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Sample records for adult-onset neurodegenerative disorder

  1. Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

    PubMed Central

    Hayden, Michael

    1988-01-01

    Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

  2. Aquatherapy for neurodegenerative disorders.

    PubMed

    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.

  3. Prions mediated neurodegenerative disorders.

    PubMed

    Huang, W-J; Chen, W-W; Zhang, X

    2015-11-01

    Prions are unprecedented infectious pathogens that are devoid of nucleic acid and cause a group of rare and invariably fatal neurodegenerative disorders, affecting approximately 1 person per 1 million inhabitants annually worldwide. These disorders include Creutzfeld-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal insomnia (FI), and variable protease-sensitive prionopathy (VPSPr), all of which involve a conformational change of the normal cellular prion protein (PrPC) into the abnormal scrapie prion protein (PrPSc) through a posttranslational process during which PrPc acquires high β-sheet content. This structural change is accompanied by profound changes in the physicochemical properties of PrPC, rendering the molecule resistant to proteolysis. The conformational change of PrPC can occur due to either spontaneous conversion, dominant mutations in the prion protein (PRNP) gene encoding PrPC, or infection with pathogenic isoform PrPsc from exogenous sources. There is general agreement that PrPC serves as a substrate for conversion to abnormal PrPSc. This latter multiplies exponentially and aggregates in the brain, forming deposits that are associated with the neurodegenerative changes. Although the understanding of the primary causes of prion-induced neurodegeneration is still limited, propagation of PrPSc and neurotoxic signaling seem to interplay in pathogenic process of prions. Here, we review recent findings that have provided fresh insights into this process, and present an overview of incidence, causes and spectrum of related disorders.

  4. Psychological impact of genetic testing for adult-onset disorders. An update for clinicians.

    PubMed

    Meiser, B; Gleeson, M A; Tucker, K M

    2000-02-01

    Testing for gene mutations that confer susceptibility to adult-onset disorders has potential benefits, but these must be balanced against the psychological harms, if any. We review published findings on the psychological effects of such testing, focusing on Huntington's disease, which has the most available data, and the hereditary cancer syndromes. Most of the evidence suggests that non-carriers and carriers differ significantly in terms of short-term, but not long-term, psychological adjustment to test results. The psychological impact of genetic testing depends more on pretest psychological distress than the test result itself. PMID:10735024

  5. Possible risk factors for primary adult onset dystonia: a case-control investigation by the Italian Movement Disorders Study Group

    PubMed Central

    Defazio, G.; Berardelli, A.; Abbruzzese, G.; Lepore, V.; Coviello, V.; Acquistapace, D.; Capus, L.; Carella, F.; De Berardinis, M. T.; Galardi, G.; Girlanda, P.; Maurri, S.; Albanese, A.; Bertolasi, L.; Liguori, R.; Rossi, A.; Santoro, L.; Tognoni, G.; Livrea, P.

    1998-01-01

    OBJECTIVES—Little is known about the aetiology of idiopathic adult onset dystonia. The Italian Movement Disorders Study Group promoted a case-control study on some hypothetical risk factors including past medical events, life events, life habits, occupational hazards, and family hystory of dystonia, parkinsonism, and tremor.
METHODS—Cases affected by idiopathic adult onset dystonia (age at symptom onset >20 years, duration of disease >one year and adult onset dystonia, whereas hypertension and cigarette smoking exerted a protective effect. The findings also suggested a positive association between local body injury—for example, previous ocular diseases and neck or trunk trauma—and dystonia of the same body part.
CONCLUSIONS—The results support the idea that environmental and genetic factors may both be important in the aetiology of adult onset dystonia, and suggest aetiological clues worthy of further analytical investigation.

 PMID:9436723

  6. Neurodegenerative disorders and metabolic disease.

    PubMed

    Pierre, Germaine

    2013-08-01

    Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated.

  7. Molecular diagnostics of neurodegenerative disorders

    PubMed Central

    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. PMID:26442283

  8. Targeting Proteostasis Through the Protein Quality Control Function of the Hsp90/Hsp70-based Chaperone Machinery for Treatment of Adult Onset Neurodegenerative Diseases

    PubMed Central

    Pratt, William B.; Gestwicki, Jason E.; Osawa, Yoichi; Lieberman, Andrew P.

    2015-01-01

    Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief, but are not disease modifying. We explore here a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polylglutamine androgen receptor (spinal and bulbar muscular atrophy), huntingtin (Huntington’s disease), α-synuclein (Parkinson’s disease) and tau (Alzheimer’s disease) are client proteins of Hsp90, and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. In protein quality control Hsp90 and Hsp70 have opposing effects on client protein stability; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes CHIP-dependent ubiquitination and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or by promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. PMID:25292434

  9. Tsallis statistics and neurodegenerative disorders

    NASA Astrophysics Data System (ADS)

    Iliopoulos, Aggelos C.; Tsolaki, Magdalini; Aifantis, Elias C.

    2016-08-01

    In this paper, we perform statistical analysis of time series deriving from four neurodegenerative disorders, namely epilepsy, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD). The time series are concerned with electroencephalograms (EEGs) of healthy and epileptic states, as well as gait dynamics (in particular stride intervals) of the ALS, PD and HDs. We study data concerning one subject for each neurodegenerative disorder and one healthy control. The analysis is based on Tsallis non-extensive statistical mechanics and in particular on the estimation of Tsallis q-triplet, namely {qstat, qsen, qrel}. The deviation of Tsallis q-triplet from unity indicates non-Gaussian statistics and long-range dependencies for all time series considered. In addition, the results reveal the efficiency of Tsallis statistics in capturing differences in brain dynamics between healthy and epileptic states, as well as differences between ALS, PD, HDs from healthy control subjects. The results indicate that estimations of Tsallis q-indices could be used as possible biomarkers, along with others, for improving classification and prediction of epileptic seizures, as well as for studying the gait complex dynamics of various diseases providing new insights into severity, medications and fall risk, improving therapeutic interventions.

  10. Parkin Regulation and Neurodegenerative Disorders

    PubMed Central

    Zhang, Cheng-Wu; Hang, Liting; Yao, Tso-Pang; Lim, Kah-Leong

    2016-01-01

    Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognition that Parkin dysfunction represents not only a predominant cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson’s disease (PD). Accordingly, keen research on Parkin over the past decade has led to an explosion of knowledge regarding its physiological roles and its relevance to PD. However, our understanding of Parkin is far from being complete. Indeed, surprises emerge from time to time that compel us to constantly update the paradigm of Parkin function. For example, we now know that Parkin’s function is not confined to mere housekeeping protein quality control (QC) roles but also includes mitochondrial homeostasis and stress-related signaling. Furthermore, emerging evidence also suggest a role for Parkin in several other major neurodegenerative diseases including Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Yet, it remains truly amazing to note that a single enzyme could serve such multitude of functions and cellular roles. Clearly, its activity has to be tightly regulated. In this review, we shall discuss this and how dysregulated Parkin function may precipitate neuronal demise in various neurodegenerative disorders. PMID:26793099

  11. The diagnostic evaluation of patients with potential adult-onset autoinflammatory disorders: our experience and review of the literature.

    PubMed

    Muscari, Isabella; Iacoponi, Francesca; Cantarini, Luca; Lucherini, Orso Maria; Simonini, Gabriele; Brizi, Maria Giuseppina; Vitale, Antonio; Frediani, Bruno; Cimaz, Rolando; Galeazzi, Mauro

    2012-11-01

    Hereditary periodic fever syndromes (HPFSs) are a group of inherited disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, which belong to the category of autoinflammatory disorders. Most HPFs typically have an onset in pediatric age, while a limited number of patients experience disease onset during adulthood. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that genetic testing is often inconclusive. Recently, we have identified a set of variables related to the probability of detecting gene mutations in MEFV, responsible for familial Mediterranean fever, and TNFRSF1A, responsible for tumor necrosis factor receptor-associated periodic syndrome. In addition, we have proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. However, before the score can be recommended for application, further evaluation by means of longitudinal studies on different ethnicities and different populations deriving from other geographical areas is needed in order to definitively verify both its sensitivity and its specificity. The present manuscript offers our suggestions on how to establish a differential diagnosis for adult-onset HPFs, as well as a review of the literature, and we also provide a score revision available online.

  12. Childhood dyspraxia predicts adult-onset nonaffective-psychosis-spectrum disorder.

    PubMed

    Schiffman, Jason; Mittal, Vijay; Kline, Emily; Mortensen, Erik L; Michelsen, Niels; Ekstrøm, Morten; Millman, Zachary B; Mednick, Sarnoff A; Sørensen, Holger J

    2015-11-01

    Several neurological variables have been investigated as premorbid biomarkers of vulnerability for schizophrenia and other related disorders. The current study examined whether childhood dyspraxia predicted later adult nonaffective-psychosis-spectrum disorders. From a standardized neurological examination performed with children (aged 10-13) at genetic high risk of schizophrenia and controls, several measures of dyspraxia were used to create a scale composed of face/head dyspraxia, oral articulation, ideomotor dyspraxia (clumsiness), and dressing dyspraxia (n = 244). Multinomial logistic regression showed higher scores on the dyspraxia scale predict nonaffective-psychosis-spectrum disorders relative to other psychiatric disorders and no mental illness outcomes, even after controlling for genetic risk, χ2 (4, 244) = 18.61, p < .001. Findings that symptoms of dyspraxia in childhood (reflecting abnormalities spanning functionally distinct brain networks) specifically predict adult nonaffective-psychosis-spectrum disorders are consistent with a theory of abnormal connectivity, and they highlight a marked early-stage vulnerability in the pathophysiology of nonaffective-psychosis-spectrum disorders. PMID:26439077

  13. Oxidative Stress and Neurodegenerative Disorders

    PubMed Central

    Li, Jie; O, Wuliji; Li, Wei; Jiang, Zhi-Gang; Ghanbari, Hossein A.

    2013-01-01

    Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs. PMID:24351827

  14. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders

    PubMed Central

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions. PMID:26999347

  15. Genetically modified pig models for neurodegenerative disorders.

    PubMed

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

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions. PMID:26446984

  16. Managing anxiety associated with neurodegenerative disorders

    PubMed Central

    Kumar, Anand

    2015-01-01

    Anxiety is a common symptom among patients with cognitive impairment. The presence of anxiety is correlated with poorer outcomes; despite this, there is limited research on anxiety related to neurodegenerative disorder. In this article, we discuss the prevalence of anxiety and factors involved in the etiology of anxiety in patients with diagnosed neurodegenerative disorders and related states of cognitive impairment as well as the evidence for currently available methods of evaluating and treating these symptoms. Specific treatments are highlighted in light of current evidence, followed by a discussion of the difficulties inherent in the study and treatment of anxiety in this population. PMID:25705388

  17. Neurodegenerative disorders and nanoformulated drug development

    PubMed Central

    Nowacek, Ari; Kosloski, Lisa M; Gendelman, Howard E

    2009-01-01

    Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders. PMID:19572820

  18. Efficacy of Natural Compounds in Neurodegenerative Disorders.

    PubMed

    Srivastava, Pranay; Yadav, Rajesh Singh

    2016-01-01

    Neurodegenerative disorders represent clusters of serious diseases that results in progressive deterioration of normal structure and physiology of central nervous system. Pathophysiology of Alzheimer's, Parkinson's or other neurodegenerative disorders involves multifaceted permutation of genetic and environmental factors. Combinations of lifestyle modification linked with environmental factor jointly or alone represent the largest share of cases of these disorders. Etiology of such neuronal degeneration involves manifestation of toxic reaction in the form of functional anomalies leading to dysfunction of the ubiquitin-proteasome system, activated inflammatory cascade, compromised neuronal survival pathway, mitochondrial dysfunction and finally neuronal apoptosis/necrosis and cell death. Furthermore, evidences from various studies exhibited role of oxidative stress and compromised anti-oxidant defense system as one of the prime factors associated with activation of various signal transduction pathways that would ultimately lead to the formation of amyloid beta or alpha synuclein in the brain. Keeping in view of complex etiology and pathophysiology along with a miniscule of available treatment options associated with these neurodegenerative disorders, the role of natural agents and herbal extracts as therapeutic alternatives alone or in combination with synthetic drugs could not be ruled out. In the same context the present chapter has been aimed to investigate the role of selected natural plants like Withania somnifera, Bacopa monnieri, Curcuma longa, Centella asiatica, Ocimum sanctum, Nardostachys jatamansi and Emblica officinalis in various neurodegenerative disorders and explore their targets to ameliorate neurotoxicity in various experimental models. The rationale for selection of these plants was based on their strong anti-inflammatory and anti-oxidant potential and large body of evidence that suggest their efficacy in preclinical as well as in clinical studies

  19. Brain drug delivery systems for neurodegenerative disorders.

    PubMed

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2012-09-01

    Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Huntington's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment. PMID:23016644

  20. MicroRNAs in neurodegenerative disorders.

    PubMed

    Junn, Eunsung; Mouradian, M Maral

    2010-05-01

    MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs regulating eukaryotic gene expression at the post-transcriptional level. During the last decade, considerable advances have been made in our understanding the biogenesis of miRNAs, the molecular mechanisms by which they regulate gene expression and their functional role in various physiological situations. miRNAs are abundant in the brain where they have crucial roles in development and synaptic plasticity. Accumulating evidence from postmortem brain analyses and animal model studies has begun to suggest that miRNA dysfunction contributes to neurodegenerative disorders. Here, we discuss several examples of investigations demonstrating the role of miRNAs in neurodegenerative disorders. As the expression of disease-causing genes is regulated by certain miRNA(s), changes in these miRNAs could lead to the accumulation of disease-causing proteins, and subsequently to neuronal dysfunction and death. Detailed understanding of these mechanisms can provide potential new therapeutic approaches to slow down or halt the progression of neurodegenerative diseases.

