} 7 hrs). Duration from episode of amnesia to SPECT was 4.32.4 days (1{approx}9 days). Precipitating factors could be identified in 6 patients: emotional stress 3, hair dyeing 1, taking a nap 1 and angioplasty 1. SPECT and MRI was visually assessed, No cerebral perfusion defect was observed on SPECT in 3 patients and their clinical outcome was all good. Among 7 patients who had cerebral perfusion defects on SPECT, 3 patients had good clinical outcome, while others did not: one had hypercholesterolemia, another had depression, and 2 patients with cerebral perfusion defects at both temporoparetal cortex was later diagnosed as early Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI was negative in 6 patients and 3 of them had excellent clinical outcome while other 3 were diagnosed as hypercholesterolemia, early AD and MCI. Among 4 patients with positive MRI, 3 showed good clinical outcome and their MRI showed lesions at medial temporal cortex and/or vertebral artery. One patient with microcalcification at left putamen was diagnosed to have depression. Large cerebral perfusion defects on SPECT may herald psychiatric or neurodegenerative diseases of transient global amnesia patients which usually shows negative MRI.

  5. Endoplasmic Reticulum (ER Stress and Endocrine Disorders

    Directory of Open Access Journals (Sweden)

    Daisuke Ariyasu

    2017-02-01

    Full Text Available The endoplasmic reticulum (ER is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR, which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI, Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2 are discussed in this article.

  6. Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

    Science.gov (United States)

    Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro

    2017-01-01

    The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. PMID:28208663

  7. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.

    Science.gov (United States)

    Kao, Aimee W; Eisenhut, Robin J; Martens, Lauren Herl; Nakamura, Ayumi; Huang, Anne; Bagley, Josh A; Zhou, Ping; de Luis, Alberto; Neukomm, Lukas J; Cabello, Juan; Farese, Robert V; Kenyon, Cynthia

    2011-03-15

    Frontotemporal lobar degeneration is a progressive neurodegenerative syndrome that is the second most common cause of early-onset dementia. Mutations in the progranulin gene are a major cause of familial frontotemporal lobar degeneration [Baker M, et al. (2006) Nature 442:916-919 and Cruts M, et al. (2006) Nature 442:920-924]. Although progranulin is involved in wound healing, inflammation, and tumor growth, its role in the nervous system and the mechanism by which insufficient levels result in neurodegeneration are poorly understood [Eriksen and Mackenzie (2008) J Neurochem 104:287-297]. We have characterized the normal function of progranulin in the nematode Caenorhabditis elegans. We found that mutants lacking pgrn-1 appear grossly normal, but exhibit fewer apoptotic cell corpses during development. This reduction in corpse number is not caused by reduced apoptosis, but instead by more rapid clearance of dying cells. Likewise, we found that macrophages cultured from progranulin KO mice displayed enhanced rates of apoptotic-cell phagocytosis. Although most neurodegenerative diseases are thought to be caused by the toxic effects of aggregated proteins, our findings suggest that susceptibility to neurodegeneration may be increased by a change in the kinetics of programmed cell death. We propose that cells that might otherwise recover from damage or injury are destroyed in progranulin mutants, which in turn facilitates disease progression.

  8. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency

    DEFF Research Database (Denmark)

    Knudsen, Stine; Gammeltoft, Steen; Jennum, Poul J

    2010-01-01

    variables were analysed in relation to cataplexy and hypocretin deficiency with uni- and multivariate logistic/linear regression models, controlling for possible rapid eye movement sleep behaviour disorder biasing factors (age, gender, disease duration, previous anti-cataplexy medication). Only hypocretin......Rapid eye movement sleep behaviour disorder is characterized by dream-enacting behaviour and impaired motor inhibition during rapid eye movement sleep. Rapid eye movement sleep behaviour disorder is commonly associated with neurodegenerative disorders, but also reported in narcolepsy with cataplexy....... Most narcolepsy with cataplexy patients lack the sleep-wake, and rapid eye movement sleep, motor-regulating hypocretin neurons in the lateral hypothalamus. In contrast, rapid eye movement sleep behaviour disorder and hypocretin deficiency are rare in narcolepsy without cataplexy. We hypothesized...

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

    Directory of Open Access Journals (Sweden)

    Anne-Claire Dupont

    2017-04-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  11. Beneficial Effects of Green Tea Catechins on Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Monira Pervin

    2018-05-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

    Wexler, Eric

    2013-11-01

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

  14. Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

    Science.gov (United States)

    Tejeda, Gonzalo S.; Díaz-Guerra, Margarita

    2017-01-01

    Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling. PMID:28134845

  15. Circulating progranulin as a biomarker for neurodegenerative diseases.

    Science.gov (United States)

    Ghidoni, Roberta; Paterlini, Anna; Benussi, Luisa

    2012-01-01

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

  16. The epigenetic bottleneck of neurodegenerative and psychiatric diseases.

    Science.gov (United States)

    Sananbenesi, Farahnaz; Fischer, Andre

    2009-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Samantha Giordano

    2014-01-01

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

  18. Cephalic Disorders

    Science.gov (United States)

    ... destructive lesions, but are sometimes the result of abnormal development. The disorder can occur before or after birth. Porencephaly most ... decade of life. SCHIZENCEPHALY is a rare developmental disorder characterized by abnormal slits, or clefts, in the cerebral hemispheres. Schizencephaly ...

  19. Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

    International Nuclear Information System (INIS)

    Na, Jung-Hyun; Lee, Won-Kyu; Kim, Yuyoung; Jeong, Cherlhyun; Song, Seung Soo; Cha, Sun-Shin; Han, Kyou-Hoon; Shin, Yeon-Kyun; Yu, Yeon Gyu

    2016-01-01

    Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

  20. Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

    Energy Technology Data Exchange (ETDEWEB)

    Na, Jung-Hyun [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Lee, Won-Kyu [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Kim, Yuyoung; Jeong, Cherlhyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Song, Seung Soo [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Cha, Sun-Shin [Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Han, Kyou-Hoon [Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 (Korea, Republic of); Shin, Yeon-Kyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011 (United States); Yu, Yeon Gyu, E-mail: ygyu@kookmin.ac.kr [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of)

    2016-08-19

    Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

  1. Content analysis of neurodegenerative and mental diseases social groups.

    Science.gov (United States)

    Martínez-Pérez, Borja; de la Torre-Díez, Isabel; Bargiela-Flórez, Beatriz; López-Coronado, Miguel; Rodrigues, Joel J P C

    2015-12-01

    This article aims to characterize the different types of Facebook and Twitter groups for different mental diseases, their purposes, and their functions. We focused the search on depressive disorders, dementia, and Alzheimer's and Parkinson's diseases and examined the Facebook (www.facebook.com) and Twitter (www.twitter.com) groups. We used four assessment criteria: (1) purpose, (2) type of creator, (3) telehealth content, and (4) free-text responses in surveys and interviews. We observed a total of 357 Parkinson groups, 325 dementia groups, 853 Alzheimer groups, and 1127 depression groups on Facebook and Twitter. Moreover, we analyze the responses provided by different users. The survey and interview responses showed that many people were interested in using social networks to support and help in the fight against these diseases. The results indicate that social networks are acceptable by users in terms of simplicity and utility. People use them for finding support, information, self-help, advocacy and awareness, and for collecting funds. © The Author(s) 2014.

  2. Using the Preschool Language Scale, Fourth Edition to Characterize Language in Preschoolers with Autism Spectrum Disorders

    Science.gov (United States)

    Volden, Joanne; Smith, Isabel M.; Szatmari, Peter; Bryson, Susan; Fombonne, Eric; Mirenda, Pat; Roberts, Wendy; Vaillancourt, Tracy; Waddell, Charlotte; Zwaigenbaum, Lonnie; Georgiades, Stelios; Duku, Eric; Thompson, Ann

    2011-01-01

    Purpose: The Preschool Language Scale, Fourth Edition (PLS-4; Zimmerman, Steiner, & Pond, 2002) was used to examine syntactic and semantic language skills in preschool children with autism spectrum disorders (ASD) to determine its suitability for use with this population. We expected that PLS-4 performance would be better in more…

  3. Panic Disorder among Adults

    Science.gov (United States)

    ... Disorder Among Adolescents Data Sources Share Panic Disorder Definition Panic Disorder is an anxiety disorder characterized by ... MSC 9663 Bethesda, MD 20892-9663 Follow Us Facebook Twitter YouTube Google Plus NIMH Newsletter NIMH RSS ...

  4. Quetiapine responsive catatonia in an autistic patient with comorbid bipolar disorder and idiopathic basal ganglia calcification.

    Science.gov (United States)

    Ishitobi, Makoto; Kawatani, Masao; Asano, Mizuki; Kosaka, Hirotaka; Goto, Takashi; Hiratani, Michio; Wada, Yuji

    2014-10-01

    Bipolar disorder (BD) has been linked with the manifestation of catatonia in subjects with autism spectrum disorders (ASD). Idiopathic basal ganglia calcification (IBGC) is characterized by movement disorders and various neuropsychiatric disturbances including mood disorder. We present a patient with ASD and IBGC who developed catatonia presenting with prominent dystonic feature caused by comorbid BD, which was treated effectively with quetiapine. In addition to considering the possibility of neurodegenerative disease, careful psychiatric interventions are important to avoid overlooking treatable catatonia associated with BD in cases of ASD presenting with both prominent dystonic features and apparent fluctuation of the mood state. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  5. Developmental Vulnerability of Synapses and Circuits Associated with Neuropsychiatric Disorders

    OpenAIRE

    Penzes, Peter; Buonanno, Andres; Passafarro, Maria; Sala, Carlo; Sweet, Robert A.

    2013-01-01

    Psychiatric and neurodegenerative disorders, including intellectual disability (ID), autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease (AD), pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorder...

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

    Directory of Open Access Journals (Sweden)

    Elizabeth A. LaMarca

    2018-04-01

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

  7. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Hall, Vanessa Jane

    2016-01-01

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

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

    Science.gov (United States)

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

    2012-01-26

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

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

    Directory of Open Access Journals (Sweden)

    Elena Sieni

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sebastian eHeinzel

    2014-07-01

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

  12. Affective disorders in neurological diseases

    DEFF Research Database (Denmark)

    Nilsson, F M; Kessing, L V; Sørensen, T M

    2003-01-01

    OBJECTIVE: To investigate the temporal relationships between a range of neurological diseases and affective disorders. METHOD: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two...... of affective disorder was lower than the incidence in the control groups. CONCLUSION: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases)....

  13. Characterization of nutrient disorders of gerbera hybrid 'Festival Light Eye Pink'

    Science.gov (United States)

    Gerbera hybrid ‘Festival Yellow with Light Eye’ plants were grown in silica sand culture to induce and photograph nutritional disorder symptoms. Plants were grown with a complete modified Hoagland's all nitrate solution: (macronutrients in mM) 15 NO3-N, 1.0 PO4-P, 6.0 K, 5.0 Ca, 2.0 Mg, and 2.0 SO4...