  1. Dysregulated microRNAs in neurodegenerative disorders.

    PubMed

    Lau, Pierre; de Strooper, Bart

    2010-09-01

    The complexity of the nervous system arises in part, from the large diversity of neural cell types that support the architecture of neuronal circuits. Recent studies have highlighted microRNAs as important players in regulating gene expression at the post-transcriptional level and therefore the phenotype of neural cells. A link between microRNAs and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease is becoming increasingly evident. Here, we discuss microRNAs in neurodegeneration, from the fruit fly and mouse utilized as experimental models to dysregulated microRNAs in human neurodegenerative disorders. We propose that studying microRNAs and their mRNA targets in the context of neurodegeneration will significantly contribute to the identification of proteins important for neuronal function and might reveal underlying molecular networks that drive these diseases.

  2. Diffusion-MRI in neurodegenerative disorders.

    PubMed

    Goveas, Joseph; O'Dwyer, Laurence; Mascalchi, Mario; Cosottini, Mirco; Diciotti, Stefano; De Santis, Silvia; Passamonti, Luca; Tessa, Carlo; Toschi, Nicola; Giannelli, Marco

    2015-09-01

    The ability to image the whole brain through ever more subtle and specific methods/contrasts has come to play a key role in understanding the basis of brain abnormalities in several diseases. In magnetic resonance imaging (MRI), "diffusion" (i.e. the random, thermally-induced displacements of water molecules over time) represents an extraordinarily sensitive contrast mechanism, and the exquisite structural detail it affords has proven useful in a vast number of clinical as well as research applications. Since diffusion-MRI is a truly quantitative imaging technique, the indices it provides can serve as potential imaging biomarkers which could allow early detection of pathological alterations as well as tracking and possibly predicting subtle changes in follow-up examinations and clinical trials. Accordingly, diffusion-MRI has proven useful in obtaining information to better understand the microstructural changes and neurophysiological mechanisms underlying various neurodegenerative disorders. In this review article, we summarize and explore the main applications, findings, perspectives as well as challenges and future research of diffusion-MRI in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and degenerative ataxias. PMID:25917917

  3. HDL and Cognition in Neurodegenerative Disorders

    PubMed Central

    Hottman, David A.; Chernick, Dustin; Cheng, Shaowu; Wang, Zhe; Li, Ling

    2014-01-01

    High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function. PMID:25131449

  4. Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders.

    PubMed

    Mosley, R Lee

    2015-12-01

    Neurodegenerative and neuropsychological disorders are becoming a greater proportion of the global disease burden; however the pathogenic mechanisms by which these disorders originate and contribute to disease progression are not well-described. Increasing evidence supports neuroinflammation as a common underlying component associated with the neuropathological processes that effect disease progression. This collection of articles explores the role of adaptive immunity in autoimmunity, neurodegeneration, neurotrauma, and psychological disorders. The section emphasizes the interactions of T cells with innate cellular responses within the CNS and the effects on neurological functions. One recurrent theme is that modified and aggregated self-proteins upregulate innate-mediated inflammation and provide a permissive environment for polarization of T cells to proinflammatory effector cells. Moreover, infiltration and reactivation of those T effector cells exacerbate neuroinflammation and oxidative stress to greater neurotoxic levels. Another recurrent theme in these disorders promotes diminished regulatory functions that reduce control over activated T effector cells and microglia, and ultimately augment proinflammatory conditions. Augmentation of regulatory control is discussed as therapeutic strategies to attenuate neuroinflammation, mitigate neurodegeneration or neuronal dysfunction, and lessen disease progression.

  5. Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?

    PubMed Central

    Nielsen, Troels T.; Nielsen, Jørgen E.

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders. PMID:24705213

  6. Neurodegenerative Models in Drosophila: Polyglutamine Disorders, Parkinson Disease, and Amyotrophic Lateral Sclerosis

    PubMed Central

    Ambegaokar, Surendra S.; Roy, Bidisha; Jackson, George R.

    2010-01-01

    Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue. PMID:20561920

  7. Adult onset retinoblastoma.

    PubMed

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-07-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  8. Adult onset retinoblastoma

    PubMed Central

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-01-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  9. History of innate immunity in neurodegenerative disorders.

    PubMed

    McGeer, Patrick L; McGeer, Edith G

    2011-01-01

    The foundations of innate immunity in neurodegenerative disorders were first laid by Del Rio Hortega (1919). He identified and named microglia, recognizing them as cells of mesodermal origin. Van Furth in 1969 elaborated the monocyte phagocytic system with microglia as the brain representatives. Validation of these concepts did not occur until 1987 when HLA-DR was identified on activated microglia in a spectrum of neurological disorders. HLA-DR had already been established as a definitive marker of immunocompetent cells of mesodermal origin. It was soon determined that the observed inflammatory reaction was an innate immune response. A rapid expansion of the field took place as other markers of an innate immune response were found that were made by neurons, astrocytes, oligodendroglia, and endothelial cells. The molecules included complement proteins and their regulators, inflammatory cytokines, chemokines, acute phase reactants, prostaglandins, proteases, protease inhibitors, coagulation factors, fibrinolytic factors, anaphylatoxins, integrins, free radical generators, and other unidentified neurotoxins. The Nimmerjahn movies demonstrated that resting microglia were constantly active, sampling the surround, and responding rapidly to brain damage. Ways of reducing the neurotoxic innate immune response and stimulating a healing response continue to be sought as a means for ameliorating the pathology in a spectrum of chronic degenerative disorders. PMID:22144960

  10. Apolipoprotein E genotype in diverse neurodegenerative disorders.

    PubMed

    Schneider, J A; Gearing, M; Robbins, R S; de l'Aune, W; Mirra, S S

    1995-07-01

    While the apolipoprotein E (ApoE) epsilon 4 allele is a recognized risk factor for Alzheimer's disease (AD), an association of epsilon 4 with other neurodegenerative diseases (NDs) has not been extensively explored. We examined 51 cases of neuropathologically confirmed ND. After eliminating 18 cases exhibiting pathology sufficient to warrant an additional diagnosis of AD, three disorders characterized by tau-related cytoskeletal pathology, i.e., Pick's disease, corticobasal degeneration, and progressive supra-nuclear palsy, showed increased epsilon 4 frequencies. Since the number of cases within each category was small, these increased epsilon 4 frequencies were not statistically significant. beta-Amyloid (beta A4) immunoreactive diffuse plaques were observed in many of these cases. While we cannot eliminate the possibility that these patients were destined to develop AD, these changes may merely reflect an independent association of epsilon 4 with amyloid deposition. These preliminary data affirm the need for further study of well-characterized cases to explore the relationship of ApoE to cytoskeletal pathology and ND. PMID:7611717

  11. Adult-onset mitochondrial myopathy.

    PubMed Central

    Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.

    1992-01-01

    Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Images Figure 1 Figure 2 PMID:1589382

  12. Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

    PubMed Central

    Uittenbogaard, Martine; Chiaramello, Anne

    2014-01-01

    In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases. PMID:24606804

  13. Adult-Onset Hypogonadism.

    PubMed

    Khera, Mohit; Broderick, Gregory A; Carson, Culley C; Dobs, Adrian S; Faraday, Martha M; Goldstein, Irwin; Hakim, Lawrence S; Hellstrom, Wayne J G; Kacker, Ravi; Köhler, Tobias S; Mills, Jesse N; Miner, Martin; Sadeghi-Nejad, Hossein; Seftel, Allen D; Sharlip, Ira D; Winters, Stephen J; Burnett, Arthur L

    2016-07-01

    In August 2015, an expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC, to discuss the common clinical scenario of men who present with low testosterone (T) and associated signs and symptoms accompanied by low or normal gonadotropin levels. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. The panel designated this syndrome adult-onset hypogonadism (AOH) because it occurs commonly in middle-age and older men. The SMSNA is a not-for-profit society established in 1994 to promote, encourage, and support the highest standards of practice, research, education, and ethics in the study of human sexual function and dysfunction. The panel consisted of 17 experts in men's health, sexual medicine, urology, endocrinology, and methodology. Participants declared potential conflicts of interest and were SMSNA members and nonmembers. The panel deliberated regarding a diagnostic process to document signs and symptoms of AOH, the rationale for T therapy, and a monitoring protocol for T-treated patients. The evaluation and management of hypogonadal syndromes have been addressed in recent publications (ie, the Endocrine Society, the American Urological Association, and the International Society for Sexual Medicine). The primary purpose of this document was to support health care professionals in the development of a deeper understanding of AOH, particularly in how it differs from classical primary and secondary hypogonadism, and to provide a conceptual framework to guide its diagnosis, treatment, and follow-up. PMID:27343020

  14. [Stem cell therapy for neurodegenerative disorders].

    PubMed

    Meyer, Morten; Jensen, Pia; Rasmussen, Jens Zimmer

    2010-09-20

    Intrastriatal, foetal neural transplants can ameliorate symptoms in patients with Parkinson's and Huntington's disease, although not stop the primary cell-loss. Several issues must, however, be addressed before general or extended clinical use of cell therapy in neurodegenerative diseases can become a reality. Improvements include standardized and safe master cell-lines derived from human embryonic stem cells, induced pluripotent stem cells and neural stem cells. Cells from these sources are expected to become available for cell replacement therapies or therapeutic production of trophic, anti-inflammatory and restorative factors within a few years.

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

    PubMed

    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.

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

    PubMed Central

    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. Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

    PubMed Central

    Holland, Celia V.; Loxton, Karen; Barghouth, Ursula

    2015-01-01

    SUMMARY Toxocara canis and T. cati are highly prevalent nematode infections of the intestines of dogs and cats. In paratenic hosts, larvae do not mature in the intestine but instead migrate through the somatic tissues and organs of the body. The presence of these migrating larvae can contribute to pathology. Toxocara larvae can invade the brains of humans, and while case descriptions of cerebral toxocariasis are historically rare, improved diagnosis and greater awareness have contributed to increased detection. Despite this, cerebral or neurological toxocariasis (NT) remains a poorly understood phenomenon. Furthermore, our understanding of cognitive deficits due to toxocariasis in human populations remains particularly deficient. Recent data describe an enhanced expression of biomarkers associated with brain injury, such as GFAP, AβPP, transforming growth factor β1 (TGF-β1), NF-L, S100B, tTG, and p-tau, in mice receiving even low doses of Toxocara ova. Finally, this review outlines a hypothesis to explore the relationship between the presence of T. canis larvae in the brain and the progression of Alzheimer's disease (AD) due to enhanced AD-associated neurodegenerative biomarker expression. PMID:26062575

  18. Tau mis-splicing in the pathogenesis of neurodegenerative disorders.

    PubMed

    Park, Sun Ah; Ahn, Sang Il; Gallo, Jean-Marc

    2016-08-01

    Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413]. PMID:27222125

  19. Clinical Translation of Stem Cells in Neurodegenerative Disorders

    PubMed Central

    Lindvall, Olle; Barker, Roger A.; Brüstle, Oliver; Isacson, Ole; Svendsen, Clive N.