  14. Fractal analysis of MRI data for the characterization of patients with schizophrenia and bipolar disorder

    Science.gov (United States)

    Squarcina, Letizia; De Luca, Alberto; Bellani, Marcella; Brambilla, Paolo; Turkheimer, Federico E.; Bertoldo, Alessandra

    2015-02-01

    Fractal geometry can be used to analyze shape and patterns in brain images. With this study we use fractals to analyze T1 data of patients affected by schizophrenia or bipolar disorder, with the aim of distinguishing between healthy and pathological brains using the complexity of brain structure, in particular of grey matter, as a marker of disease. 39 healthy volunteers, 25 subjects affected by schizophrenia and 11 patients affected by bipolar disorder underwent an MRI session. We evaluated fractal dimension of the brain cortex and its substructures, calculated with an algorithm based on the box-count algorithm. We modified this algorithm, with the aim of avoiding the segmentation processing step and using all the information stored in the image grey levels. Moreover, to increase sensitivity to local structural changes, we computed a value of fractal dimension for each slice of the brain or of the particular structure. To have reference values in comparing healthy subjects with patients, we built a template by averaging fractal dimension values of the healthy volunteers data. Standard deviation was evaluated and used to create a confidence interval. We also performed a slice by slice t-test to assess the difference at slice level between the three groups. Consistent average fractal dimension values were found across all the structures in healthy controls, while in the pathological groups we found consistent differences, indicating a change in brain and structures complexity induced by these disorders.

  15. Fractal analysis of MRI data for the characterization of patients with schizophrenia and bipolar disorder

    International Nuclear Information System (INIS)

    Squarcina, Letizia; Bellani, Marcella; De Luca, Alberto; Bertoldo, Alessandra; Brambilla, Paolo; Turkheimer, Federico E

    2015-01-01

    Fractal geometry can be used to analyze shape and patterns in brain images. With this study we use fractals to analyze T1 data of patients affected by schizophrenia or bipolar disorder, with the aim of distinguishing between healthy and pathological brains using the complexity of brain structure, in particular of grey matter, as a marker of disease. 39 healthy volunteers, 25 subjects affected by schizophrenia and 11 patients affected by bipolar disorder underwent an MRI session. We evaluated fractal dimension of the brain cortex and its substructures, calculated with an algorithm based on the box-count algorithm. We modified this algorithm, with the aim of avoiding the segmentation processing step and using all the information stored in the image grey levels. Moreover, to increase sensitivity to local structural changes, we computed a value of fractal dimension for each slice of the brain or of the particular structure. To have reference values in comparing healthy subjects with patients, we built a template by averaging fractal dimension values of the healthy volunteers data. Standard deviation was evaluated and used to create a confidence interval. We also performed a slice by slice t-test to assess the difference at slice level between the three groups. Consistent average fractal dimension values were found across all the structures in healthy controls, while in the pathological groups we found consistent differences, indicating a change in brain and structures complexity induced by these disorders. (paper)

  16. Patient Characterization Protocols for Psychophysiological Studies of Traumatic Brain Injury and Post-TBI Psychiatric Disorders

    Science.gov (United States)

    2013-07-22

    and Post-TBI Psychiatric Disorders 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK...in (282–285)]. Based on a review of the literature, Graham and Cardon reported that substance abuse rates decline following TBI, including mild TBI...preva- lence and outcomes research (1994-2004). Neuropsychol Rehabil (2006) 16(5):537–60. doi:10.1080/09602010500231875 285. Graham DP, Cardon AL. An

  17. Epidemiological and clinical characterization following a first psychotic episode in major depressive disorder: comparisons with schizophrenia and bipolar I disorder in the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

    Science.gov (United States)

    Owoeye, Olabisi; Kingston, Tara; Scully, Paul J; Baldwin, Patrizia; Browne, David; Kinsella, Anthony; Russell, Vincent; O'Callaghan, Eadbhard; Waddington, John L

    2013-07-01

    While recent research on psychotic illness has focussed on the nosological, clinical, and biological relationships between schizophrenia and bipolar disorder, little attention has been directed to the most common other psychotic diagnosis, major depressive disorder with psychotic features (MDDP). As this diagnostic category captures the confluence between dimensions of psychotic and affective psychopathology, it is of unappreciated heuristic potential to inform on the nature of psychotic illness. Therefore, the epidemiology and clinical characteristics of MDDP were compared with those of schizophrenia and bipolar disorder within the Cavan-Monaghan First Episode Psychosis Study (n = 370). Epidemiologically, the first psychotic episode of MDDP (n = 77) was uniformly distributed across the adult life span, while schizophrenia (n = 73) and bipolar disorder (n = 73) were primarily disorders of young adulthood; the incidence of MDDP, like bipolar disorder, did not differ between the sexes, while the incidence of schizophrenia was more common in males than in females. Clinically, MDDP was characterized by negative symptoms, executive dysfunction, neurological soft signs (NSS), premorbid intellectual function, premorbid adjustment, and quality of life similar to those for schizophrenia, while bipolar disorder was characterized by less prominent negative symptoms, executive dysfunction and NSS, and better quality of life. These findings suggest that what we currently categorize as MDDP may be more closely aligned with other psychotic diagnoses than has been considered previously. They indicate that differences in how psychosis is manifested vis-à-vis depression and mania may be quantitative rather than qualitative and occur within a dimensional space, rather than validating categorical distinctions.

  18. Epidemiological and clinical characterization following a first psychotic episode in major depressive disorder: Comparisons with Schizophrenia and Bipolar I Disorder in the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

    LENUS (Irish Health Repository)

    Owoeye, Olabisi

    2013-05-28

    While recent research on psychotic illness has focussed on the nosological, clinical, and biological relationships between schizophrenia and bipolar disorder, little attention has been directed to the most common other psychotic diagnosis, major depressive disorder with psychotic features (MDDP). As this diagnostic category captures the confluence between dimensions of psychotic and affective psychopathology, it is of unappreciated heuristic potential to inform on the nature of psychotic illness. Therefore, the epidemiology and clinical characteristics of MDDP were compared with those of schizophrenia and bipolar disorder within the Cavan-Monaghan First Episode Psychosis Study (n = 370). Epidemiologically, the first psychotic episode of MDDP (n = 77) was uniformly distributed across the adult life span, while schizophrenia (n = 73) and bipolar disorder (n = 73) were primarily disorders of young adulthood; the incidence of MDDP, like bipolar disorder, did not differ between the sexes, while the incidence of schizophrenia was more common in males than in females. Clinically, MDDP was characterized by negative symptoms, executive dysfunction, neurological soft signs (NSS), premorbid intellectual function, premorbid adjustment, and quality of life similar to those for schizophrenia, while bipolar disorder was characterized by less prominent negative symptoms, executive dysfunction and NSS, and better quality of life. These findings suggest that what we currently categorize as MDDP may be more closely aligned with other psychotic diagnoses than has been considered previously. They indicate that differences in how psychosis is manifested vis-à-vis depression and mania may be quantitative rather than qualitative and occur within a dimensional space, rather than validating categorical distinctions.

  19. Prevalence and characterization of neonatal skin disorders in the first 72 h of life

    Directory of Open Access Journals (Sweden)

    Flávia Pereira Reginatto

    2017-05-01

    Conclusions: Dermatological findings are frequent during the first days of life and some of them characterize the newborn's skin. Mixed‐race newborns and those whose mothers had some gestational risk factor had more dermatological findings. The gestational age, newborn's ethnicity, gender, Apgar at the first and fifth minutes of life, type of delivery, and seasonality influenced the presence of specific neonatal dermatological findings.

  20. Modulatory Effects of Dietary Amino Acids on Neurodegenerative Diseases.

    Science.gov (United States)

    Rajagopal, Senthilkumar; Sangam, Supraj Raja; Singh, Shubham; Joginapally, Venkateswara Rao

    2016-01-01

    Proteins are playing a vital role in maintaining the cellular integrity and function, as well as for brain cells. Protein intake and supplementation of individual amino acids can affect the brain functioning and mental health, and many of the neurotransmitters in the brain are made from amino acids. The amino acid supplementation has been found to reduce symptoms, as they are converted into neurotransmitters which in turn extenuate the mental disorders. The biosynthesis of amino acids in the brain is regulated by the concentration of amino acids in plasma. The brain diseases such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD) are the most common mental disorders that are currently widespread in numerous countries. The intricate biochemical and molecular machinery contributing to the neurological disorders is still unknown, and in this chapter, we revealed the involvement of dietary amino acids on neurological diseases.

  1. Neuroanatomy of Shared Conversational Laughter in Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Peter S. Pressman

    2018-06-01

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

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

    OpenAIRE

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

    2011-01-01

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

  3. The applications of pharmacogenomics to neurological disorders.

    Science.gov (United States)

    Gilman, C; McSweeney, C; Mao, Y

    2014-01-01

    The most common neurological disorders, including neurodegenerative diseases and psychiatric disorders, have received recent attention with regards to pharmacogenomics and personalized medicine. Here, we will focus on a neglected neurodegenerative disorder, cerebral ischemic stroke (CIS), and highlight recent advances in two disorders, Parkinson's disease (PD) and Alzheimer's diseases (AD), that possess both similar and distinct mechanisms in regards to potential therapeutic targets. In the first part of this review, we will focus primarily on mechanisms that are somewhat specific to each disorder which are involved in neurodegeneration (i.e., protease pathways, calcium homeostasis, reactive oxygen species regulation, DNA repair mechanisms, neurogenesis regulation, mitochondrial function, etc.). In the second part of this review, we will discuss the applications of the genome-wide technology on pharmacogenomics of mental illnesses including schizophrenia (SCZ), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD).

  4. Effect of disorder and defects in ion-implanted semiconductors optical and photothermal characterization

    CERN Document Server

    Willardson, R K; Christofides, Constantinos; Ghibaudo, Gerard

    1997-01-01

    Defects in ion-implanted semiconductors are important and will likely gain increased importance as annealing temperatures are reduced with successive IC generations. Novel implant approaches, such as MdV implantation, create new types of defects whose origin and annealing characteristics will need to be addressed. Publications in this field mainly focus on the effects of ion implantation on the material and the modification in the implanted layer after high temperature annealing. The editors of this volume and Volume 45 focus on the physics of the annealing kinetics of the damaged layer. An overview of characterization tehniques and a critical comparison of the information on annealing kinetics is also presented. Key Features * Provides basic knowledge of ion implantation-induced defects * Focuses on physical mechanisms of defect annealing * Utilizes electrical, physical, and optical characterization tools for processed semiconductors * Provides the basis for understanding the problems caused by the defects g...

  5. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

    Science.gov (United States)

    Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

    Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Nicola Gaetano Gatta

    2016-11-01

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

  7. Risk characterization of hospitalizations for mental illness and/or behavioral disorders with concurrent heat-related illness.

    Directory of Open Access Journals (Sweden)

    Michael T Schmeltz

    Full Text Available Many studies have found significant associations between high ambient temperatures and increases in heat-related morbidity and mortality. Several studies have demonstrated that increases in heat-related hospitalizations are elevated among individuals with diagnosed mental illnesses and/or behavioral disorders (MBD. However, there are a limited number of studies regarding risk factors associated with specific mental illnesses that contribute, at least in part, to heat-related illnesses (HRI in the United States.To identify and characterize individual and environmental risk factors associated with MBD hospitalizations with a concurrent HRI diagnosis.This study uses hospitalization data from the Nationwide Inpatient Sample (2001-2010. Descriptive analyses of primary and secondary diagnoses of MBDs with an HRI were examined. Risk ratios (RR were calculated from multivariable models to identify risk factors for hospitalizations among patients with mental illnesses and/or behavioral disorders and HRI.Nondependent alcohol/drug abuse, dementia, and schizophrenia were among the disorders that were associated with increased frequency of HRI hospitalizations among MBD patients. Increased risk of MBD hospitalizations with HRI was observed for Males (RR, 3.06, African Americans (RR, 1.16, Native Americans (RR, 1.70, uninsured (RR, 1.92, and those 40 years and older, compared to MBD hospitalizations alone.Previous studies outside the U.S. have found that dementia and schizophrenia are significant risk factors for HRI hospitalizations. Our results suggest that hospitalizations among substance abusers may also be an important risk factor associated with heat morbidity. Improved understanding of these relative risks could help inform future public health strategies.

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

    Science.gov (United States)

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

    2018-01-01

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

  9. Molecular origin of polyglutamine aggregation in neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    2005-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Grégory Ben-Sadoun

    2018-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Ailton Melo

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sahar eAl-Mahdawi

    2014-12-01

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

  13. From narcissistic personality disorder to frontotemporal dementia: a case report.

    Science.gov (United States)

    Poletti, Michele; Bonuccelli, Ubaldo

    2011-01-01

    Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disorders more at risk to develop a dementia than mentally healthy subjects? This topic is discussed presenting the clinical case of a patient who suffered of a probable Narcissistic Personality Disorder and subsequently developed a clinically diagnosed Frontotemporal Dementia.

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

    Directory of Open Access Journals (Sweden)

    Yenisetti SC

    2016-06-01

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

  15. Quinoline Fluorescent Probes for Zinc - from Diagnostic to Therapeutic Molecules in Treating Neurodegenerative Diseases.

    Science.gov (United States)

    Czaplinska, Barbara; Spaczynska, Ewelina; Musiol, Robert

    2018-01-01

    Fluorescent compounds had gained strong attention due to their wide and appealing applications. Microscopic techniques and visualization are good examples among others. Introduction of fluorescent dyes into microbiology opens the possibility to observe tissues, organisms or organelle with exceptional sensitivity and resolution. Probes for detection of biologically relevant metals as zinc, iron or copper seems to be particularly important for drug design and pharmaceutical sciences. Quinoline derivatives are well known for their good metal affinity and wide spectrum of biological activity. In this regard, molecular sensors built on this scaffold may be useful not only as analytical but also as therapeutic agents. In the present review, application of quinoline moiety in designing of novel fluorescent probes for zinc is presented and discussed. Zinc cations are relevant for vast majority of processes and recently attract a great deal of attention for their role in neurodegenerative diseases. Compounds interacting with Zn2+ may be used for early diagnosis of such disorders, for example the Alzheimer disease. Quinoline-based zinc probes may exert some beneficial role in organism acting as theranostic agents. First preliminary drugs for Alzheimer therapy that are based on quinoline moiety are good example of this trend. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-12-01

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

  17. Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Matthew J Haney

    Full Text Available The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD. This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.

  18. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

    Science.gov (United States)

    Felder, Christian C; Goldsmith, Paul J; Jackson, Kimberley; Sanger, Helen E; Evans, David A; Mogg, Adrian J; Broad, Lisa M

    2018-01-25

    The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. Copyright © 2018. Published by Elsevier Ltd.

  19. [Cost of therapy for neurodegenerative diseases. Applying an activity-based costing system].

    Science.gov (United States)

    Sánchez-Rebull, María-Victoria; Terceño Gómez, Antonio; Travé Bautista, Angeles

    2013-01-01

    To apply the activity based costing (ABC) model to calculate the cost of therapy for neurodegenerative disorders in order to improve hospital management and allocate resources more efficiently. We used the case study method in the Francolí long-term care day center. We applied all phases of an ABC system to quantify the cost of the activities developed in the center. We identified 60 activities; the information was collected in June 2009. The ABC system allowed us to calculate the average cost per patient with respect to the therapies received. The most costly and commonly applied technique was psycho-stimulation therapy. Focusing on this therapy and on others related to the admissions process could lead to significant cost savings. ABC costing is a viable method for costing activities and therapies in long-term day care centers because it can be adapted to their structure and standard practice. This type of costing allows the costs of each activity and therapy, or combination of therapies, to be determined and aids measures to improve management. Copyright © 2012 SESPAS. Published by Elsevier Espana. All rights reserved.

  20. Basic pathologies of neurodegenerative dementias and their relevance for state-of-the-art molecular imaging studies

    International Nuclear Information System (INIS)

    Drzezga, Alexander

    2008-01-01

    Rising life-expectancy in the modern society has resulted in a rapidly growing prevalence of dementia, particularly of Alzheimer's disease (AD). Dementia turns into one of the most common age-related disorders with deleterious consequences for the concerned patients and their relatives, as well as worrying effects on the socio-economic systems. These facts justify strengthened scientific efforts to identify the pathologic origin of dementing disorders, to improve diagnosis, and to interfere therapeutically with the disease progression. In the recent years, remarkable progress has been made concerning the identification of molecular mechanisms underlying the pathology of neurodegenerative disorders. Growing evidence indicates that a common basis of many neurodegenerative dementias can be found in increased production, misfolding and pathological aggregation of proteins, such as ss-amyloid, tau protein, a-synuclein, or the recently described ubiquitinated TDP-43. This progressive insight in pathological processes is paralleled by the development of new therapeutic approaches. However, the exact contribution or mechanism of different pathologies with regard to the development of disease is not yet sufficiently clear. Considerable overlap of pathologies has been documented in different types of clinically defined dementias post mortem, and it has been difficult to correlate post mortem histopathology data with disease-expression during life. Molecular imaging procedures may play a valuable role to circumvent this limitation. In general, methods of molecular imaging have recently experienced an impressive advance, with numerous new and improved technologies emerging. These exciting tools may play a key role in the future regarding the evaluation of pathomechanisms, preclinical evaluation of new diagnostic procedures in animal models, selection of patients for clinical trials, and therapy monitoring. In this overview, molecular key pathologies, which are currently

  1. Effect of disorder and defects in ion-implanted semiconductors electrical and physiochemical characterization

    CERN Document Server

    Willardson, Robert K; Christofides, Constantinos; Ghibaudo, Gerard

    2014-01-01

    Defects in ion-implanted semiconductors are important and will likely gain increased importance in the future as annealing temperatures are reduced with successive IC generations. Novel implant approaches, such as MdV implantation, create new types of defects whose origin and annealing characteristics will need to be addressed. Publications in this field mainly focus on the effects of ion implantation on the material and the modification in the implanted layer afterhigh temperature annealing.Electrical and Physicochemical Characterization focuses on the physics of the annealing kine

  2. Mitochondrial Mutations in Subjects with Psychiatric Disorders

    NARCIS (Netherlands)

    V. Sequeira (Vasco); S.M. Rollins; C. Magnan (Christophe); M. van Oven (Mannis); P. Baldi (Pierre); R.M. Myers (Richard M.); J.D. Barchas (Jack D.); A.F. Schatzberg (Alan F); S.J. Watson (Stanley J); H. Akil (Huda); W.E. Bunney (William E.); M.P. Vawter (Marquis)

    2015-01-01

    textabstractA considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear

  3. p75 neurotrophin receptor positive dental pulp stem cells: new hope for patients with neurodegenerative disease and neural injury.

    Science.gov (United States)

    Dai, Jie-wen; Yuan, Hao; Shen, Shun-yao; Lu, Jing-ting; Zhu, Xiao-fang; Yang, Tong; Zhang, Jiang-fei; Shen, Guo-fang

    2013-08-01

    Neurodegenerative diseases and neural injury are 2 of the most feared disorders that afflict humankind by leading to permanent paralysis and loss of sensation. Cell based treatment for these diseases had gained special interest in recent years. Previous studies showed that dental pulp stem cells (DPSCs) could differentiate toward functionally active neurons both in vitro and in vivo, and could promote neuranagenesis through both cell-autonomous and paracrine neuroregenerative activities. Some of these neuroregenerative activities were unique to tooth-derived stem cells and superior to bone marrow stromal cells. However, DPSCs used in most of these studies were mixed and unfractionated dental pulp cells that contain several types of cells, and most were fibroblast cells while just contain a small portion of DPSCs. Thus, there might be weaker ability of neuranagenesis and more side effects from the fibroblast cells that cannot differentiate into neural cells. p75 neurotrophin receptor (p75NTR) positive DPSCs subpopulation was derived from migrating cranial neural crest cells and had been isolated from DPSCs, which had capacity of differentiation into neurons and repairing neural system. In this article, we hypothesize that p75NTR positive DPSCs simultaneously have greater propensity for neuronal differentiation and fewer side effects from fibroblast, and in vivo transptantation of autologous p75NTR positive DPSCs is a novel method for neuranagenesis. This will bring great hope to patients with neurodegenerative disease and neural injury.

  4. The Mircen project, neuro-degenerative disease: mechanisms, therapeutics and imaging research Unit URA Cea Cnrs 2210

    International Nuclear Information System (INIS)

    Hantraye, Ph.

    2006-01-01

    During the post-genomic era, significant advances in our understanding of the molecular basis of disease have been made. The power of functional and molecular imaging in translating this knowledge into effective therapy is now being more and more recognized. Thus, molecular imaging plays a vital role in the early identification of disease-related molecular markers, in the development of molecular-targeted therapies, and in monitoring phenotypic response to therapy both in experimental animals and in human patients. In this context, MIRCen (acronym for Molecular Imaging Research Center ) provides a comprehensive resource available to empower basic, translational, and clinical research through the application of imaging and drug, cell, and gene based technologies. The MIR center will be dedicated to the development of pre-clinical trials for the treatment of various seriously debilitating diseases such as neuro-degenerative diseases, cardiac and hepatic disorders, and infectious diseases (AIDS). Despite the fact that many of these pathologies are still incurable, recent advances in drug, cell and gene therapy point to the feasibility of new therapeutic approaches. The long term goals of MIRCen are therefore to develop and validate: - pertinent animal models for neuro-degenerative, hepatic, cardiac and infectious diseases in rodents as well as non-human primates, - novel technologies for in vivo sensing and imaging of disease-related molecular events,- drug, gene and cell based palliative and or curative therapeutic strategies aiming at protecting and /or restoring damaged or lost functions. (author)

  5. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

    2016-12-20

    Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

  6. High internal noise and poor external noise filtering characterize perception in autism spectrum disorder.

    Science.gov (United States)

    Park, Woon Ju; Schauder, Kimberly B; Zhang, Ruyuan; Bennetto, Loisa; Tadin, Duje

    2017-12-14

    An emerging hypothesis postulates that internal noise is a key factor influencing perceptual abilities in autism spectrum disorder (ASD). Given fundamental and inescapable effects of noise on nearly all aspects of neural processing, this could be a critical abnormality with broad implications for perception, behavior, and cognition. However, this proposal has been challenged by both theoretical and empirical studies. A crucial question is whether and how internal noise limits perception in ASD, independently from other sources of perceptual inefficiency, such as the ability to filter out external noise. Here, we separately estimated internal noise and external noise filtering in ASD. In children and adolescents with and without ASD, we computationally modeled individuals' visual orientation discrimination in the presence of varying levels of external noise. The results revealed increased internal noise and worse external noise filtering in individuals with ASD. For both factors, we also observed high inter-individual variability in ASD, with only the internal noise estimates significantly correlating with severity of ASD symptoms. We provide evidence for reduced perceptual efficiency in ASD that is due to both increased internal noise and worse external noise filtering, while highlighting internal noise as a possible contributing factor to variability in ASD symptoms.