    2014-01-01

    Stem cells and their derivatives show tremendous potential for treating many disorders, including neurode-generative diseases. We discuss here the challenges and potential for the translation of stem-cell-based approaches into treatments for Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. PMID:22305565

  20. Visually Impaired Children with Progressive, Terminal Neurodegenerative Disorders.

    ERIC Educational Resources Information Center

    Koehler, W.; Loftin, M.

    1994-01-01

    This article presents general information on visually impaired children with progressive, terminal neurodegenerative disorders including implications for the classroom, specific techniques to help the child live and learn, and the development of multidisciplinary support systems including both professionals and family members. (DB)

  1. Clinical translation of stem cells in neurodegenerative disorders.

    PubMed

    Lindvall, Olle; Barker, Roger A; Brüstle, Oliver; Isacson, Ole; Svendsen, Clive N

    2012-02-01

    Stem cells and their derivatives show tremendous potential for treating many disorders, including neurodegenerative diseases. We discuss here the challenges and potential for the translation of stem-cell-based approaches into treatments for Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

  2. Biometals in rare neurodegenerative disorders of childhood

    PubMed Central

    Parker, Sarah J.; Koistinaho, Jari; White, Anthony R.; Kanninen, Katja M.

    2013-01-01

    Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future. PMID:23531702

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

    PubMed

    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.

  4. miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy.

    PubMed

    Karnati, Hanuma Kumar; Panigrahi, Manas Kumar; Gutti, Ravi Kumar; Greig, Nigel H; Tamargo, Ian A

    2015-01-01

    MicroRNAs (miRNAs) are endogenous, ∼22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention.

  5. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.

    PubMed

    Mancini, Cecilia; Nassani, Stefano; Guo, Yiran; Chen, Yulan; Giorgio, Elisa; Brussino, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Lo Buono, Nicola; Funaro, Ada; Pizio, Nicola Renato; Nmezi, Bruce; Kyttala, Aija; Santorelli, Filippo Maria; Padiath, Quasar Salem; Hakonarson, Hakon; Zhang, Hao; Brusco, Alfredo

    2015-01-01

    Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.

  6. Prions and prion-like pathogens in neurodegenerative disorders.

    PubMed

    Peggion, Caterina; Sorgato, Maria Catia; Bertoli, Alessandro

    2014-02-18

    Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders-known as transmissible spongiform encephalopathies, or prion diseases-which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate.

  7. Circulating miRNAs as biomarkers for neurodegenerative disorders.

    PubMed

    Grasso, Margherita; Piscopo, Paola; Confaloni, Annamaria; Denti, Michela A

    2014-05-23

    Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementias (FTD), are considered distinct entities, however, there is increasing evidence of an overlap from the clinical, pathological and genetic points of view. All neurodegenerative diseases are characterized by neuronal loss and death in specific areas of the brain, for example, hippocampus and cortex for AD, midbrain for PD, frontal and temporal lobes for FTD. Loss of neurons is a relatively late event in the progression of neurodegenerative diseases that is typically preceded by other events such as metabolic changes, synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities, such as axonal transport defects. The brain's ability to compensate for these dysfunctions occurs over a long period of time and results in late clinical manifestation of symptoms, when successful pharmacological intervention is no longer feasible. Currently, diagnosis of AD, PD and different forms of dementia is based primarily on analysis of the patient's cognitive function. It is therefore important to find non-invasive diagnostic methods useful to detect neurodegenerative diseases during early, preferably asymptomatic stages, when a pharmacological intervention is still possible. Altered expression of microRNAs (miRNAs) in many disease states, including neurodegeneration, and increasing relevance of miRNAs in biofluids in different pathologies has prompted the study of their possible application as neurodegenerative diseases biomarkers in order to identify new therapeutic targets. Here, we review what is known about the role of miRNAs in the pathogenesis of neurodegeneration and the possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative conditions.

  8. Amylin at the interface between metabolic and neurodegenerative disorders

    PubMed Central

    Lutz, Thomas A.; Meyer, Urs

    2015-01-01

    The pancreatic peptide amylin is best known for its role as a satiation hormone in the control of food intake and as the major component of islet amyloid deposits in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Epidemiological studies have established a clear association between metabolic and neurodegenerative disorders in general, and between T2DM and Alzheimer's disease (AD) in particular. Here, we discuss that amylin may be an important player acting at the interface between these metabolic and neurodegenerative disorders. Abnormal amylin production is a hallmark peripheral pathology both in the early (pre-diabetic) and late phases of T2DM, where hyperamylinemic (early phase) and hypoamylinemic (late phase) conditions coincide with hyper- and hypo-insulinemia, respectively. Moreover, there are notable biochemical similarities between amylin and β-amyloids (Aβ), which are both prone to amyloid plaque formation and to cytotoxic effects. Amylin's propensity to form amyloid plaques is not restricted to pancreatic islet cells, but readily extends to the CNS, where it has been found to co-localize with Aβ plaques in at least a subset of AD patients. Hence, amylin may constitute a “second amyloid” in neurodegenerative disorders such as AD. We further argue that hyperamylinemic conditions may be more relevant for the early processes of amyloid formation in the CNS, whereas hypoamylinemic conditions may be more strongly associated with late stages of central amyloid pathologies. Advancing our understanding of these temporal relationships may help to establish amylin-based interventions in the treatment of AD and other neurodegenerative disorders with metabolic comorbidities. PMID:26136651

  9. Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity in Neurodegenerative Disorders

    PubMed Central

    Liang, Bo; Schroeder, David; Zhang, Zhong-wei; Cox, Gregory A.; Li, Yun; Lin, Da-Ting

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Here using TDP-43A315T mice, an ALS and FTD model with profound cortical pathology, we demonstrated that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PN) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PN and alleviated neurodegeneration, suggesting a novel therapeutic target for ALS and FTD. PMID:26900927

  10. Transposable Elements in TDP-43-Mediated Neurodegenerative Disorders

    PubMed Central

    Hammell, Molly; Dubnau, Josh

    2012-01-01

    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. PMID:22957047

  11. POTENTIAL FUTURE NEUROPROTECTIVE THERAPIES FOR NEURODEGENERATIVE DISORDERS AND STROKE

    PubMed Central

    Tarawneh, Rawan; Galvin, James E.

    2009-01-01

    The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) each have distinct clinical symptoms and pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, inflammation, apoptosis and mitochondrial injury that contribute to neuronal loss. Although cerebrovascular disease is due to etiologies quite different from the neurodegenerative disorders, many of the same common disease mechanisms come into play following a stroke. Novel therapies that target each of these mechanisms may be effective in decreasing the risk of disease, abating symptoms or slowing down their progression. While most of these therapies are experimental, and require further investigation, a few seem to offer promise in the near future. PMID:20176298

  12. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.

    PubMed

    Jucker, Mathias; Walker, Lary C

    2011-10-01

    The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations

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

    PubMed

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

    2015-12-01

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

  14. Memory Loss and Frontal Cognitive Dysfunction in a Patient with Adult-onset Neuronal Intranuclear Inclusion Disease.

    PubMed

    Araki, Kunihiko; Sone, Jun; Fujioka, Yusuke; Masuda, Michihito; Ohdake, Reiko; Tanaka, Yasuhiro; Nakamura, Tomohiko; Watanabe, Hirohisa; Sobue, Gen

    2016-01-01

    Neuronal intranuclear inclusion disease (NIID) is an uncommon progressive neurodegenerative disorder. Adult-onset NIID can result in prominent dementia. We herein describe the case of a 74-year-old man who presented with dementia, cerebellar ataxia, neuropathy, and autonomic dysfunction. Diffusion-weighted imaging showed hyperintensity of the corticomedullary junction. Fluid-attenuated inversion recovery images showed frontal-dominant white matter hyperintensity. NIID was diagnosed from the presence of intranuclear inclusions in a skin biopsy sample. Neuropsychological testing revealed memory loss and frontal cognitive dysfunction, especially in relation to language and executive functions. We were therefore able to confirm the association of NIID with cognitive dysfunction. PMID:27523009

  15. Staging neurodegenerative disorders: structural, regional, biomarker, and functional progressions.

    PubMed

    Archer, Trevor; Kostrzewa, Richard M; Beninger, Richard J; Palomo, Tomas

    2011-02-01

    The notion of staging in the neurodegenerative disorders is modulated by the constant and progressive loss of several aspects of brain structural integrity, circuitry, and neuronal processes. These destructive processes eventually remove individuals' abilities to perform at sufficient and necessary functional capacity at several levels of disease severity. The classification of (a) patients on the basis of diagnosis, risk prognosis, and intervention outcome, forms the basis of clinical staging, and (b) laboratory animals on the basis of animal model of brain disorder, extent of insult, and dysfunctional expression, provides the components for the clinical staging and preclinical staging, respectively, expressing associated epidemiological, biological, and genetic characteristics. The major focus of clinical staging in the present account stems from the fundamental notions of Braak staging as they describe the course and eventual prognosis for Alzheimer's disease, Lewy Body dementia, and Parkinson's disease. Mild cognitive impairment, which expresses the decline in episodic and semantic memory performance below the age-adjusted normal range without marked loss of global cognition or activities of daily living, and the applications of longitudinal magnetic resonance imaging, major instruments for the monitoring of either disease progression in dementia, present important challenges for staging concepts. Although Braak notions present the essential basis for further developments, current staging conceptualizations seem inadequate to comply with the massive influx of information dealing with neurodegenerative processes in brain, advanced both under clinical realities, and discoveries in the laboratory setting. The contributions of various biomarkers of disease progression, e.g., amyloid precursor protein, and neurotransmitter system imbalances, e.g., dopamine receptor supersensitivity and interactive propensities, await their incorporation into the existing staging

  16. Iron biomineralization of brain tissue and neurodegenerative disorders

    NASA Astrophysics Data System (ADS)

    Mikhaylova (Mikhailova), Albina

    The brain is an organ with a high concentration of iron in specific areas, particularly in the globus pallidus, the substantia nigra, and the red nucleus. In certain pathological states, such as iron overload disease and neurodegenerative disorders, a disturbed iron metabolism can lead to increased accumulation of iron not only in these areas, but also in the brain regions that are typically low in iron content. Recent studies of the physical and magnetic properties of metalloproteins, and in particular the discovery of biogenic magnetite in human brain tissue, have raised new questions about the role of biogenic iron formations in living organisms. Further investigations revealed the presence of magnetite-like crystalline structures in human ferritin, and indicated that released ferritin iron might act as promoter of oxidative damage to tissue, therefore contributing to pathogenesis of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. The purpose of this work was to examine the elemental composition and structure of iron deposits in normal brain tissue as well as tissue affected by neurodegenerative disorders. Employing the methods of X-ray microfocus fluorescence mapping, X-ray Absorption Near Edge Structure (XANES), X-ray Absorption Fine Structure spectroscopy (XAFS), and light and electron microscopic examinations allows one to obtain qualitative as well as quantitative data with respect to the cellular distribution and chemical state of iron at levels not detected previously. The described tissue preparation technique allows not only satisfactory XAS iron elemental imaging in situ but also multimodal examination with light and electron microscopes of the same samples. The developed protocol has assured consistent and reproducible results on relatively large sections of flat-embedded tissue. The resulting tissue samples were adequate for XAS examination as well as sufficiently well-preserved for future microscopy studies

  17. Alterations of eye movement control in neurodegenerative movement disorders.

    PubMed

    Gorges, Martin; Pinkhardt, Elmar H; Kassubek, Jan

    2014-01-01

    The evolution of the fovea centralis, the most central part of the retina and the area of the highest visual accuracy, requires humans to shift their gaze rapidly (saccades) to bring some object of interest within the visual field onto the fovea. In addition, humans are equipped with the ability to rotate the eye ball continuously in a highly predicting manner (smooth pursuit) to hold a moving target steadily upon the retina. The functional deficits in neurodegenerative movement disorders (e.g., Parkinsonian syndromes) involve the basal ganglia that are critical in all aspects of movement control. Moreover, neocortical structures, the cerebellum, and the midbrain may become affected by the pathological process. A broad spectrum of eye movement alterations may result, comprising smooth pursuit disturbance (e.g., interrupting saccades), saccadic dysfunction (e.g., hypometric saccades), and abnormal attempted fixation (e.g., pathological nystagmus and square wave jerks). On clinical grounds, videooculography is a sensitive noninvasive in vivo technique to classify oculomotion function alterations. Eye movements are a valuable window into the integrity of central nervous system structures and their changes in defined neurodegenerative conditions, that is, the oculomotor nuclei in the brainstem together with their directly activating supranuclear centers and the basal ganglia as well as cortical areas of higher cognitive control of attention. PMID:24955249

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

    PubMed

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

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. PMID:26899010

  19. Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

    PubMed Central

    Kabanov, A.V.; Gendelman, H.E.