  7. Major depressive disorder is characterized by greater reward network activation to monetary than pleasant image rewards.

    Science.gov (United States)

    Smoski, Moria J; Rittenberg, Alison; Dichter, Gabriel S

    2011-12-30

    Anhedonia, the loss of interest or pleasure in normally rewarding activities, is a hallmark feature of unipolar Major Depressive Disorder (MDD). A growing body of literature has identified frontostriatal dysfunction during reward anticipation and outcomes in MDD. However, no study to date has directly compared responses to different types of rewards such as pleasant images and monetary rewards in MDD. To investigate the neural responses to monetary and pleasant image rewards in MDD, a modified Monetary Incentive Delay task was used during functional magnetic resonance imaging to assess neural responses during anticipation and receipt of monetary and pleasant image rewards. Participants included nine adults with MDD and 13 affectively healthy controls. The MDD group showed lower activation than controls when anticipating monetary rewards in right orbitofrontal cortex and subcallosal cortex, and when anticipating pleasant image rewards in paracingulate and supplementary motor cortex. The MDD group had relatively greater activation in right putamen when anticipating monetary versus pleasant image rewards, relative to the control group. Results suggest reduced reward network activation in MDD when anticipating rewards, as well as relatively greater hypoactivation to pleasant image than monetary rewards. 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Nuclear magnetic resonance characterization of metabolite disorder in orange trees caused by citrus sudden death disease.

    Science.gov (United States)

    Prestes, Rosilene A; Colnago, Luiz A; Forato, Lucimara A; Carrilho, Emanuel; Bassanezi, Renato B; Wulff, Nelson A

    2009-01-01

    Citrus sudden death (CSD) is a new disease of sweet orange and mandarin trees grafted on Rangpur lime and Citrus volkameriana rootstocks. It was first seen in Brazil in 1999, and has since been detected in more than four million trees. The CSD causal agent is unknown and the current hypothesis involves a virus similar to Citrus tristeza virus or a new virus named Citrus sudden death-associated virus. CSD symptoms include generalized foliar discoloration, defoliation and root death, and, in most cases, it can cause tree death. One of the unique characteristics of CSD disease is the presence of a yellow stain in the rootstock bark near the bud union. This region also undergoes profound anatomical changes. In this study, we analyse the metabolic disorder caused by CSD in the bark of sweet orange grafted on Rangpur lime by nuclear magnetic resonance (NMR) spectroscopy and imaging. The imaging results show the presence of a large amount of non-functional phloem in the rootstock bark of affected plants. The spectroscopic analysis shows a high content of triacylglyceride and sucrose, which may be related to phloem blockage close to the bud union. We also propose that, without knowing the causal CSD agent, the determination of oil content in rootstock bark by low-resolution NMR can be used as a complementary method for CSD diagnosis, screening about 300 samples per hour.

  9. Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset.

    Science.gov (United States)

    Collongues, N; Marignier, R; Jacob, A; Leite, M I; Siva, A; Paul, F; Zephir, H; Akman-Demir, G; Elsone, L; Jarius, S; Papeix, C; Mutch, K; Saip, S; Wildemann, B; Kitley, J; Karabudak, R; Aktas, O; Kuscu, D; Altintas, A; Palace, J; Confavreux, C; De Seze, J

    2014-07-01

    Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death. © The Author(s) 2013.

  10. Characterization of the deleted in autism 1 protein family: implications for studying cognitive disorders.

    Science.gov (United States)

    Aziz, Azhari; Harrop, Sean P; Bishop, Naomi E

    2011-01-19

    Autism spectrum disorders (ASDs) are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1) and cXorf36 or Deleted in Autism-1 Related (DIA1R) are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1-related gene we named DIA1-Like (DIA1L), lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1-family members will have implications for our understanding of autism and mental retardation.

  11. Characterization of the deleted in autism 1 protein family: implications for studying cognitive disorders.

    Directory of Open Access Journals (Sweden)

    Azhari Aziz

    2011-01-01

    Full Text Available Autism spectrum disorders (ASDs are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1 and cXorf36 or Deleted in Autism-1 Related (DIA1R are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1-related gene we named DIA1-Like (DIA1L, lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1-family members will have implications for our understanding of autism and mental

  12. Increased Anterior Pelvic Angle Characterizes the Gait of Children with Attention Deficit/Hyperactivity Disorder (ADHD).

    Science.gov (United States)

    Naruse, Hiroaki; Fujisawa, Takashi X; Yatsuga, Chiho; Kubota, Masafumi; Matsuo, Hideaki; Takiguchi, Shinichiro; Shimada, Seiichiro; Imai, Yuto; Hiratani, Michio; Kosaka, Hirotaka; Tomoda, Akemi

    2017-01-01

    Children with attention deficit/hyperactivity disorder (ADHD) frequently have motor problems. Previous studies have reported that the characteristic gait in children with ADHD is immature and that subjects demonstrate higher levels of variability in gait characteristics for the lower extremities than healthy controls. However, little is known about body movement during gait in children with ADHD. The purpose of this study was to identify the characteristic body movements associated with ADHD symptoms in children with ADHD. Using a three-dimensional motion analysis system, we compared gait variables in boys with ADHD (n = 19; mean age, 9.58 years) and boys with typical development (TD) (n = 21; mean age, 10.71 years) to determine the specific gait characteristics related to ADHD symptoms. We assessed spatiotemporal gait variables (i.e. speed, stride length, and cadence), and kinematic gait variables (i.e. angle of pelvis, hip, knee, and ankle) to measure body movement when walking at a self-selected pace. In comparison with the TD group, the ADHD group demonstrated significantly higher values in cadence (t = 3.33, p = 0.002) and anterior pelvic angle (t = 3.08, p = 0.004). In multiple regression analysis, anterior pelvic angle was associated with the ADHD rating scale hyperactive/impulsive scores (β = 0.62, t = 2.58, p = 0.025), but not other psychiatric symptoms in the ADHD group. Our results suggest that anterior pelvic angle represents a specific gait variable related to ADHD symptoms. Our kinematic findings could have potential implications for evaluating the body movement in boys with ADHD.

  13. Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy

    DEFF Research Database (Denmark)

    Dauvilliers, Yves; Jennum, Poul; Plazzi, Giuseppe

    2013-01-01

    Narcolepsy is a rare disabling hypersomnia disorder that may include cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) periods, but also disrupted nighttime sleep by nocturnal awakenings, and REM sleep behavior disorder (RBD). RBD is characterized...... by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with neurodegenerative disorders including Parkinsonisms, but is also reported in narcolepsy in up to 60% of patients. RBD in patients with narcolepsy is, however...... with narcolepsy often present dissociated sleep features including RSWA, increased density of phasic chin EMG and frequent shift from REM to NREM sleep, with or without associated clinical RBD. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. Tonic and phasic...

  14. Somatic Symptom Disorder in Semantic Dementia: The Role of Alexisomia.

    Science.gov (United States)

    Gan, Joanna J; Lin, Andrew; Samimi, Mersal S; Mendez, Mario F

    Semantic dementia (SD) is a neurodegenerative disorder characterized by loss of semantic knowledge. SD may be associated with somatic symptom disorder due to excessive preoccupation with unidentified somatic sensations. To evaluate the frequency of somatic symptom disorder among patients with SD in comparison to comparably demented patients with Alzheimer׳s disease. A retrospective cohort study was conducted using clinical data from a referral-based behavioral neurology program. Fifty-three patients with SD meeting criteria for imaging-supported semantic variant primary progressive aphasia (another term for SD) were compared with 125 patients with clinically probable Alzheimer disease. Logistic regression controlled for sex, age, disease duration, education, overall cognitive impairment, and depression. The prevalence of somatic symptom disorder was significantly higher among patients with SD (41.5%) compared to patients with Alzheimer disease (11.2%) (odds ratio = 6:1; p Cotard syndrome or the delusion that unidentified somatic symptoms signify death or deterioration. SD, a disorder of semantic knowledge, is associated with somatic symptom disorder from impaired identification of somatic sensations. Their inability to read and name somatic sensations, or "alexisomia," results in disproportionate and persistent concern about somatic sensations with consequent significant disability. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

  15. Prevalence and characterization of neonatal skin disorders in the first 72h of life.

    Science.gov (United States)

    Reginatto, Flávia Pereira; DeVilla, Damie; Muller, Fernanda M; Peruzzo, Juliano; Peres, Letícia P; Steglich, Raquel B; Cestari, Tania F

    To determine the prevalence of neonatal dermatological findings and analyze whether there is an association between these findings and neonatal and pregnancy characteristics and seasonality. Newborns from three maternity hospitals in a Brazilian capital city were randomly selected to undergo dermatological assessment by dermatologists. 2938 neonates aged up to three days of life were randomly selected, of whom 309 were excluded due to Intensive Care Unit admission. Of the 2530 assessed neonates, 49.6% were Caucasians, 50.5% were males, 57.6% were born by vaginal delivery, and 92.5% of the mothers received prenatal care. Some dermatological finding was observed in 95.8% of neonates; of these, 88.6% had transient neonatal skin conditions, 42.6% had congenital birthmarks, 26.8% had some benign neonatal pustulosis, 2% had lesions secondary to trauma (including scratches), 0.5% had skin malformations, and 0.1% had an infectious disease. The most prevalent dermatological findings were: lanugo, which was observed in 38.9% of the newborns, sebaceous hyperplasia (35%), dermal melanocytosis (24.61%), skin desquamation (23.3%), erythema toxicum neonatorum (23%), salmon patch (20.4%), skin erythema (19%), genital hyperpigmentation (18.4%), eyelid edema (17.4%), milia (17.3%), genital hypertrophy (12%), and skin xerosis (10.9%). Dermatological findings are frequent during the first days of life and some of them characterize the newborn's skin. Mixed-race newborns and those whose mothers had some gestational risk factor had more dermatological findings. The gestational age, newborn's ethnicity, gender, Apgar at the first and fifth minutes of life, type of delivery, and seasonality influenced the presence of specific neonatal dermatological findings. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

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

    Science.gov (United States)

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

    2017-12-01

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

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

    Science.gov (United States)

    Brady, Scott T; Morfini, Gerardo A

    2017-09-01

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

  18. Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Alexei Vazquez

    Full Text Available The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.