    2009-01-01

    Neurodegenerative and infectious disorders including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population’s age. Alzheimer’s disease alone currently affects 4.5 million Americans, and more than $100 billion is spent per year on medical and institutional care for affected people. Such numbers will double in the ensuing decades. Currently disease diagnosis for all disorders is made, in large measure, on clinical grounds as laboratory and neuroimaging tests confirm what is seen by more routine examination. Achieving early diagnosis would enable improved disease outcomes. Drugs, vaccines or regenerative proteins present “real” possibilities for positively affecting disease outcomes, but are limited in that their entry into the brain is commonly restricted across the blood–brain barrier. This review highlights how these obstacles can be overcome by polymer science and nanotechnology. Such approaches may improve diagnostic and therapeutic outcomes. New developments in polymer science coupled with cell-based delivery strategies support the notion that diseases that now have limited therapeutic options can show improved outcomes by advances in nanomedicine. PMID:20234846

  20. Matrix Metalloproteinases, New Insights into the Understanding of Neurodegenerative Disorders

    PubMed Central

    Kim, Yoon-Seong; Joh, Tong H.

    2012-01-01

    Matrix metalloproteinases (MMPs) are a subfamily of zinc-dependent proteases that are responsible for degradation and remodeling of extracellular matrix proteins. The activity of MMPs is tightly regulated at several levels including cleavage of prodomain, allosteric activation, compartmentalization and complex formation with tissue inhibitor of metalloproteinases (TIMPs). In the central nervous system (CNS), MMPs play a wide variety of roles ranging from brain development, synaptic plasticity and repair after injury to the pathogenesis of various brain disorders. Following general discussion on the domain structure and the regulation of activity of MMPs, we emphasize their implication in various brain disorder conditions such as Alzheimer’s disease, multiple sclerosis, ischemia/reperfusion and Parkinson’s disease. We further highlight accumulating evidence that MMPs might be the culprit in Parkinson’s disease (PD). Among them, MMP-3 appears to be involved in a range of pathogenesis processes in PD including neuroinflammation, apoptosis and degradation of α-synuclein and DJ-1. MMP inhibitors could represent potential novel therapeutic strategies for treatments of neurodegenerative diseases. PMID:24116286

  1. Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

    PubMed

    Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

    2016-07-01

    Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD. PMID:27254466

  2. Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

    PubMed

    Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

    2016-07-01

    Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD.

  3. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne

    PubMed Central

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14–17 years in females and 16–19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  4. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne.

    PubMed

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14-17 years in females and 16-19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  5. Adult-Onset Acquired Partial Lipodystrophy Accompanied by Rheumatoid Arthritis

    PubMed Central

    Muto, Yusuke; Fujimura, Taku; Kakizaki, Aya; Tsuchiyama, Kenichiro; Kusakari, Yoshiyuki; Aiba, Setsuya

    2015-01-01

    Lipodystrophy is a group of metabolic disorders, possibly caused by autoimmune disease. In this report, we describe a case of adult-onset acquired partial lipodystrophy accompanied by rheumatoid arthritis without a family history. Interestingly, immunohistochemical staining revealed dense infiltration of IL-27-producing cells as well as MMP-7-and MMP-28-expressing cells, both of which have been reported to facilitate the development of autoimmune disease. Our present case might suggest possible mechanisms for acquired partial lipodystrophy. PMID:26034476

  6. Hoofbeats and zebras: neurodegenerative disorder presenting as a "first episode" of psychosis.

    PubMed

    Ozkan, Banu; Phutane, Vivek; Jonas, Elizabeth; Tek, Cenk; Srihari, Vinod

    2011-01-01

    Neurodegenerative disorders can include diverse neuropsychiatric symptoms. Here we present a case referred to a "first-episode" psychosis clinic with socio-occupational decline, auditory hallucinations and paranoid ideation who subsequently exhibited a rapid, severe cognitive and behavioral decline. The brain magnetic resonance imaging findings of the patient have shown a progressive cortical atrophy prominent in the frontal lobes due to a neurodegenerative disorder.

  7. Adult-onset bulbar ptosis in Joubert syndrome

    PubMed Central

    Burt, Benjamin; Levine, Johanan; Le, Kim

    2012-01-01

    In this case report, we describe a case of adult-onset bulbar ptosis in a patient with Joubert syndrome. Joubert syndrome is a rare neurodevelopmental disorder with malformations in cerebellum and brainstem. Many ocular abnormalities have been noted in Joubert syndrome, but the association of this syndrome with adult-onset ptosis has not been described to date. This 24-year-old Joubert patient developed a cerebrospinal fluid cyst in her midbrain. She had signs of bilateral third nerve palsy and abducens palsy in the left eye. The bilateral central third nerve palsy causing functional blindness secondary to severe bilateral levator palsy was treated successfully with silicone sling frontalis suspension, as the seventh nerve nucleus was not involved. PMID:22291457

  8. [Adult-onset rare diseases].

    PubMed

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.). PMID:24566697

  9. Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

    PubMed Central

    Scholz, Sonja W.; Bras, Jose

    2015-01-01

    Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions. PMID:26501269

  10. Adult-Onset Still's Disease: From Pathophysiology to Targeted Therapies

    PubMed Central

    Mavragani, Clio P.; Spyridakis, Evangelos G.; Koutsilieris, Michael

    2012-01-01

    Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder affecting primarily young individuals. The diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders. Given the lack of solid data in regard to the underlying pathogenetic mechanisms, treatment of AOSD has been for years largely empirical. Recent advances have revealed a pivotal role of several proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) in disease pathogenesis, giving rise to the development of new targeted therapies aiming at optimal disease control. PMID:22792508

  11. [Kimura's disease: an unrecognized cause of adult-onset nephrotic syndrome with minimal change disease].

    PubMed

    Shehwaro, N; Langlois, A-L; Gueutin, V; Debchi, L; Charlotte, F; Rouvier, P; Rottembourg, J; Izzedine, H

    2014-02-01

    Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Kidney disease is thought to be rare in KD. About a case of adult-onset nephrotic syndrome with minimal change disease, we comment Kimura's disease and its associated kidney damage. Kimura disease should be suspected and included in the diagnosis of adult-onset nephrotic syndrome with minimal change disease.

  12. [Adult onset Still's disease with the initial symptom of pharyngalgia: a case report].

    PubMed

    Zhou, Enhui; Chen, Xiaoping; Zhang, Jingfei

    2015-09-01

    Adult onset Still's disease is a rare inflammatory disease characterized by spiking fevers, arthritis/ arthralgias, typical salmon-colored bumpy rash, pharyngalgia, myalgia and possible involvement of visceral organs. The diagnosis is exclusively based on clinical symptoms, according to the criteria, after the exclusion of well-known infectious, neoplastic, or other autoimmune/autoinflammatory disorders. This report includes one case of adult onset Still's disease with the initial symptom of pharyngalgia. PMID:26647549

  13. The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data.

    PubMed

    Vitaliti, Giovanna; Tabatabaie, Omidreza; Matin, Nassim; Ledda, Caterina; Pavone, Piero; Lubrano, Riccardo; Serra, Agostino; Di Mauro, Paola; Cocuzza, Salvatore; Falsaperla, Raffaele

    2015-01-01

    Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourette's Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders.

  14. The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data.

    PubMed

    Vitaliti, Giovanna; Tabatabaie, Omidreza; Matin, Nassim; Ledda, Caterina; Pavone, Piero; Lubrano, Riccardo; Serra, Agostino; Di Mauro, Paola; Cocuzza, Salvatore; Falsaperla, Raffaele

    2015-01-01

    Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourette's Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders. PMID:26266339

  15. Prions, prion-like prionoids, and neurodegenerative disorders.

    PubMed

    Verma, Ashok

    2016-01-01

    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.

  16. Prions, prion-like prionoids, and neurodegenerative disorders

    PubMed Central

    Verma, Ashok

    2016-01-01

    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. PMID:27293325

  17. Lessons Learned From Nocebo Effects in Clinical Trials for Pain Conditions and Neurodegenerative Disorders.

    PubMed

    Amanzio, Martina; Palermo, Sara; Skyt, Ina; Vase, Lene

    2016-10-01

    It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments. PMID:27580494

  18. Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders.

    PubMed

    Schneider, Anja; Simons, Mikael

    2013-04-01

    The intercellular transfer of misfolded proteins has received increasing attention in various neurodegenerative diseases characterized by the aggregation of specific proteins, as observed in Alzheimer's, Parkinson's and Huntington's disease. One hypothesis holds that intercellular dissemination of these aggregates within the central nervous system results in the seeded assembly of the cognate soluble protein in target cells, similar to that proposed for transmissible prion diseases. The molecular mechanisms underlying the intercellular transfer of these proteinaceous aggregates are poorly understood. Various transfer modes of misfolded proteins including continuous cell-cell contacts such as nanotubes, unconventional secretion or microvesicle/exosome-associated dissemination have been suggested. Cells can release proteins, lipids and nucleic acids by vesicular exocytosis pathways destined for horizontal transfer. Encapsulation into microvesicular/exosomal vehicles not only protects these molecules from degradation and dilution in the extracellular space but also facilitates delivery over large distances, e.g. within the blood flow or interstitial fluid. Specific surface ligands might allow the highly efficient and targeted uptake of these vesicles by recipient cells. In this review, we focus on the cell biology and function of neuronal microvesicles/exosomes and discuss the evidence for pathogenic intercellular protein transfer mediated by vesicular carriers.

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

    PubMed Central

    Rasool, Mahmood; Malik, Arif; Qureshi, Muhammad Saeed; Manan, Abdul; Pushparaj, Peter Natesan; Asif, Muhammad; Qazi, Mahmood Husain; Qazi, Aamer Mahmood; Kamal, Mohammad Amjad; Gan, Siew Hua; Sheikh, Ishfaq Ahmed

    2014-01-01

    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. PMID:24864161

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    2016-01-01

    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. PMID:27230456

  2. Prospects for neurodegenerative and psychiatric disorder drug discovery.

    PubMed

    Williams, Michael; Enna, S J

    2011-05-01

    The discovery of CNS-active drugs has, to a major extent, resulted from clinical serendipity. Once targets for such compounds were identified, conventional mechanism-based approaches were used to identify new chemical entities for the treatment of neurological and psychiatric disorders. Most of these have, however, failed to display any greater efficacy than existing psychotherapeutics and may, in fact, be less efficacious because of side effect liabilities. Among the reasons for this lack of success in drug discovery include a lack of fundamental knowledge regarding the causes of CNS disorders, the absence of biomarkers for diagnosing and monitoring these conditions, a paucity of animal models that are congruent with the human disease state and the increasing likelihood that CNS conditions are multifactorial in their etiology. These challenges force the inclusion of a Phase IIa proof of concept trial as a component of the drug discovery program. Unlike other therapeutic areas, serendipity is a major factor in the CNS translational medicine interface requiring a close collaboration between preclinical and clinical scientists trained to appreciate unusual behavioral phenotypes. When combined with conventional target-based drug discovery technologies, this increases the likelihood of identifying truly novel drugs for the treatment of CNS disorders. PMID:22646072

  3. Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders.

    PubMed

    Janssen, Freek J; van der Stelt, Mario

    2016-08-15

    2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the cannabinoid receptors type 1 and 2. It also serves as an important lipid precursor for the eicosanoid signaling pathway. Consequently, 2-AG is involved in many physiological functions, including anxiety, food intake, inflammation, memory, pain sensation and neurotransmission. Diacylglycerol lipases (DAGLs) are the main biosynthetic enzymes for 2-AG and their role in several pathophysiological conditions is currently under investigation. In this Digest we review all DAGL inhibitors reported to date and their effects in preclinical models of neurodegeneration and metabolic disorders. PMID:27394666

  4. Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders.

    PubMed

    Janssen, Freek J; van der Stelt, Mario

    2016-08-15

    2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the cannabinoid receptors type 1 and 2. It also serves as an important lipid precursor for the eicosanoid signaling pathway. Consequently, 2-AG is involved in many physiological functions, including anxiety, food intake, inflammation, memory, pain sensation and neurotransmission. Diacylglycerol lipases (DAGLs) are the main biosynthetic enzymes for 2-AG and their role in several pathophysiological conditions is currently under investigation. In this Digest we review all DAGL inhibitors reported to date and their effects in preclinical models of neurodegeneration and metabolic disorders.