  19. Chronic Neurodegenerative Illnesses and Epilepsy in Danish Adventists and Baptists: A Nationwide Cohort Study.

    Science.gov (United States)

    Thygesen, Lau Caspar; Gimsing, Louise NØrreslet; Bautz, Andrea; Hvidt, Niels Christian; Johansen, Christoffer

    2017-01-01

    Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exists. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco. We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer's disease, Parkinson's disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age. We compared hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence ratios (SIR) stratified by sex, age, and calendar time were calculated. SIR of dementia or Alzheimer's disease was significantly decreased for members of both communities (SDA, 0.78; 95% CI, 0.67-#x2013;0.90 and Baptists, 0.59; 0.47-#x2013;0.73). The SIRs of Parkinson's disease and epilepsy were not significantly different compared to the general population. We observe reduced incidence for dementia or Alzheimer's disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system.

  20. REM Sleep Behavior Disorder in Parkinson's Disease and Other Synucleinopathies.

    Science.gov (United States)

    St Louis, Erik K; Boeve, Angelica R; Boeve, Bradley F

    2017-05-01

    Rapid eye movement sleep behavior disorder is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. Rapid eye movement sleep behavior disorder may be idiopathic or symptomatic and in both settings is highly associated with synucleinopathy neurodegeneration, especially Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Rapid eye movement sleep behavior disorder frequently manifests years to decades prior to overt motor, cognitive, or autonomic impairments as the presenting manifestation of synucleinopathy, along with other subtler prodromal "soft" signs of hyposmia, constipation, and orthostatic hypotension. Between 35% and 91.9% of patients initially diagnosed with idiopathic rapid eye movement sleep behavior disorder at a sleep center later develop a defined neurodegenerative disease. Less is known about the long-term prognosis of community-dwelling younger patients, especially women, and rapid eye movement sleep behavior disorder associated with antidepressant medications. Patients with rapid eye movement sleep behavior disorder are frequently prone to sleep-related injuries and should be treated to prevent injury with either melatonin 3-12 mg or clonazepam 0.5-2.0 mg to limit injury potential. Further evidence-based studies about rapid eye movement sleep behavior disorder are greatly needed, both to enable accurate prognostic prediction of end synucleinopathy phenotypes for individual patients and to support the application of symptomatic and neuroprotective therapies. Rapid eye movement sleep behavior disorder as a prodromal synucleinopathy represents a defined time point at which neuroprotective therapies could potentially be applied for the prevention of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. © 2017

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

    Science.gov (United States)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  5. 4 Tesla Whole Body MRI MRSI System for Investigation of Neurodegenerative Diseases

    National Research Council Canada - National Science Library

    Weiner, Michael W

    2004-01-01

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

  6. Prevalence and characterization of neonatal skin disorders in the first 72 h of life

    Directory of Open Access Journals (Sweden)

    Flávia Pereira Reginatto

    2017-05-01

    Full Text Available Objective: To determine the prevalence of neonatal dermatological findings and analyze whether there is an association between these findings and neonatal and pregnancy characteristics and seasonality. Methods: Newborns from three maternity hospitals in a Brazilian capital city were randomly selected to undergo dermatological assessment by dermatologists. Results: 2938 neonates aged up to three days of life were randomly selected, of whom 309 were excluded due to Intensive Care Unit admission. Of the 2530 assessed neonates, 49.6% were Caucasians, 50.5% were males, 57.6% were born by vaginal delivery, and 92.5% of the mothers received prenatal care. Some dermatological finding was observed in 95.8% of neonates; of these, 88.6% had transient neonatal skin conditions, 42.6% had congenital birthmarks, 26.8% had some benign neonatal pustulosis, 2% had lesions secondary to trauma (including scratches, 0.5% had skin malformations, and 0.1% had an infectious disease. The most prevalent dermatological findings were: lanugo, which was observed in 38.9% of the newborns, sebaceous hyperplasia (35%, dermal melanocytosis (24.61%, skin desquamation (23.3%, erythema toxicum neonatorum (23%, salmon patch (20.4%, skin erythema (19%, genital hyperpigmentation (18.4%, eyelid edema (17.4%, milia (17.3%, genital hypertrophy (12%, and skin xerosis (10.9%. Conclusions: Dermatological findings are frequent during the first days of life and some of them characterize the newborn's skin. Mixed-race newborns and those whose mothers had some gestational risk factor had more dermatological findings. The gestational age, newborn's ethnicity, gender, Apgar at the first and fifth minutes of life, type of delivery, and seasonality influenced the presence of specific neonatal dermatological findings. Resumo: Objetivo: Verificar a prevalência dos achados dermatológicos nos primeiros dias de vida e analisar se há associação com características neonatais, gestacionais e

  7. Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

    Science.gov (United States)

    Lattante, Serena; Millecamps, Stéphanie; Stevanin, Giovanni; Rivaud-Péchoux, Sophie; Moigneu, Carine; Camuzat, Agnès; Da Barroca, Sandra; Mundwiller, Emeline; Couarch, Philippe; Salachas, François; Hannequin, Didier; Meininger, Vincent; Pasquier, Florence; Seilhean, Danielle; Couratier, Philippe; Danel-Brunaud, Véronique; Bonnet, Anne-Marie; Tranchant, Christine; LeGuern, Eric; Brice, Alexis; Le Ber, Isabelle; Kabashi, Edor

    2014-09-09

    The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. © 2014 American Academy of Neurology.

  8. The Wnt antagonist, Dickkopf-1, as a target for the treatment of neurodegenerative disorders

    NARCIS (Netherlands)

    Caraci, Filippo; Busceti, Carla; Biagioni, Francesca; Aronica, Eleonora; Mastroiacovo, Federica; Cappuccio, Irene; Battaglia, Giuseppe; Bruno, Valeria; Caricasole, Andrea; Copani, Agata; Nicoletti, Ferdinando

    2008-01-01

    The canonical Wnt pathway contributes to the regulation of neuronal survival and homeostasis in the CNS. Recent evidence suggests that an increased expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the canonical Wnt pathway, is causally related to processes of

  9. Neurotoxins and Neurodegenerative Disorders in Japanese-American Men Living in Hawaii

    Science.gov (United States)

    2008-09-01

    Bugianesi R, Maiani G, Valtuena S, De Santis S, Crozier A. Plasma antioxidants from chocolate . Nature 2003;424:1013. 19. Jenner P, Olanow CW...0.004). Additional adjustment for insomnia, cognitive function, depressed mood , midlife cigarette smoking and coffee drinking, and other factors failed...coffee intake, daily bowel movement frequency, cognitive performance, depressed mood , and the use of antidepressants, antipsychotics, and sedatives

  10. Krabbe Disease: Report of a Rare Lipid Storage and Neurodegenerative Disorder.

    Science.gov (United States)

    Pavuluri, Pratyusha; Vadakedath, Sabitha; Gundu, Rajkumar; Uppulety, Sushmitha; Kandi, Venkataramana

    2017-01-01

    Krabbe disease is a rare (one in 100,000 births) autosomal recessive condition, usually noticed among children. It causes sphingolipidosis (dysfunctional metabolism of sphingolipids) and leads to fatal degenerative changes affecting the myelin sheath of the nervous system. We report a case of a six-year-old male child who presented with symptoms of muscle spasticity and irritability. Diagnosis of this disease can only be made with clinical suspicion. Laboratory diagnosis includes brain magnetic resonance imaging (MRI), magnetic resonance (MR) spectroscopy, biochemical analysis of cerebrospinal fluid, and genetic analysis for detecting mutation in genes coding for galactosyl cerebroside (GALC). We report a case of late infantile Krabbe disease.

  11. Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

    National Research Council Canada - National Science Library

    Browne, Susan E

    2004-01-01

    ... Generation in Parkinson's Disease", which was appended to the original grant number. This project is to assess in vivo whether mitochondria are the source of free radical generation in animal models of Parkinson's disease (PD...

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

    Directory of Open Access Journals (Sweden)

    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. Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

    National Research Council Canada - National Science Library

    Brown, Susan

    1999-01-01

    ... (HE) and familial amyotrophic lateral sclerosis (FALS), using transgenic mouse models. Studies in this first year employed C-14-2-deoxyglucose in vivo autoradiography and spectrophotometric metabolic enzyme assays...

  14. Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

    Science.gov (United States)

    2005-06-01

    perman- ganate, fungicides, and gasoline additives containing manganese (Albin, 2000). The symptom phenotype of manganese toxicity results from the...activity, followed by hypokinesis and locomotor de- chromosome were inserted into the appropriate position in Hdh terioration. Mice die prematurely (24-32

  15. Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future.

    Science.gov (United States)

    Moos, Walter H; Faller, Douglas V; Glavas, Ioannis P; Harpp, David N; Irwin, Michael H; Kanara, Iphigenia; Pinkert, Carl A; Powers, Whitney R; Steliou, Kosta; Vavvas, Demetrios G; Kodukula, Krishna

    2017-01-01

    Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.

  16. Chemistry and functional properties in prevention of neurodegenerative disorders of five Cistus species essential oils.

    Science.gov (United States)

    Loizzo, Monica Rosa; Ben Jemia, Mariem; Senatore, Felice; Bruno, Maurizio; Menichini, Francesco; Tundis, Rosa

    2013-09-01

    The chemical composition of Cistus creticus, Cistus salvifolius, Cistus libanotis, Cistus monspeliensis and Cistus villosus essential oils has been examined by GC and GC-MS analysis. Height-nine constituents were identified in C. salvifolius oil, sixty in C. creticus, fifty-six in C. libanotis, fifty-four in C. villosus, forty-five in C. monspeliensis. Although the five species belong to the same genus, the composition showed interesting differences. Essential oils were screened also for their potential antioxidant effects (by DPPH, ABTS, FRAP and β-carotene bleaching test) and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, useful for prevention and treatment of Alzheimer's disease. C. monspeliensis exhibited the most promising activity in β-carotene bleaching test (IC₅₀ of 54.7 μg/mL). In FRAP test C. libanotis showed a value of 19.2 μM Fe(II)/g. C. salvifolius showed the highest activity against AChE (IC₅₀ of 58.1 μg/mL) while C. libanotis, C. creticus, C. salvifolius demonstrated a good inhibitory activity against BChE with IC₅₀ values of 23.7, 29.1 and 34.2 μg/mL, respectively. Overall our results could promote the use of the essential oil of different Cistus species as food additives and for formulation of herbal infusion or nutraceutical products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Novel mitochondrial substrates of omi indicate a new regulatory role in neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Felicity Johnson

    Full Text Available The mitochondrial protease OMI (also known as HtrA2 has been implicated in Parkinson's Disease (PD and deletion or protease domain point mutations have shown profound neuropathologies in mice. A beneficial role by OMI, in preserving cell viability, is assumed to occur via the avoidance of dysfunctional protein turnover. However relatively few substrates for mitochondrial Omi are known. Here we report our identification of three novel mitochondrial substrates that impact metabolism and ATP production. Using a dual proteomic approach we have identified three interactors based upon ability to bind to OMI, and/or to persist in the proteome after OMI activity has been selectively inhibited. One candidate, the chaperone HSPA8, was common to each independent study. Two others (PDHB subunit and IDH3A subunit did not appear to bind to OMI, however persisted in the mito-proteome when OMI was inhibited. Pyruvate dehydrogenase (PDH and isocitrate dehydrogenase (IDH are two key Kreb's cycle enzymes that catalyse oxidative decarboxylation control points in mitochondrial respiration. We verified both PDHB and IDH3A co-immunoprecipitate with HSPA8 and after elution, were degraded by recombinant HtrA2 in vitro. Additionally our gene expression studies, using rotenone (an inhibitor of Complex I showed Omi expression was silenced when pdhb and idh3a were increased when a sub-lethal dose was applied. However higher dose treatment caused increased Omi expression and decreased levels of pdhb and idh3a transcripts. This implicates mitochondrial OMI in a novel mechanism relating to metabolism.