  5. Functional Genomics Approach for Identification of Molecular Processes Underlying Neurodegenerative Disorders in Prion Diseases

    PubMed Central

    Basu, Urmila; Guan, Le Luo; Moore, Stephen S

    2012-01-01

    Prion diseases or transmissible spongiform encephalopathies (TSEs) are infectious neurodegenerative disorders leading to death. These include Cresutzfeldt-Jakob disease (CJD), familial, sporadic and variant CJD and kuru in humans; and animal TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) of mule deer and elk, and transmissible mink encephalopathy. All these TSEs share common pathological features such as accumulation of mis-folded prion proteins in the central nervous system leading to cellular dysfunction and cell death. It is important to characterize the molecular pathways and events leading to prion induced neurodegeneration. Here we discuss the impact of the functional genomics approaches including microarrays, subtractive hybridization and microRNA profiling in elucidating transcriptional cascades at different stages of disease. Many of these transcriptional changes have been observed in multiple neurodegenerative diseases which may aid in identification of biomarkers for disease. A comprehensive characterization of expression profiles implicated in neurodegenerative disorders will undoubtedly advance our understanding on neuropathology and dysfunction during prion disease and other neurodegenerative disorders. We also present an outlook on the future work which may focus on analysis of structural genetic variation, genome and transcriptome sequencing using next generation sequencing with an integrated approach on animal and human TSE related studies. PMID:23372423

  6. Ca2+ dysfunction in neurodegenerative disorders: Alzheimer's disease.

    PubMed

    Fedrizzi, Laura; Carafoli, Ernesto

    2011-01-01

    More than one century ago "a peculiar disorder of the cerebral cortex" was noticed in a middle-aged patient who had been affected by dementia in the last years of his life. The postmortem hallmarks of his brain were protein plaques, neurofibrillary tangles, and atherosclerotic changes: the neuropathologist who found these alterations and gave his name to the disease that underlied them was Alois Alzheimer (Alzheimer et al., Clin Anat 1995;8:429-431). Following its discovery, the disease has been studied with a vigor that went parallel to the increase of its social importance. The amount of information amassed in the literature is impressive, but knowledge on the mechanism underlying its onset and its progression is still very limited. Numerous hypotheses on the molecular pathogenesis of the Alzheimer's disease (AD) have been proposed and two have gradually gained wide consensus: (i) the amyloid cascade hypothesis, first proposed on the basis of the toxicity evoked by the deposition of amyloid β (Aβ) aggregates; (ii) the Ca(2+) hypothesis, which focuses on the correlation between the dysfunction of Ca(2+) homeostasis and the neurodegeneration process. This succinct review will discuss the essential aspects of the role of Ca(2+) homeostasis dysregulation in the onset and development of AD.

  7. Adult onset retinoblastoma: A diagnostic dilemma.

    PubMed

    Raj, Amit; Arya, Sudesh Kumar; Punia, Rajpal Singh; Kohli, Piyush

    2016-01-01

    Retinoblastoma is the most common intraocular tumor of childhood. About 95% of retinoblastoma cases are diagnosed before the age of 5 years. Not more than 30 cases of Adult-onset retinoblastoma have been reported in literature. A 32 year old male presented with a painful blind eye. There was sudden loss of vision accompanied by severe pain and redness in right eye about 1 year ago, for which some surgery was done with neither a gain in vision nor any relief from pain. Then he was put on maximum tolerable medical therapy, later cyclocryotherapy was done. Now he presented to us with complains of extreme pain and bleeding from right eye since 2 days. There is no history of any ocular trauma. Right eye had no perception of light & showed anterior staphyloma with perforation. Right eye evisceration was done & material sent for histopathological examination, which revealed an adult-onset retinoblastoma. CECT scan revealed thickening of optic nerve throughout its entire length with contrast enhancement. He was further taken up for enucleation of residual sclera with maximum optic nerve stump removal to reconfirm the diagnosis. Histopathological examination revealed tumor deposits present in orbital soft tissue, resection margins and optic nerve cut end.Retinoblastoma presenting in adult age creates a diagnostic dilemma because of its low frequency and atypical features. We want to highlight the importance of high clinical suspicion and imaging modalities before taking any patient for evisceration with unexplained vision loss. One should send the eviscerated material for histopathological examination. PMID:26709674

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

    Albani, Diego; Gloria, Antonio; Giordano, Carmen; Rodilossi, Serena; Russo, Teresa; D'Amora, Ugo; Tunesi, Marta; Cigada, Alberto; Ambrosio, Luigi; Forloni, Gianluigi

    2013-01-01

    Hydrogel-based materials are widely employed in the biomedical field. With regard to central nervous system (CNS) neurodegenerative disorders, the design of injectable nanocomposite hydrogels for in situ drug or cell release represents an interesting and minimally invasive solution that might play a key role in the development of successful treatments. In particular, biocompatible and biodegradable hydrogels can be designed as specific injectable tools and loaded with nanoparticles (NPs), to improve and to tailor their viscoelastic properties upon injection and release profile. An intriguing application is hydrogel loading with mesenchymal stem cells (MSCs) that are a very promising therapeutic tool for neurodegenerative or traumatic disorders of the CNS. This multidisciplinary review will focus on the basic concepts to design acellular and cell-loaded materials with specific and tunable rheological and functional properties. The use of hydrogel-based nanocomposites and mesenchymal stem cells as a synergistic strategy for nervous tissue applications will be then discussed. PMID:24459423

  10. Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders.

    PubMed

    Forlenza, O V; De-Paula, V J R; Diniz, B S O

    2014-06-18

    Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3β) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.

  11. Hydrogel-based nanocomposites and mesenchymal stem cells: a promising synergistic strategy for neurodegenerative disorders therapy.

    PubMed

    Albani, Diego; Gloria, Antonio; Giordano, Carmen; Rodilossi, Serena; Russo, Teresa; D'Amora, Ugo; Tunesi, Marta; Cigada, Alberto; Ambrosio, Luigi; Forloni, Gianluigi

    2013-01-01

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

  12. CREB-regulated transcription coactivator 1: important roles in neurodegenerative disorders.

    PubMed

    Xue, Zhan-Cheng; Wang, Chuang; Wang, Qin-Wen; Zhang, Jun-Fang

    2015-04-25

    The cAMP-responsive element binding protein (CREB)-regulated transcription coactivator, CRTC (also known as transducer of regulated CREB, TORC), is identified as a potent modulator of cAMP response element (CRE)-driven gene transcription. The CRTC family consists of three members (CRTC1-3), among which the CRTC1 shows the highest expression in the brain. Several studies have demonstrated that the CRTC1 plays critical roles in neuronal dendritic growth, long-term synaptic plasticity, memory consolidation and reconsolidation etc., whereas dysfunction of CRTC1 is mainly involved in neurodegenerative disorders. In light of these findings, we aim to review recent research reports that indicate the CRTC1 dysfunction and its underlying mechanisms in the neurodegenerative disorders.

  13. The Pediatric Cerebellum in Inherited Neurodegenerative Disorders: A Pattern-recognition Approach.

    PubMed

    Blaser, Susan I; Steinlin, Maja; Al-Maawali, Almundher; Yoon, Grace

    2016-08-01

    Evaluation of imaging studies of the cerebellum in inherited neurodegenerative disorders is aided by attention to neuroimaging patterns based on anatomic determinants, including biometric analysis, hyperintense signal of structures, including the cerebellar cortex, white matter, dentate nuclei, brainstem tracts, and nuclei, the presence of cysts, brain iron, or calcifications, change over time, the use of diffusion-weighted/diffusion tensor imaging and T2*-weighted sequences, magnetic resonance spectroscopy; and, in rare occurrences, the administration of contrast material. PMID:27423800

  14. The Wnt signaling pathway as a target for the treatment of neurodegenerative disorders.

    PubMed

    Terstappen, Georg C; Gaviraghi, Giovanni; Caricasole, Andrea

    2006-01-01

    Although significant progress in understanding brain function has been made in the last 15 years, the unmet medical need for effective therapeutic treatment of devastating neurodegenerative disorders is still enormous and represents a formidable challenge at the beginning of the 21st century. With the recent accumulation of evidence that the Wnt signaling pathway might be impaired in such diseases, a new avenue for potential therapeutic intervention has been opened which comprises many putative drug targets.

  15. CLP1 as a novel player in linking tRNA splicing to neurodegenerative disorders.

    PubMed

    Weitzer, Stefan; Hanada, Toshikatsu; Penninger, Josef M; Martinez, Javier

    2015-01-01

    Defects in RNA metabolic pathways are well-established causes for neurodegenerative disorders. Several mutations in genes involved in pre-messenger RNA (pre-mRNA) and tRNA metabolism, RNA stability and protein translation have been linked to motor neuron diseases. Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA-derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor-sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases.

  16. Neuronal histaminergic system in aging and age-related neurodegenerative disorders.

    PubMed

    Shan, Ling; Swaab, Dick F; Bao, Ai-Min

    2013-07-01

    The neuronal histaminergic system is involved in many physiological functions and is severely affected in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). The properties of the neuronal histaminergic system in experimental animals and the alterations observed in postmortem brain material of PD or AD patients are reviewed. The production of neuronal histamine shows diurnal fluctuations in control subjects who had no neuropsychiatric disorders, while this fluctuation was strongly altered in patients with neurodegenerative diseases, including PD and AD. In addition, different alterations shown as expression levels of histidine decarboxylase (the key enzyme for histamine production), histamine-methyltransferase (the histamine deactivating enzyme), and histamine receptors (H(1-4)R) were found in various neurodegenerative disorders. Discrepancies between results from animal models and postmortem human brain material studies have made clear that the validation of animal models is absolutely necessary and that studies on patients and human postmortem material are essential to understand the changes of neuronal histaminergic system occurring in neuropsychiatric disorders.

  17. ‘The clocks that time us’—circadian rhythms in neurodegenerative disorders

    PubMed Central

    Videnovic, Aleksandar; Lazar, Alpar S.; Barker, Roger A.; Overeem, Sebastiaan

    2015-01-01

    Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep–wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep–wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep–wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep–wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases. PMID:25385339

  18. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  19. Supplemental substances derived from foods as adjunctive therapeutic agents for treatment of neurodegenerative diseases and disorders.

    PubMed

    Bigford, Gregory E; Del Rossi, Gianluca

    2014-07-01

    Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury. PMID:25022989

  20. Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders.

    PubMed

    Zucconi, G G; Cipriani, S; Scattoni, R; Balgkouranidou, I; Hawkins, D P; Ragnarsdottir, K V

    2007-04-01

    Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.

  1. Childhood Psychosocial Stressors and Adult Onset Arthritis: Broad Spectrum Risk Factors and Allostatic Load

    PubMed Central

    Von Korff, Michael; Alonso, Jordi; Ormel, Johan; Angermeyer, Matthais; Bruffaerts, Ronny; Fleiz, Clara; de Girolamo, Giovanni; Kessler, Ronald C.; Kovess-Masfety, Viviane; Posada-Villa, José; Scott, Kate M.; Uda, Hidenori

    2009-01-01

    Neural, endocrine and immune stress mediators are hypothesized to increase risks of diverse chronic diseases, including arthritis. Retrospective data from the World Mental Health Surveys (N=18,309) were employed to assess whether adult onset of arthritis was associated with childhood adversities and early onset psychological disorder. Cox proportional hazard models assessed the association of number of childhood adversities and the presence of early onset psychological disorder with arthritis age of onset. Controlling for age, sex and early onset mental disorder, relative to persons with no childhood adversities, persons with two adversities had increased risk of adult onset arthritis (Hazard ratio=1.27, 95% CI= 1.08, 1.50), while persons with three or more adversities had higher risk (HR=1.44, CI=1.24,1.67). Early onset depressive and/or anxiety disorder was associated with increased risk of adult-onset arthritis after controlling for childhood adversities (HR=1.43, CI=1.28, 1.61). Since psychosocial stressors may be broad spectrum risk factors that increase risks of diverse chronic conditions in later life (e.g., arthritis, heart disease, diabetes, asthma, chronic pain), prospective studies of childhood psychosocial stressors may be most productive if multiple disease outcomes are assessed in the same study. Results from this study provide methodological guidance for future prospective studies of the relationship between childhood psychosocial stressors and subsequent risk of adult onset arthritis. PERSPECTIVE Retrospective reports of early onset mood-anxiety disorder and multiple childhood adversities were independently associated with increased risk of adult onset arthritis. Carrying out prospective studies of these relationships entails significant challenges. Since childhood psychosocial stressors may be broad spectrum risk factors for diverse chronic conditions, multiple disease outcomes should be assessed in prospective studies assessing health consequences

  2. Targeting MicroRNAs in Prevention and Treatment of Neurodegenerative Disorders.

    PubMed

    Gupta, Smriti; Verma, Savita; Mantri, Shrikant; Berman, Nancy E; Sandhir, Rajat

    2015-11-01

    Preclinical Research microRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that are key regulators of gene expression. They act on wide range of targets by binding to mRNA via imperfect complementarity at 3' UTR. Evidence suggests that miRNAs regulate many biological processes including neuronal development, differentiation, and disease. Altered expression of several miRNAs has been reported in many neurodegenerative disorders (NDDs). Many miRNAs are altered in these diseases, but miRNA 15, miRNA 21, and miRNA 146a have been shown to play critical role in many neurodegenerative conditions. As these miRNAs regulate many genes, miRNA targeted approaches would allow concurrently targeting of multiple effectors of pathways that regulate disease progression. In this review, we describe the role of miRNAs in various NDDs and their potential as therapeutic tools in prevention and treatment of neurological conditions.