  18. Bipolar disorders

    DEFF Research Database (Denmark)

    Vieta, Eduard; Berk, Michael; Schulze, Thomas G

    2018-01-01

    Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease...... and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand...... a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary....

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

    Directory of Open Access Journals (Sweden)

    Nicolas Delcourt

    2017-12-01

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

  20. Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder.

    Science.gov (United States)

    Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S; Lee, Jong-Min; Alonso, Isabel; Gusella, James F; Smoller, Jordan W; Sklar, Pamela; MacDonald, Marcy E; Perlis, Roy H

    2015-06-01

    Huntington's disease is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms that are caused by huntingtin gene (HTT) CAG trinucleotide repeat alleles of 36 or more units. A greater than expected prevalence of incompletely penetrant HTT CAG repeat alleles observed among individuals diagnosed with major depressive disorder raises the possibility that another mood disorder, bipolar disorder, could likewise be associated with Huntington's disease. We assessed the distribution of HTT CAG repeat alleles in a cohort of individuals with bipolar disorder. HTT CAG allele sizes from 2,229 Caucasian individuals diagnosed with DSM-IV bipolar disorder were compared to allele sizes in 1,828 control individuals from multiple cohorts. We found that HTT CAG repeat alleles > 35 units were observed in only one of 4,458 chromosomes from individuals with bipolar disorder, compared to three of 3,656 chromosomes from control subjects. These findings do not support an association between bipolar disorder and Huntington's disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Association between environmental exposure to pesticides and neurodegenerative diseases

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  3. Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds

    Directory of Open Access Journals (Sweden)

    Saif Khan

    2015-01-01

    Full Text Available Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer’s disease (AD, Parkinson’s disease (PD, Huntington’s disease (HD, and amyotrophic lateral sclerosis (ALS. The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

  4. REM Sleep Behavior Disorder and Prodromal Neurodegeneration - Where are We Headed?

    Directory of Open Access Journals (Sweden)

    Ronald B. Postuma

    2013-04-01

    Full Text Available Rapid eye movement (REM sleep behavior disorder (RBD is characterized by loss of normal atonia during REM sleep, such that patients appear to act out their dreams. The most important implication of research into this area is that patients with idiopathic RBD are at very high risk of developing synucleinmediated neurodegenerative disease (Parkinson's disease [PD], dementia with Lewy bodies [DLB], and multiple system atrophy, with risk estimates that approximate 40–65% at 10 years. Thus, RBD disorder is a very strong feature of prodromal synucleinopathy. This provides several opportunities for future research. First, patients with REM sleep behavior disorder can be studied to test other predictors of disease, which could potentially be applied to the general population. These studies have demonstrated that olfactory loss, decreased color vision, slowing on quantitative motor testing, and abnormal substantia nigra neuroimaging findings can predict clinical synucleinopathy. Second, prospectively studying patients with RBD allows a completely unprecedented opportunity to directly evaluate patients as they transition into clinical neurodegenerative disease. Studies assessing progression of markers of neurodegeneration in prodromal PD are beginning to appear. Third, RBD are very promising subjects for neuroprotective therapy trials because they have a high risk of disease conversion with a sufficiently long latency, which provides an opportunity for early intervention. As RBD research expands, collaboration between centers will become increasingly essential.

  5. Applying chaperones to protein-misfolding disorders: molecular chaperones against α-synuclein in Parkinson's disease.

    Science.gov (United States)

    Chaari, Ali; Hoarau-Véchot, Jessica; Ladjimi, Moncef

    2013-09-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD. Published by Elsevier B.V.

  6. Neuro degenerative diseases: clinical concerns; Les maladies neuro-degeneratives: problemes cliniques

    Energy Technology Data Exchange (ETDEWEB)

    Ibanez, V. [Hopitaux Universitaires de Geneve (HUG), Unite de Neuroimagerie, Dept. de Psychiatrie (Switzerland)

    2005-04-15

    Idiopathic Parkinson's disease (PD) and Alzheimer's disease (AD) are the main neuro-degenerative diseases (NDDs) seen clinically. They share some common clinical symptoms and neuro-pathological findings. The increase of life expectancy in the developed countries will inevitably contribute to enhance the prevalence of these diseases. Behavioral disorders, common in NDDs, will produce major care management challenges. Idiopathic Parkinson's disease corresponds to a histopathological diagnosis, based on the observation of a de-pigmentation and a neuronal loss in the substantia nigra, as well as on the presence of intra-neuronal inclusion bodies. AD is insidious with slowly progressive dementia in which the decline in memory constitutes the main complaint. The diagnosis of definite AD requires the presence of clinical criteria as well as the histopathological confirmation of brain lesions. The two main lesions are the presence of senile plaques and neuro-fibrillary tangles. Positron emission tomography (PET) explores cerebral metabolism and neurotransmitter kinetics in NDDs using principally [{sup 18}F]-deoxyglucose and [{sup 18}F]-dopa. Nigrostriatal dopaminergic function is altered in PD, as evidenced by the low uptake of [{sup 18}F]-dopa in the posterior putamen as compared to anterior putamen and caudate nucleus. In contrast, [{sup 18}F]-dopa uptake is equally depressed in all striatal structures in progressive supra-nuclear palsy. Regional glucose metabolism at rest is preserved in elderly once cerebral atrophy is taken into account. On the contrary, glucose metabolism is globally reduced in AD, with marked decrease in the parietal and temporal regions. PET has proved to be useful to study in vivo neurochemical processes in patients suffering from NDDs. The potential of this approach is still largely unexploited, and depends on new ligand production to establish early diagnosis and treatment follow-up. (author)

  7. 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.

  8. Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Fabio Guerriero

    2016-01-01

    Full Text Available Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer's disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

  9. Bipolar disorder, a precursor of Parkinson's disease?

    Directory of Open Access Journals (Sweden)

    Tânia M.S. Novaretti

    Full Text Available ABSTRACT Parkinson's disease is a neurodegenerative disorder predominantly resulting from dopamine depletion in the substantia nigra pars compacta. Some psychiatric disorders may have dopaminergic dysfunction as their substrate. We describe a well-documented case of Parkinson's disease associated with Bipolar Disorder. Although there is some knowledge about the association between these diseases, little is known about its pathophysiology and correlation. We believe that among various hypotheses, many neurotransmitters are linked to this pathophysiology.

  10. A J-modulated protonless NMR experiment characterizes the conformational ensemble of the intrinsically disordered protein WIP

    Energy Technology Data Exchange (ETDEWEB)

    Rozentur-Shkop, Eva; Goobes, Gil; Chill, Jordan H., E-mail: Jordan.Chill@biu.ac.il [Bar Ilan University, Department of Chemistry (Israel)

    2016-12-15

    Intrinsically disordered proteins (IDPs) are multi-conformational polypeptides that lack a single stable three-dimensional structure. It has become increasingly clear that the versatile IDPs play key roles in a multitude of biological processes, and, given their flexible nature, NMR is a leading method to investigate IDP behavior on the molecular level. Here we present an IDP-tailored J-modulated experiment designed to monitor changes in the conformational ensemble characteristic of IDPs by accurately measuring backbone one- and two-bond J({sup 15}N,{sup 13}Cα) couplings. This concept was realized using a unidirectional (H)NCO {sup 13}C-detected experiment suitable for poor spectral dispersion and optimized for maximum coverage of amino acid types. To demonstrate the utility of this approach we applied it to the disordered actin-binding N-terminal domain of WASp interacting protein (WIP), a ubiquitous key modulator of cytoskeletal changes in a range of biological systems. One- and two-bond J({sup 15}N,{sup 13}Cα) couplings were acquired for WIP residues 2–65 at various temperatures, and in denaturing and crowding environments. Under native conditions fitted J-couplings identified in the WIP conformational ensemble a propensity for extended conformation at residues 16–23 and 45–60, and a helical tendency at residues 28–42. These findings are consistent with a previous study of the based upon chemical shift and RDC data and confirm that the WIP{sup 2–65} conformational ensemble is biased towards the structure assumed by this fragment in its actin-bound form. The effects of environmental changes upon this ensemble were readily apparent in the J-coupling data, which reflected a significant decrease in structural propensity at higher temperatures, in the presence of 8 M urea, and under the influence of a bacterial cell lysate. The latter suggests that crowding can cause protein unfolding through protein–protein interactions that stabilize the unfolded

  11. Characterizing sexual function in patients with generalized anxiety disorder: a pooled analysis of three vilazodone studies

    Directory of Open Access Journals (Sweden)

    Clayton AH

    2016-06-01

    Full Text Available Anita H Clayton,1 Suresh Durgam,2 Xiongwen Tang,2 Changzheng Chen,2 Adam Ruth,3 Carl Gommoll2 1Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, 2Forest Research Institute, Jersey City, NJ, 3Prescott Medical Communications Group, Chicago, IL, USA Background: Vilazodone has been shown to reduce core symptoms of generalized anxiety disorder (GAD in three randomized, double-blind, placebo-controlled trials. Since sexual dysfunction (SD is not well characterized in GAD, a post hoc analysis of these trials was conducted to evaluate the effects of vilazodone on sexual functioning in GAD patients. Materials and methods: Data were pooled from one fixed-dose trial of vilazodone 20 and 40 mg/day (NCT01629966 and two flexible-dose studies of vilazodone 20–40 mg/day (NCT01766401, NCT01844115 in adults with GAD. Sexual functioning was assessed using the Changes in Sexual Functioning Questionnaire (CSFQ. Outcomes included mean change from baseline to end of treatment (EOT in CSFQ total score and percentage of patients shifting from SD at baseline (CSFQ total score ≤47 for males, ≤41 for females to normal functioning at EOT. Treatment-emergent adverse events related to sexual functioning were also analyzed. Results: A total of 1,373 patients were included in the analyses. SD at baseline was more common in females (placebo, 46.4%; vilazodone, 49% than in males (placebo, 35.1%; vilazodone, 40.9%. CSFQ total score improvement was found in both females (placebo, +1.2; vilazodone, +1.6 and males (placebo, +2.1; vilazodone, +1.0, with no statistically significant differences between treatment groups. The percentage of patients who shifted from SD at baseline to normal sexual functioning at EOT was higher in males (placebo, 40.6%; vilazodone, 35.7% than in females (placebo, 24.9%; vilazodone, 34.9%; no statistical testing was performed. Except for erectile dysfunction and delayed ejaculation in vilazodone

  12. Virulence test using nematodes to prescreen Nocardia species capable of inducing neurodegeneration and behavioral disorders

    Directory of Open Access Journals (Sweden)

    Claire Bernardin Souibgui

    2017-10-01

    Full Text Available Background Parkinson’s disease (PD is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin. Nocardia are Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS are N. farcinica, N. nova, N. brasiliensis and N. cyriacigeorgica. Some studies have highlighted the ability of N. cyriacigeorgica to induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked. Methods Here we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments. Results The nematode Caenorhabditis elegans allowed us to demonstrate that Nocardia strains belonging to N. cyriacigeorgica and N. farcinica species can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability of Nocardia strains to induce neurodegeneration. These behavioral disorders were induced by N. cyriacigeorgica species (N. cyriacigeorgica GUH-2 and N. cyriacigeorgica 44484 and N. farcinica 10152. Discussion We conclude that C. elegans is a good model for detecting Nocardia strains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to

  13. Conduct disorders

    NARCIS (Netherlands)

    Buitelaar, J.K.; Smeets, K.C.; Herpers, P.; Scheepers, F.; Glennon, J.; Rommelse, N.N.J.

    2013-01-01

    Conduct disorder (CD) is a frequently occurring psychiatric disorder characterized by a persistent pattern of aggressive and non-aggressive rule breaking antisocial behaviours that lead to considerable burden for the patients themselves, their family and society. This review paper updates diagnostic

  14. Molecular Imaging and Precision Medicine in Dementia and Movement Disorders.

    Science.gov (United States)

    Mallik, Atul K; Drzezga, Alexander; Minoshima, Satoshi

    2017-01-01

    Precision medicine (PM) has been defined as "prevention and treatment strategies that take individual variability into account." Molecular imaging (MI) is an ideally suited tool for PM approaches to neurodegenerative dementia and movement disorders (MD). Here we review PM approaches and discuss how they may be applied to other associated neurodegenerative dementia and MD. With ongoing major therapeutic research initiatives that include the use of molecular imaging, we look forward to established interventions targeted to specific molecular pathophysiology and expect the potential benefit of MI PM approaches in neurodegenerative dementia and MD will only increase. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Garth L. Nicolson

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2011-01-01

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

  18. Paraneoplastic autoimmune movement disorders.

    Science.gov (United States)

    Lim, Thien Thien

    2017-11-01

    To provide an overview of paraneoplastic autoimmune disorders presenting with various movement disorders. The spectrum of paraneoplastic autoimmune disorders has been expanding with the discovery of new antibodies against cell surface and intracellular antigens. Many of these paraneoplastic autoimmune disorders manifest as a form of movement disorder. With the discovery of new neuronal antibodies, an increasing number of idiopathic or neurodegenerative movement disorders are now being reclassified as immune-mediated movement disorders. These include anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis which may present with orolingual facial dyskinesia and stereotyped movements, CRMP-5 IgG presenting with chorea, anti-Yo paraneoplastic cerebellar degeneration presenting with ataxia, anti-VGKC complex (Caspr2 antibodies) neuromyotonia, opsoclonus-myoclonus-ataxia syndrome, and muscle rigidity and episodic spasms (amphiphysin, glutamic acid decarboxylase, glycine receptor, GABA(A)-receptor associated protein antibodies) in stiff-person syndrome. Movement disorders may be a presentation for paraneoplastic autoimmune disorders. Recognition of these disorders and their common phenomenology is important because it may lead to the discovery of an occult malignancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Oral Language Impairments in Developmental Disorders Characterized by Language Strengths: A Comparison of Asperger Syndrome and Nonverbal Learning Disabilities

    Science.gov (United States)

    Stothers, M. E.; Cardy, J. Oram

    2012-01-01

    Asperger syndrome (AS) and nonverbal learning disabilities (NLD) are developmental disorders in which linguistic ability is reported to be stronger than in disorders from which they must be distinguished for diagnosis. Children and adults with AS and NLD share pragmatic weaknesses, atypical social behaviours, and some cognitive features. To date,…

  20. REM Behaviour Disorder Detection Associated with Neurodegerative Diseases

    DEFF Research Database (Denmark)

    Kempfner, Jacob; Sørensen, Gertrud Laura; 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...... is proposed by analyzing the motor activity during sleep. Method: A total number of twelve patients have been involved in this study, six normal controls and six patients diagnosed with Parkinsons Disease (PD) with RBD. All subjects underwent at least one ambulant polysomnographic (PSG) recording. The sleep...... recordings were scored, according to the new sleep-scoring standard from the American Academy of Sleep Medicine, by two independent sleep specialists. A follow-up analysis of the scoring consensus between the two specialists has been conducted. Based on the agreement of the two manual scorings...

  1. The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder.

    Science.gov (United States)

    Maurya, Pawan Kumar; Noto, Cristiano; Rizzo, Lucas B; Rios, Adiel C; Nunes, Sandra O V; Barbosa, Décio Sabbatini; Sethi, Sumit; Zeni, Maiara; Mansur, Rodrigo B; Maes, Michael; Brietzke, Elisa

    2016-02-04

    Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising.

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

    Directory of Open Access Journals (Sweden)

    Yang FU

    2018-04-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Science.gov (United States)

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

    2018-06-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-08-01

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

  8. Huntington's Disease in a Patient Misdiagnosed as Conversion Disorder.

    Science.gov (United States)

    Nogueira, João Machado; Franco, Ana Margarida; Mendes, Susana; Valadas, Anabela; Semedo, Cristina; Jesus, Gustavo

    2018-01-01

    Huntington's disease (HD) is an inherited, progressive, and neurodegenerative neuropsychiatric disorder caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide in Interested Transcript (IT) 15 gene on chromosome 4. This pathology typically presents in individuals aged between 30 and 50 years and the age of onset is inversely correlated with the length of the CAG repeat expansion. It is characterized by chorea, cognitive deficits, and psychiatric symptoms. Usually the psychiatric disorders precede motor and cognitive impairment, Major Depressive Disorder and anxiety disorders being the most common presentations. We present a clinical case of a 65-year-old woman admitted to our Psychiatric Acute Unit. During the 6 years preceding the admission, the patient had clinical assessments made several times by different specialties that focused only on isolated symptoms, disregarding the syndrome as a whole. In the course of her last admission, the patient was referred to our Neuropsychiatric Team, which made the provisional diagnosis of late-onset Huntington's disease, later confirmed by genetic testing. This clinical vignette highlights the importance of a multidisciplinary approach to atypical clinical presentations and raises awareness for the relevance of investigating carefully motor symptoms in psychiatric patients.

  9. TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation

    NARCIS (Netherlands)

    Jansen, Jos C.; Timal, Sharita; van Scherpenzeel, Monique; Michelakakis, Helen; Vicogne, Dorothée; Ashikov, Angel; Moraitou, Marina; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; van den Boogert, Marjolein A. W.; Porta, Francesco; Calvo, Pier Luigi; Mavrikou, Mersyni; Cenacchi, Giovanna; van den Bogaart, Geert; Salomon, Jody; Holleboom, Adriaan G.; Rodenburg, Richard J.; Drenth, Joost P. H.; Huynen, Martijn A.; Wevers, Ron A.; Morava, Eva; Foulquier, François; Veltman, Joris A.; Lefeber, Dirk J.

    2016-01-01

    Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously

  10. [Eating disorders].

    Science.gov (United States)

    Miyake, Yoshie; Okamoto, Yuri; Jinnin, Ran; Shishida, Kazuhiro; Okamoto, Yasumasa

    2015-02-01

    Eating disorders are characterized by aberrant patterns of eating behavior, including such symptoms as extreme restriction of food intake or binge eating, and severe disturbances in the perception of body shape and weight, as well as a drive for thinness and obsessive fears of becoming fat. Eating disorder is an important cause for physical and psychosocial morbidity in young women. Patients with eating disorders have a deficit in the cognitive process and functional abnormalities in the brain system. Recently, brain-imaging techniques have been used to identify specific brain areas that function abnormally in patients with eating disorders. We have discussed the clinical and cognitive aspects of eating disorders and summarized neuroimaging studies of eating disorders.

  11. Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging.

    Science.gov (United States)

    Brosh, Robert M; Bellani, Marina; Liu, Yie; Seidman, Michael M

    2017-01-01

    Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features. Published by Elsevier B.V.

  12. Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

    Directory of Open Access Journals (Sweden)

    Katerina Markopoulou

    Full Text Available Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L, which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may

  13. Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

    Science.gov (United States)

    Markopoulou, Katerina; Chase, Bruce A; Robowski, Piotr; Strongosky, Audrey; Narożańska, Ewa; Sitek, Emilia J; Berdynski, Mariusz; Barcikowska, Maria; Baker, Matt C; Rademakers, Rosa; Sławek, Jarosław; Klein, Christine; Hückelheim, Katja; Kasten, Meike; Wszolek, Zbigniew K

    2016-01-01

    Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the

  14. Circadian Rhythms, Sleep, and Disorders of Aging.

    Science.gov (United States)

    Mattis, Joanna; Sehgal, Amita

    2016-04-01

    Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Context-dependent neural activation: internally and externally guided rhythmic lower limb movement in individuals with and without neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Madeleine Eve Hackney

    2015-12-01

    Full Text Available Parkinson’s Disease (PD is a neurodegenerative disorder that has received considerable attention in allopathic medicine over the past decades. However, it is clear that, to date, pharmacological and surgical interventions do not fully address symptoms of PD and patients’ quality of life. As both an alternative therapy and as an adjuvant to conventional approaches, several types of rhythmic movement (e.g., movement strategies, dance, tandem biking, tai chi have shown improvements to motor symptoms, lower limb control and postural stability in people with PD (Amano, Nocera, Vallabhajosula, Juncos, Gregor, Waddell et al., 2013; Earhart, 2009; M. E. Hackney & Earhart, 2008; Kadivar, Corcos, Foto, & Hondzinski, 2011; Morris, Iansek, & Kirkwood, 2009; Ridgel, Vitek, & Alberts, 2009. However, while these programs are increasing in number, still little is known about the neural mechanisms underlying motor improvements attained with such interventions. Studying limb motor control under task specific contexts can help determine the mechanisms of rehabilitation effectiveness. Both internally guided (IG and externally guided (EG movement strategies have evidence to support their use in rehabilitative programs. However, there appears to be a degree of differentiation in the neural substrates involved in IG versus EG designs. Because of the potential task specific benefits of rhythmic training within a rehabilitative context, this report will consider the use of IG and EG movement strategies, and observations produced by functional magnetic resonance imaging (fMRI and other imaging techniques. This review will present findings from lower limb imaging studies, under IG and EG conditions for populations with and without movement disorders. We will discuss how these studies might inform movement disorders rehabilitation (in the form of rhythmic, music-based movement training and highlight research gaps. We believe better understanding of lower limb neural

  16. Dysregulation of the HPA axis as a core pathophysiology mediating co-morbid depression in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Xin eDu

    2015-03-01

    Full Text Available There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.