  3. Changes in mitochondrial function are pivotal in neurodegenerative and psychiatric disorders: How important is BDNF?

    PubMed Central

    Markham, A; Bains, R; Franklin, P; Spedding, M

    2014-01-01

    The brain is at the very limit of its energy supply and has evolved specific means of adapting function to energy supply, of which mitochondria form a crucial link. Neurotrophic and inflammatory processes may not only have opposite effects on neuroplasticity, but also involve opposite effects on mitochondrial oxidative phosphorylation and glycolytic processes, respectively, modulated by stress and glucocorticoids, which also have marked effects on mood. Neurodegenerative processes show marked disorders in oxidative metabolism in key brain areas, sometimes decades before symptoms appear (Parkinson's and Alzheimer's diseases). We argue that brain-derived neurotrophic factor couples activity to changes in respiratory efficiency and these effects may be opposed by inflammatory cytokines, a key factor in neurodegenerative processes. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24720259

  4. The relation of SMI and the VSEP in a risk sample for neurodegenerative disorders.

    PubMed

    Hagen, Katja; Ehlis, Ann-Christine; Haeussinger, Florian B; Beeretz, Stefan; Kromer, Gina V; Heinzel, Sebastian; Maetzler, Walter; Eschweiler, Gerhard W; Berg, Daniela; Fallgatter, Andreas J; Metzger, Florian G

    2015-08-01

    Vagus somatosensory evoked potentials (VSEP) have been shown to have higher latencies with aging, which are even more increased in patients with Alzheimer's disease and subjects with mild cognitive impairment compared to age-matched healthy controls. In this study, the association of VSEP with subjective memory impairment (SMI), a potential risk or prodromal marker for Alzheimer's disease, was examined. The association of VSEP latencies and SMI was studied in a healthy risk cohort, including 358 elderly subjects, who are in a longitudinal study of risk factors for neurodegenerative disorders. The results show increased VSEP latencies for peak P2 at Fz-F4 in subjects who report SMI and are worried about it as compared to subjects who report memory impairment, but are not concerned and subjects without complaints. The results support a potential role of VSEP for the detection of very early neurodegenerative processes which may precede Alzheimer's disease.

  5. Stem cells in human neurodegenerative disorders--time for clinical translation?

    PubMed

    Lindvall, Olle; Kokaia, Zaal

    2010-01-01

    Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.

  6. Stem cells in neuroinjury and neurodegenerative disorders: challenges and future neurotherapeutic prospects.

    PubMed

    Mouhieddine, Tarek H; Kobeissy, Firas H; Itani, Muhieddine; Nokkari, Amaly; Wang, Kevin K W

    2014-05-01

    The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other biochemical drug-based approaches to ameliorate these disorders. Unfortunately, we are still facing many obstacles that are rendering current neurotherapies ineffective in clinical trials for reasons that are yet to be discovered. That is why we should start by fully understanding the complex mechanisms of neurogenesis and the factors that affect it, or else, all our suggested therapies would fail since they would not be targeting the essence of the neurological disorder but rather the symptoms. One possible paradigm shift is to switch from neuroprotectant therapies towards neurodegeneration/neurorestorative approaches. In addition, other and our laboratories are increasingly focusing on combining the use of pharmacological agents (such as Rho-associated kinase (ROCK) inhibitors or other growth factors (such as brain-derived neurotrophic factor (BDNF)) and stem cell treatment to enhance the survivability and/or differentiation capacity of transplanted stem cells in neurotrauma or other neurodegeneration animal models. Ongoing stem cell research is surely on the verge of a breakthrough of multiple effective therapeutic options for neurodegenerative disorders. Once, we fully comprehend the process of neurogenesis and its components, we will fully be capable of manipulating and utilizing it. In this work, we discuss the current knowledge of neuroregenerative therapies and their associated challenges.

  7. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma.

    PubMed

    Ilmarinen, Pinja; Tuomisto, Leena E; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  8. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma

    PubMed Central

    Ilmarinen, Pinja; Tuomisto, Leena E.; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  9. Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders

    PubMed Central

    Jucker, Mathias; Walker, Lary C.

    2011-01-01

    The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer’s disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prion-like induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson’s/Lewy body disease, Huntington’s disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic

  10. [Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene].

    PubMed

    Laffita-Mesa, José Miguel; Bauer, Peter

    2014-10-21

    Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro-RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes. DNA methylation involves the covalent addition of methyl group to cytosine of the DNA, which is mediated by methyltransferases enzymes. DNA methylation regulates gene expression by repressing transcription, while de-methylation activates gene transcription. Several human diseases are related with the epigenetic process: cancer, Alzheimer disease, stroke, Parkinson disease, and diabetes. We present here the basis of epigenetic inheritance and show the pathogenic mechanisms relating epigenetics in human diseases, specifically with regard to neurodegeneration. We discuss current concepts aimed at understanding the contribution of epigenetics to human neurodegenerative diseases. We also discuss recent findings obtained in our and other centers regarding the ATXN2 gene that causes spinocerebellar ataxia 2 and amyotrophic lateral sclerosis. Epigenetics play a pivotal role in the pathogenesis of human diseases and in several neurodegenerative disorders, and this knowledge will illuminate the pathways in the diagnostic and therapeutic field, which ultimately will be translated into the clinic context of neurodegenerative diseases.

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

    PubMed Central

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

    2014-01-01

    Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications. PMID:24936084

  12. Visual hallucinations in the psychosis spectrum and comparative information from neurodegenerative disorders and eye disease.

    PubMed

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

    2014-07-01

    Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications.

  13. Quantitative characterization of glycoproteins in neurodegenerative disorders using iTRAQ.

    PubMed

    Shi, Min; Hwang, Hyejin; Zhang, Jing

    2013-01-01

    Aberrant protein glycosylation has been recognized to be associated with many neurodegenerative disorders, including Alzheimer and Parkinson disease. Using mass spectrometry-based technologies to catalog and quantify glycoproteins in these diseases is expected to provide insight into not only the biochemical pathogenesis of neurodegeneration but also the biomarker discovery. This chapter describes a multidisciplinary approach to accomplish the goal of glycoprotein identification and quantification in human brain tissue and cerebrospinal fluid, which includes sample preparation, isobaric tag labeling of digested peptides, glycopeptide enrichment using hydrazide chemistry, protein/peptide identification and quantification by liquid chromatography-based high-resolution tandem mass spectrometry, as well as bioinformatic data processing. PMID:23296538

  14. Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders

    PubMed Central

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

    2014-01-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders. PMID:25412207

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

    PubMed

    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.

  16. RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders

    PubMed Central

    Canal, Mercè; Romaní-Aumedes, Joan; Martín-Flores, Núria; Pérez-Fernández, Víctor; Malagelada, Cristina

    2014-01-01

    Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson’s disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders. PMID:25324725

  17. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases

    PubMed Central

    2013-01-01

    Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer′s disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases. PMID:24678247

  18. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases.

    PubMed

    Zeliger, Harold I

    2013-09-01

    Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases.

  19. Current Neurogenic and Neuroprotective Strategies to Prevent and Treat Neurodegenerative and Neuropsychiatric Disorders.

    PubMed

    Carvalho, I M; Coelho, P B; Costa, P C; Marques, C S; Oliveira, R S; Ferreira, D C

    2015-12-01

    The adult central nervous system is commonly known to have a very limited regenerative capacity. The presence of functional stem cells in the brain can therefore be seen as a paradox, since in other organs these are known to counterbalance cell loss derived from pathological conditions. This fact has therefore raised the possibility to stimulate neural stem cell differentiation and proliferation or survival by either stem cell replacement therapy or direct administration of neurotrophic factors or other proneurogenic molecules, which in turn has also originated regenerative medicine for the treatment of otherwise incurable neurodegenerative and neuropsychiatric disorders that take a huge toll on society. This may be facilitated by the fact that many of these disorders converge on similar pathophysiological pathways: excitotoxicity, oxidative stress, neuroinflammation, mitochondrial failure, excessive intracellular calcium and apoptosis. This review will therefore focus on the most promising achievements in promoting neuroprotection and neuroregeneration reported to date.

  20. The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells.

    PubMed

    Sanberg, Paul R; Eve, David J; Willing, Alison E; Garbuzova-Davis, Svitlana; Tan, Jun; Sanberg, Cyndy D; Allickson, Julie G; Cruz, L Eduardo; Borlongan, Cesar V

    2011-01-01

    Stem cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent, and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement, have been detected in both transplanted cells.

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

    PubMed

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

    2016-09-01

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

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

    PubMed

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

    2016-09-01

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

  3. Pathological Propagation through Cell-to-Cell Transmission of Non-Prion Protein Aggregates in Neurodegenerative Disorders

    PubMed Central

    Lee, Seung-Jae; Desplats, Paula; Sigurdson, Christina; Tsigelny, Igor; Masliah, Eliezer

    2016-01-01

    Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, fronto-temporal dementia, Huntington's Disease and Creutzfeldt-Jakob Disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between protein synthesis, aggregation and clearance. While protein misfolding and aggregation occur in most neurodegenerative disorders, the concept of spreading and infectivity of aggregates in the CNS has been reserved to prion diseases such as CJD and bovine spongiform encephalopathy. Emerging evidence suggests that prion-like spreading may occur in other neurodegenerative disorders, taking place with secreted proteins, such as amyloid-β,) and cytosolic proteins, such as tau, huntingtin and α-synuclein. Underlying molecular mechanisms and therapeutic implications are discussed. PMID:21045796

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

    PubMed Central

    2016-01-01

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

  5. Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation.

    PubMed

    Du, Liqin; Pertsemlidis, Alexander

    2011-06-01

    Although cancer and neurodegenerative disease are two distinct pathological disorders, emerging evidence indicates that these two types of disease share common mechanisms of genetic and molecular abnormalities. Recent studies show that individual microRNAs (miRNAs) could be involved in the pathology of both diseases, indicating that the mechanisms of these two seemingly dichotomous diseases converge in the dysregulation of gene expression at the post-transcriptional level. Given the increasing evidence showing that miRNA-based therapeutic strategies that modulate the activity of one or more miRNAs are potentially effective for a wide range of pathological conditions, the involvement of miRNAs in the common pathways of leading both diseases suggests a bright future for developing common therapeutic approaches for both diseases. Moreover, the miRNAs that are dysregulated in both diseases may hold promise as uniquely informative diagnostic markers. Here, we review recent studies on the miRNAs that have been implicated in both cancer and neurodegenerative diseases.

  6. Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders.

    PubMed

    Colpo, Gabriela D; Ascoli, Bruna M; Wollenhaupt-Aguiar, Bianca; Pfaffenseller, Bianca; Silva, Emily G; Cirne-Lima, Elizabeth O; Quevedo, João; Kapczinski, Flávio; Rosa, Adriane R

    2015-08-01

    Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and anti-inflammatory effects. For instance, there is evidence that MSCs can regulate the immune system by inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition to regulating inflammation, they can promote other beneficial effects, such as neuronal growth, decrease free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarified, hindering the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce, despite the promising results of MSCs therapies in this field as well.

  7. Two sporadic cases of adult-onset progressive mucinous histiocytosis.

    PubMed

    Young, A; Olivere, J; Yoo, S; Martins, C; Barrett, T

    2006-02-01

    Progressive mucinous histiocytosis is a rare, benign, non-Langerhans' cell histiocytosis limited to the skin. Ten cases--all women--in four families and one sporadic case have been described in the literature. The disorder usually begins in childhood and progresses slowly. We report two sporadic cases of adult-onset progressive mucinous histiocytosis in unrelated African-American women, aged 48 and 55 years, respectively, who developed red-brown and flesh-coloured, asymptomatic papules on the face, the arms and the legs without truncal, mucosal or visceral involvement. The lesions showed no spontaneous regression. Both patients lacked associated systemic symptoms, including polyuria, polydipsia or seizures. There was no underlying hyperlipidaemia, paraproteinaemia or lymphoproliferative disease. No family history of similar lesions could be identified. Light microscopy revealed dermal proliferation of spindle-shaped histiocytes with abundant mucin deposition. Electron microscopy demonstrated a high number of myelin figures or zebra bodies in the cytoplasm of histiocytes. On immunohistochemistry, positive staining with macrophage markers--CD68, HAM56 and lysozyme--and factor XIIIa, a transglutaminase present in dermal dendrocytes, and negative staining with Langerhans' cell markers--CD1a and S100--and CD34, a marker present in dermal dendritic cells derived from uncommitted mesenchymal cells, were observed. PMID:16420313

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

    PubMed Central

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P.

    2015-01-01

    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. PMID:26134141

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

    PubMed

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P

    2015-01-01

    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. PMID:26134141

  10. [Signaling molecules in the brain and epigenetic factors in neurodegenerative and mental disorders].

    PubMed

    Gomazkov, O A

    2015-01-01

    The literature on a role of signaling molecules in the organization of memory and cognitive functions is analyzed basing on mechanisms of memory physiology determined by a complex of biochemical processes initiated by the transmission of the signal to the synapse and completed by the synthesis of functionally significant molecules in the neuronal genetic apparatus. The center of these processes is a coordinated system of signal transduction, transcription, epigenetic and neurotrophic molecules. The dissonance of signal mechanisms is a prime cause of memory impairment and cognitive dysfunction as social maladaptation factors. The results of experimental and clinical studies of a role of the multilevel signaling system in age-related, neurodegenerative (Alzheimer’s disease) and mental (depression) disorders are discussed. At the same time, signaling molecules may be considered as particular targets for new therapeutic approaches. PMID:26649375

  11. Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?

    PubMed

    Wislet-Gendebien, Sabine; Laudet, Emerence; Neirinckx, Virginie; Rogister, Bernard

    2012-01-01

    The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy.

  12. Tool use disorders in neurodegenerative diseases: Roles of semantic memory and technical reasoning.

    PubMed

    Baumard, Josselin; Lesourd, Mathieu; Jarry, Christophe; Merck, Catherine; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Belliard, Serge; Moreaud, Olivier; Croisile, Bernard; Osiurak, François; Le Gall, Didier

    2016-09-01

    In the field of apraxia, it has been suggested that the ability to use tools and objects in daily life depends not only on semantic knowledge about tool function and context of use but also on technical reasoning about mechanical properties of tools and objects. The aim of the present work was to assess tool use abilities regarding these hypotheses in patients with neurodegenerative diseases and reduced autonomy. Performance of patients with Alzheimer's disease (AD) (n = 31), semantic dementia (SD) (n = 16) and corticobasal syndrome (CBS) (n = 7) was compared to that of healthy control participants (n = 31) in familiar tool use tasks, functional/contextual associations and mechanical problem solving (MPS). A conversion method was applied to data in order to avoid ceiling effects. Tool use disorders were found in all patient groups but the underlying reasons were different. Patients with SD had difficulties in imagining and selecting familiar tools due to the semantic loss but they performed in normal range in MPS tasks. Interestingly, they performed better with only one tool and its corresponding object, which is interpreted as a partial compensation of semantic loss by spared technical reasoning. Patients with CBS exhibited the reverse pattern, that is, MPS deficits without semantic loss. However, additional qualitative research is needed to disentangle the relative contributions of motor and technical reasoning deficits to this pattern. Both of these profiles were found in patients with AD. For all that, these patients did not commit the same errors as stroke patients with left brain-damage documented in previous works. Several hypotheses are proposed to account for the specificity of tool use disorders in neurodegenerative diseases, and recommendations are provided to caregivers. PMID:27376932

  13. The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

    PubMed Central

    Collingwood, Joanna F.; Davidson, Mark R.

    2014-01-01

    There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems. The micro- and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis. PMID:25191270

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

    PubMed

    Zech, Michael; Nübling, Georg; Castrop, Florian; Jochim, Angela; Schulte, Eva C; Mollenhauer, Brit; Lichtner, Peter; Peters, Annette; Gieger, Christian; Marquardt, Thorsten; Vanier, Marie T; Latour, Philippe; Klünemann, Hans; Trenkwalder, Claudia; Diehl-Schmid, Janine; Perneczky, Robert; Meitinger, Thomas; Oexle, Konrad; Haslinger, Bernhard; Lorenzl, Stefan; Winkelmann, Juliane

    2013-01-01

    Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted. PMID:24386122

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

    PubMed Central

    Sehgal, Sheikh Arslan; Mannan, Shazia; Ali, Sannia

    2016-01-01

    Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand–receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT. PMID:27226709

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

    PubMed

    Sehgal, Sheikh Arslan; Mannan, Shazia; Ali, Sannia

    2016-01-01

    Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand-receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT. PMID:27226709

  17. Adult-onset Nemaline Myopathy Coexisting With Myasthenia Gravis: A Case Report.

    PubMed

    Cao, Lingling; Wang, Yanling; Liu, Xiaofeng; Hu, Yanxia; Li, Nianchun; Qiu, Guoping; Luo, Yun; Li, Weidong

    2016-01-01

    Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder which is characterized by fluctuating muscle fatigue. However, the association of MG with nemaline myopathy is rarely reported. Here we report a case of MG coexisting with adult-onset nemaline myopathy. A 55-year-old man endured fluctuating muscle weakness with positive acetylcholine receptor and titin antibodies. After the patient was administrated cholinergic drugs and immunosuppression, the muscle weakness of the patient had mildly been alleviated. Electromyography showed a progressive decrement in the amplitude of muscle action potential at low frequency. Muscle biopsy showed numerous nemalines in the muscle fibers. This is the first reported case of nemalines present in the muscle fibers of adult patient with MG. The pathogenesis of nemaline may be related to titin antibody in adult-onset nemaline myopathy with MG. PMID:26825889

  18. [Pathophysiology, subtypes, and treatments of adult-onset Still's disease: An update].

    PubMed

    Gerfaud-Valentin, M; Sève, P; Hot, A; Broussolle, C; Jamilloux, Y

    2015-05-01

    Adult-onset Still's disease is a rare and difficult to diagnose multisystemic disorder considered as a multigenic autoinflammatory syndrome. Its immunopathogenesis seems to be at the crossroads between inflammasomopathies and hemophagocytic lymphohistiocytosis, the most severe manifestation of the disease. According to recent insights in the pathophysiology and thanks to cohort studies and therapeutic trials, two phenotypes of adult-onset Still's disease may be distinguished: a systemic pattern, initially highly symptomatic and with a higher risk to exhibit life-threatening complications such as reactive hemophagocytic lymphohistiocytosis, where interleukin-1 blockade seems to be very effective, a chronic articular pattern, more indolent with arthritis in the foreground and less severe systemic manifestations, which would threat functional outcome and where interleukin-6 blockade seems to be more effective. This review focuses on these data.

  19. Posterior spinal instrumented fusion for idiopathic scoliosis in patients with multisystemic neurodegenerative disorder: a report of two cases.

    PubMed

    Loh, K W; Chan, C Yw; Chiu, C K; Bin Hasan, M S; Kwan, M K

    2016-08-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a progressive multisystemic neurodegenerative disorder. MELAS syndrome impairs oxidative phosphorylation and predisposes patients to lactic acidosis, particularly under metabolic stress. We report 2 siblings with MELAS-associated idiopathic scoliosis who underwent posterior spinal instrumented fusion with measures taken to minimise anaesthetic and surgical stress, blood loss, and operating time. PMID:27574278

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

  2. Yoga as Therapy for Neurodegenerative Disorders: A Case Report of Therapeutic Yoga for Adrenomyeloneuropathy

    PubMed Central

    Muhammad, Charlene Marie; Moonaz, Steffany Haaz

    2014-01-01

    Yoga is a promising therapeutic modality for neurodegenerative diseases. This case study presents a therapeutic yoga protocol for adrenomyeloneuropathy (AMN) and its effect on a patient’s quality of life (QOL), agility, balance, and peripheral dexterity. A 61-y-old man diagnosed with AMN who was experiencing (1) peripheral neuropathy in his legs and feet, (2) lower-back pain (LBP), and (3) osteoarthritis received 60-min weekly therapeutic yoga sessions for a 10-mo period. Yoga therapy included hatha yoga asanas (poses) and pranayama (breathing exercises). Hatha yoga asanas were aligned with 7 Berg Balance Scale (BBS) indicators to measure improvement in balance and range of motion. The 10-mo course of therapeutic yoga resulted in improved LBP; improved flexion of the patient’s hips, knees, and ankles; improved propulsion phase of walking; and improvement in the patient’s ability to stand and balance without an assistive device. The effect of yoga therapy on the patient in this case study aligns with current QOL improvements noted in current research on yoga therapy for neurological disorders. The described concepts and methods of employing therapeutic yoga provide insights for clinicians into a modality that is low risk and low cost and that can support individuals with other neurological disorders, such as multiple sclerosis (MS), fibromyalgia (FM), and diseases of the peripheral nervous system. Further study is warranted to help determine the safety and efficacy of yoga therapy for these conditions. PMID:26770098

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

    PubMed Central

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

    2015-01-01

    Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. PMID:26295258

  4. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment. PMID:26998855

  5. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment.

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

    PubMed

    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. PMID:27527825

  7. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders

    PubMed Central

    Salcedo, Isidro; Tweedie, David; Li, Yazhou; Greig, Nigel H

    2012-01-01

    Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders. PMID:22519295

  8. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.

    PubMed

    Fernández-Ruiz, Javier; Moro, María A; Martínez-Orgado, José

    2015-10-01

    Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

  9. 'Language of the past' - Exploring past tense disruption during autobiographical narration in neurodegenerative disorders.

    PubMed

    Irish, Muireann; Kamminga, Jody; Addis, Donna Rose; Crain, Stephen; Thornton, Rosalind; Hodges, John R; Piguet, Olivier

    2016-09-01

    Compromised retrieval of autobiographical memory (ABM) is well established in neurodegenerative disorders. The recounting of autobiographical events is inextricably linked to linguistic knowledge, yet no study to date has investigated whether tense use during autobiographical narration is disrupted in dementia syndromes. This study investigated the incidence of correct past tense use during ABM narration in patients with Alzheimer's disease (AD, n = 10) and semantic dementia (SD, n = 10) in comparison with healthy older Controls (n = 10). Autobiographical narratives were analysed for episodic content (internal/external) and classified according to tense use (past/present). Across both patient groups, use of the past tense was significantly compromised relative to Controls, with increased levels of off-target present tense verbs observed. Voxel-based morphometry analyses based on structural MRI revealed differential associations between past tense use and regions of grey matter intensity in the brain. Bilateral temporal cortices were implicated in the SD group, whereas frontal, lateral, and medial temporal regions including the right hippocampus emerged in AD. This preliminary study provides the first demonstration of the disruption of specific linguistic constructs during autobiographical narration in AD and SD. Future studies are warranted to clarify at what point in the disease trajectory such deficits in tense use emerge, and whether these deficits are a product or contributing factor in memory disruption in these syndromes. PMID:26014271

  10. Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders.