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

    Science.gov (United States)

    Duffy, Joseph R.; Josephs, Keith A.

    2012-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Pamela Sarkar

    2017-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Marjana Brkic

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2018-03-15

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

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

    Science.gov (United States)

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

    2018-01-22

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  7. Generalized Anxiety Disorder (GAD) and Comorbid Major Depression with GAD Are Characterized by Enhanced Nitro-oxidative Stress, Increased Lipid Peroxidation, and Lowered Lipid-Associated Antioxidant Defenses.

    Science.gov (United States)

    Maes, Michael; Bonifacio, Kamila Landucci; Morelli, Nayara Rampazzo; Vargas, Heber Odebrecht; Moreira, Estefânia Gastaldello; St Stoyanov, Drozdstoy; Barbosa, Décio Sabbatini; Carvalho, André F; Nunes, Sandra Odebrecht Vargas

    2018-05-07

    Accumulating evidence shows that nitro-oxidative pathways play an important role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD) and maybe anxiety disorders. The current study aims to examine superoxide dismutase (SOD1), catalase, lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), malondialdehyde (MDA), glutathione (GSH), paraoxonase 1 (PON1), high-density lipoprotein cholesterol (HDL), and uric acid (UA) in participants with and without generalized anxiety disorder (GAD) co-occurring or not with BD, MDD, or tobacco use disorder. Z unit-weighted composite scores were computed as indices of nitro-oxidative stress driving lipid and protein oxidation. SOD1, LOOH, NOx, and uric acid were significantly higher and HDL and PON1 significantly lower in participants with GAD than in those without GAD. GAD was more adequately predicted by increased SOD + LOOH + NOx and lowered HDL + PON1 composite scores. Composite scores of nitro-oxidative stress coupled with aldehyde and AOPP production were significantly increased in participants with comorbid GAD + MDD as compared with all other study groups, namely MDD, GAD + BD, BD, GAD, and healthy controls. In conclusion, GAD is characterized by increased nitro-oxidative stress and lipid peroxidation and lowered lipid-associated antioxidant defenses, while increased uric acid levels in GAD may protect against aldehyde production and protein oxidation. This study suggests that increased nitro-oxidative stress and especially increased SOD1 activity, NO production, and lipid peroxidation as well as lowered HDL-cholesterol and PON1 activity could be novel drug targets for GAD especially when comorbid with MDD.

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

    Directory of Open Access Journals (Sweden)

    Anita eReinhardt

    2012-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Alana M. Horowitz

    2017-08-01

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

  10. Characterizing Early Psychosocial Functioning of Parents of Children with Moderate to Severe Genital Ambiguity due to Disorders of Sex Development.

    Science.gov (United States)

    Suorsa, Kristina I; Mullins, Alexandria J; Tackett, Alayna P; Reyes, Kristy J Scott; Austin, Paul; Baskin, Laurence; Bernabé, Kerlly; Cheng, Earl; Fried, Allyson; Frimberger, Dominic; Galan, Denise; Gonzalez, Lynette; Greenfield, Saul; Kropp, Bradley; Meyer, Sabrina; Meyer, Theresa; Nokoff, Natalie; Palmer, Blake; Poppas, Dix; Paradis, Alethea; Yerkes, Elizabeth; Wisniewski, Amy B; Mullins, Larry L

    2015-12-01

    We examined the psychosocial characteristics of parents of children with disorders of sex development at early presentation to a disorders of sex development clinic. Parental anxiety, depression, quality of life, illness uncertainty and posttraumatic stress symptoms were assessed. Additionally we evaluated the relationship of assigned child gender to parental outcomes. A total of 51 parents of children with ambiguous or atypical genitalia were recruited from 7 centers specializing in treatment of disorders of sex development. At initial assessment no child had undergone genitoplasty. Parents completed the Cosmetic Appearance Rating Scale, Beck Anxiety Inventory, Beck Depression Inventory, SF-36, Parent Perception of Uncertainty Scale and Impact of Event Scale-Revised. A large percentage of parents (54.5%) were dissatisfied with the genital appearance of their child, and a small but significant percentage reported symptoms of anxiety, depression, diminished quality of life, uncertainty and posttraumatic stress. Few gender differences emerged. Although many parents function well, a subset experience significant psychological distress around the time of diagnosis of a disorder of sex development in their child. Early screening to assess the need for psychosocial interventions is warranted. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  11. Array-CGH Analysis in a Cohort of Phenotypically Well-Characterized Individuals with "Essential" Autism Spectrum Disorders

    Science.gov (United States)

    Napoli, Eleonora; Russo, Serena; Casula, Laura; Alesi, Viola; Amendola, Filomena Alessandra; Angioni, Adriano; Novelli, Antonio; Valeri, Giovanni; Menghini, Deny; Vicari, Stefano

    2018-01-01

    Copy-number variants (CNVs) are associated with susceptibility to autism spectrum disorder (ASD). To detect the presence of CNVs, we conducted an array-comparative genomic hybridization (array-CGH) analysis in 133 children with "essential" ASD phenotype. Genetic analyses documented that 12 children had causative CNVs (C-CNVs), 29…

  12. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

    Science.gov (United States)

    Jones, Simon P; Franco, Nunzio F; Varney, Bianca; Sundaram, Gayathri; Brown, David A; de Bie, Josien; Lim, Chai K; Guillemin, Gilles J; Brew, Bruce J

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

  13. Avoidant/Restrictive Food Intake Disorder

    Science.gov (United States)

    ... Eating Disorder Bulimia Nervosa Pica Rumination Disorder Avoidant/restrictive food intake disorder is characterized by eating very little food and/or avoiding eating certain foods. People with this disorder eat ...

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

    Science.gov (United States)

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

    2009-03-01

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

  15. Mass and charge distributions of amyloid fibers involved in neurodegenerative diseases: mapping heterogeneity and polymorphism† †Electronic supplementary information (ESI) available: Experimental section and supplementary figures. See DOI: 10.1039/c7sc04542e

    Science.gov (United States)

    Pansieri, Jonathan; Halim, Mohammad A.; Vendrely, Charlotte; Dumoulin, Mireille; Legrand, François; Sallanon, Marcelle Moulin; Chierici, Sabine; Denti, Simona; Dagany, Xavier; Dugourd, Philippe; Marquette, Christel

    2018-01-01

    Heterogeneity and polymorphism are generic features of amyloid fibers with some important effects on the related disease development. We report here the characterization, by charge detection mass spectrometry, of amyloid fibers made of three polypeptides involved in neurodegenerative diseases: Aβ1–42 peptide, tau and α-synuclein. Beside the mass of individual fibers, this technique enables to characterize the heterogeneity and the polymorphism of the population. In the case of Aβ1–42 peptide and tau protein, several coexisting species could be distinguished and characterized. In the case of α-synuclein, we show how the polymorphism affects the mass and charge distributions. PMID:29732065

  16. An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS

    Directory of Open Access Journals (Sweden)

    Enrique Meléndez Hevia

    2008-10-01

    Full Text Available Salvador Harguindey1, Gorka Orive2,6, Ramón Cacabelos3, Enrique Meléndez Hevia4, Ramón Díaz de Otazu5, et al1Institute of Clinical Biology and Metabolism, Vitoria, Spain; 2Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of The Basque Country, Vitoria, Spain; 3Department of Clinical Neuroscience, EuroEspes Biomedical Research Center, Bergondo, La Coruña, Spain; 4Institute for Cellular Metabolism, Tenerife, Spain; 5Department of Pathology, Hospital Txagorritxu, Vitoria, Spain; 6Biotechnology Institute (BTI, Vitoria, SpainAbstract: A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H+ and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or deficiency of different growth factors (GFs in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases.  Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The “trophic factor withdrawal syndrome” is described for the first time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specific and nonspecific

  17. Morbidities in rapid eye movement sleep behavior disorder

    DEFF Research Database (Denmark)

    Jennum, Poul; Mayer, Geert; Ju, Yo-El

    2013-01-01

    Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, RBD without any obvious comorbid major neurological disease), is strongly associated with numerous comorbid conditions. The most prominent is that with neurodegenerative disorders, especially synuclein-mediated disorders, above all...... function, neuropsychiatric manifestations and sleep complaints. Furthermore, patients with PD and RBD may have worse prognosis in terms of impaired cognitive function and overall morbidity/mortality; in dementia, the presence of RBD is strongly associated with clinical hallmarks and pathological findings...

  18. Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome.

    Science.gov (United States)

    Xavier, Jean; Bourvis, Nadège; Tanet, Antoine; Ramos, Tatiana; Perisse, Didier; Marey, Isabelle; Cohen, David; Consoli, Angèle

    2016-10-01

    Wolfram syndrome (WS, MIM 222300) is a rare autosomal, recessive neurodegenerative disorder associated with mutations in WFS1, a gene that has been associated with bipolar disorder (BD). WS, characterized by the association of juvenile-onset diabetes mellitus (DM) and bilateral progressive optic atrophy (BPOA), encompasses several other clinical features, including cognitive impairments and psychiatric disorders. Detailed data on the psychiatric phenotype are still scarce, and how WS relates to BD is still unknown. A 17-year-old girl with WS was hospitalized for early-onset BD. A multidisciplinary and developmental assessment was carried out to control mood symptoms and address how BD could be related to WS. Besides DM and BPOA, the patient had several risk factors for BD/mood disorders as follows: (1) a history of abuse and maltreatment; (2) a history of specific language disorder and borderline intelligence associated with academic failure; and (3) a comorbid hypothyroidism. Treatment encompassed all aspects of the adolescent's conditions, such as the use of mood stabilizers, addressing psychosocial and scholastic problems, and treating hypothyroid dysfunction. Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.

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

    Directory of Open Access Journals (Sweden)

    Suk-yu Yau

    2014-01-01

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

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

    International Nuclear Information System (INIS)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2016-10-15

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

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

    Science.gov (United States)

    Fortier, J; Besnard, J; Allain, P

    2018-04-01

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

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

    OpenAIRE

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

    2016-01-01

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

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

    Science.gov (United States)

    Gibson, Gary E; Huang, Hsueh-Meei

    2004-08-01

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

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Science.gov (United States)

    Tofaris, George K; Schapira, Anthony H V

    2015-05-01

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

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

    Science.gov (United States)

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

    2017-08-04

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

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

    Directory of Open Access Journals (Sweden)

    Kelly A. Gola

    2017-01-01

    Full Text Available Intentional facial expression of emotion is critical to healthy social interactions. Patients with neurodegenerative disease, particularly those with right temporal or prefrontal atrophy, show dramatic socioemotional impairment. This was an exploratory study examining the neural and behavioral correlates of intentional facial expression of emotion in neurodegenerative disease patients and healthy controls. One hundred and thirty three participants (45 Alzheimer's disease, 16 behavioral variant frontotemporal dementia, 8 non-fluent primary progressive aphasia, 10 progressive supranuclear palsy, 11 right-temporal frontotemporal dementia, 9 semantic variant primary progressive aphasia patients and 34 healthy controls were video recorded w