    PubMed

    Madabattula, Surya T; Strautman, Joel C; Bysice, Andrew M; O'Sullivan, Julia A; Androschuk, Alaura; Rosenfelt, Cory; Doucet, Kacy; Rouleau, Guy; Bolduc, Francois

    2015-01-01

    Locomotive defects resulting from neurodegenerative disorders can be a late onset symptom of disease, following years of subclinical degeneration, and thus current therapeutic treatment strategies are not curative. Through the use of whole exome sequencing, an increasing number of genes have been identified to play a role in human locomotion. Despite identifying these genes, it is not known how these genes are crucial to normal locomotive functioning. Therefore, a reliable assay, which utilizes model organisms to elucidate the role of these genes in order to identify novel targets of therapeutic interest, is needed more than ever. We have designed a sensitized version of the negative geotaxis assay that allows for the detection of milder defects earlier and has the ability to evaluate these defects over time. The assay is performed in a glass graduated cylinder, which is sealed with a wax barrier film. By increasing the threshold distance to be climbed to 17.5 cm and increasing the experiment duration to 2 min we have observed a greater sensitivity in detecting mild mobility dysfunctions. The assay is cost effective and does not require extensive training to obtain highly reproducible results. This makes it an excellent technique for screening candidate drugs in Drosophila mutants with locomotion defects. PMID:26132637

  11. Improvement of neuronal bioenergetics by neurosteroids: implications for age-related neurodegenerative disorders.

    PubMed

    Grimm, Amandine; Schmitt, Karen; Lang, Undine E; Mensah-Nyagan, Ayikoe Guy; Eckert, Anne

    2014-12-01

    The brain has high energy requirements to maintain neuronal activity. Consequently impaired mitochondrial function will lead to disease. Normal aging is associated with several alterations in neurosteroid production and secretion. Decreases in neurosteroid levels might contribute to brain aging and loss of important nervous functions, such as memory. Up to now, extensive studies only focused on estradiol as a promising neurosteroid compound that is able to ameliorate cellular bioenergetics, while the effects of other steroids on brain mitochondria are poorly understood or not investigated at all. Thus, we aimed to characterize the bioenergetic modulating profile of a panel of seven structurally diverse neurosteroids (progesterone, estradiol, estrone, testosterone, 3α-androstanediol, DHEA and allopregnanolone), known to be involved in brain function regulation. Of note, most of the steroids tested were able to improve bioenergetic activity in neuronal cells by increasing ATP levels, mitochondrial membrane potential and basal mitochondrial respiration. In parallel, they modulated redox homeostasis by increasing antioxidant activity, probably as a compensatory mechanism to a slight enhancement of ROS which might result from the rise in oxygen consumption. Thereby, neurosteroids appeared to act via their corresponding receptors and exhibited specific bioenergetic profiles. Taken together, our results indicate that the ability to boost mitochondria is not unique to estradiol, but seems to be a rather common mechanism of different steroids in the brain. Thus, neurosteroids may act upon neuronal bioenergetics in a delicate balance and an age-related steroid disturbance might be involved in mitochondrial dysfunction underlying neurodegenerative disorders. PMID:25281013

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

    PubMed

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

    2015-11-27

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

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

    PubMed Central

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

    2015-01-01

    Ascorbic acid is a key antioxidant of the Central Nervous System (CNS). Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS) generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders. PMID:26633354

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

    PubMed Central

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

    2013-01-01

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

  15. Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.

    PubMed

    Kumar, Raman; Corbett, Mark A; Smith, Nicholas J C; Jolly, Lachlan A; Tan, Chuan; Keating, Damien J; Duffield, Michael D; Utsumi, Toshihiko; Moriya, Koko; Smith, Katherine R; Hoischen, Alexander; Abbott, Kim; Harbord, Michael G; Compton, Alison G; Woenig, Joshua A; Arts, Peer; Kwint, Michael; Wieskamp, Nienke; Gijsen, Sabine; Veltman, Joris A; Bahlo, Melanie; Gleeson, Joseph G; Haan, Eric; Gecz, Jozef

    2015-04-01

    We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

  16. Alaskan Husky encephalopathy--a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome).

    PubMed

    Brenner, O; Wakshlag, J J; Summers, B A; de Lahunta, A

    2000-07-01

    The gross and histopathological findings in the brain and spinal cord of five Alaskan Husky dogs with a novel incapacitating and ultimately fatal familial and presumed hereditary neurodegenerative disorder are described. Four dogs presented with neurological deficits before the age of 1 year (7-11 months) and one animal at 2.5 years old. Clinical signs in all dogs were of acute onset and included ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulties in prehension of food. In animals allowed to survive, the disease was static but with frequent recurrences. Pathological findings were limited to the central nervous system. Grossly visible bilateral and symmetrical cavitated foci were consistently present in the thalamus with variable extension into the caudal brain stem. Microscopic lesions were more widespread and included foci of bilateral and symmetrical degeneration in the basal nuclei, midbrain, pons and medulla, as well as multifocal lesions at the base of sulci in the cerebral cortex and in the gray matter of cerebellar folia in the ventral vermis. Neuronal loss with concomitant neuronal sparing, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation and transient mixed inflammatory infiltration were the main histopathological findings. In addition, a population of reactive gemistocytic astrocytes with prominent cytoplasmic vacuolation was noted in the thalamus. Lesions of this nature in this distribution within the neuroaxis have not been reported in dogs. The neuropathological findings resemble Leigh's disease/subacute necrotizing encephalomyelopathy of man. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point to the possible pathogenetic role of astrocytes in the evolution of these lesions. An inherited metabolic derangement of unknown nature is postulated as the cause of this breed-specific disorder.

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

    PubMed

    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

  18. Adult-onset laryngomalacia: case reports and review of management.

    PubMed

    Hey, Shi Ying; Oozeer, Nashreen Banon; Robertson, Stuart; MacKenzie, Kenneth

    2014-12-01

    Laryngomalacia is a dynamic airway condition characterised by inward collapse of flaccid supraglottic structures during inspiration. Although the most common cause of stridor in the paediatric population, adult-onset laryngomalacia remains a rare entity and its management, challenging. Two cases of adult-onset laryngomalacia are reported. A review of the English literature is performed and additional publications identified by hand-searching relevant papers; 13 case reports/series comprising 28 cases of adult-onset laryngomalacia were identified, divided into two main groups: idiopathic (6/28) and acquired (22/28). The aetiology of the acquired form includes neurological, traumatic and iatrogenic. Reported therapeutic measures used are laser supraglottoplasty, epiglottopexy, partial epiglottidectomy, defunctioning tracheostomy and intubation whilst correcting the underlying cause. The majority of patients only required one therapeutic procedure (follow-up of 2-24 months). A strong index of suspicion is required to diagnose adult-onset laryngomalacia aided by in-office laryngoscopy. The rarity of this condition prevents management-based randomised controlled trials. PMID:24615649

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

    PubMed

    Atri, Alireza

    2016-01-01

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

  20. Clinical profile of patients with adult-onset eosinophilic asthma

    PubMed Central

    Storm, Huib; Amelink, Marijke; de Nijs, Selma B.; Eichhorn, Edwin; Reitsma, Bennie H.; Bel, Elisabeth H.D.; ten Brinke, Anneke

    2016-01-01

    Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×109 L−1) were compared with 361 adult-onset asthma patients with low (<0.3×109 L−1) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7–8.1), 3.0 (95% CI 1.1–8.1) and 2.4 (95% CI 1.3–4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice. PMID:27730197

  1. Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders

    PubMed Central

    de Pedro-Cuesta, Jesús; Martínez-Martín, Pablo; Rábano, Alberto; Alcalde-Cabero, Enrique; José García López, Fernando; Almazán-Isla, Javier; Ruiz-Tovar, María; Medrano, Maria-José; Avellanal, Fuencisla; Calero, Olga; Calero, Miguel

    2016-01-01

    Background: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific “drivers”, i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities. Objectives and Methods: Redefining drivers as “neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms”, we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. Results: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson’s disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer’s disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. Conclusion: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these. PMID:26923014

  2. Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult-onset Inherited Hemophagocytic Lymphohistiocytosis.

    PubMed

    Kuriyama, Takuro; Kato, Koji; Sakamoto, Keiji; Hayashi, Masayasu; Takashima, Shuichiro; Mori, Yasuo; Takenaka, Katsuto; Iwasaki, Hiromi; Teshima, Takanori; Harada, Naoki; Nagafuji, Koji; Miyamoto, Toshihiro; Akashi, Koichi

    2016-01-01

    Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications. PMID:26984088

  3. Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope.

    PubMed

    Sonkusare, S K; Kaul, C L; Ramarao, P

    2005-01-01

    trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.

  4. The implications of angiotensin-converting enzymes and their modulators in neurodegenerative disorders: current and future perspectives.

    PubMed

    Kaur, Parneet; Muthuraman, Arunachalam; Kaur, Manjinder

    2015-04-15

    Angiotensin converting enzyme (ACE) is a dipeptidyl peptidase transmembrane bound enzyme. Generally, ACE inhibitors are used for the cardiovascular disorders. ACE inhibitors are primary agents for the management of hypertension, so these cannot be avoided for further use. The present Review focuses on the implications of angiotensin converting enzyme inhibitors in neurodegenerative disorders such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and diabetic neuropathy. ACE inhibitors such as ramipril, captopril, perindopril, quinapril, lisinopril, enalapril, and trandolapril have been documented to ameliorate the above neurodegenerative disorders. Neurodegeneration occurs not only by angiotensin II, but also by other endogenous factors, such as the formation of free radicals, amyloid beta, immune reactions, and activation of calcium dependent enzymes. ACE inhibitors interact with the above cellular mechanisms. Thus, these may act as a promising factor for future medicine for neurological disorders beyond the cardiovascular actions. Central acting ACE inhibitors can be useful in the future for the management of neuropathic pain due to following actions: (i) ACE-2 converts angiotensinogen to angiotensin(1-7) (hepatapeptide) which produces neuroprotective action; (ii) ACE inhibitors downregulate kinin B1 receptors in the peripheral nervous system which is responsible for neuropathic pain. However, more extensive research is required in the field of neuropathic pain for the utilization of ACE inhibitors in human.

  5. Office Work Exposures and Adult-Onset Asthma

    PubMed Central

    Jaakkola, Maritta S.; Jaakkola, Jouni J.K.

    2007-01-01

    Background Office exposures have been linked to symptoms of sick building syndrome, but their relation to the development of asthma has not been studied previously. These exposures have increasing importance because an increasing proportion of the workforce is working in office environments. Objectives The aim of this study was to assess the relations of exposure to carbonless copy paper (CCP), paper dust, and fumes from photocopiers and printers to adult-onset asthma. Methods We conducted a population-based incident case–control study of adults 21–63 years of age living in the Pirkanmaa District in South Finland. All new clinically diagnosed cases (n = 521) of asthma were recruited during a 3-year study period. A random sample of the source population formed the controls (n = 1,016). This part focused on 133 cases and 316 controls who were office workers according to their current occupation classified by the 1988 International Standard Classification of Occupations. All participants answered a questionnaire on health, smoking, occupation, and exposures at work and home. Subjects with previous asthma were excluded. Results Exposures to paper dust [adjusted odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.25–3.10] and CCP (OR = 1.66; 95% CI, 1.03–2.66) were related to significantly increased risk of adult-onset asthma. An exposure–response relation was observed between exposure to paper dust and risk of asthma. Conclusions This study provides new evidence that exposures to paper dust and CCP in office work are related to increased risk of adult-onset asthma. Reduction of these exposures could prevent asthma in office workers. Clinicians seeing asthma patients should be aware of this link to office exposures. PMID:17637914

  6. Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties

    SciTech Connect

    Spencer, P.S.; Ludolph, A.C.; Kisby, G.E. )

    1992-05-11

    At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity.41 references.

  7. Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties?

    PubMed

    Spencer, P S; Ludolph, A C; Kisby, G E

    1992-05-11

    At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity. PMID:1322079

  8. FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders.

    PubMed

    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.

  9. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive. PMID:20623001

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

    PubMed Central

    Hofmann-Apitius, Martin; Ball, Gordon; Gebel, Stephan; Bagewadi, Shweta; de Bono, Bernard; Schneider, Reinhard; Page, Matt; Kodamullil, Alpha Tom; Younesi, Erfan; Ebeling, Christian; Tegnér, Jesper; Canard, Luc

    2015-01-01

    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 (EFPIA) and the European

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

    PubMed

    Hofmann-Apitius, Martin; Ball, Gordon; Gebel, Stephan; Bagewadi, Shweta; de Bono, Bernard; Schneider, Reinhard; Page, Matt; Kodamullil, Alpha Tom; Younesi, Erfan; Ebeling, Christian; Tegnér, Jesper; Canard, Luc

    2015-01-01

    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 (EFPIA) and the European

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

    PubMed

    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.

  13. Driving and neurodegenerative diseases.

    PubMed

    Uc, Ergun Y; Rizzo, Matthew

    2008-09-01

    The proportion of elderly people in the general population is rising, resulting in greater numbers of drivers with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. These neurodegenerative disorders impair cognition, visual perception, and motor function, leading to reduced driver fitness and greater crash risk. Yet neither medical diagnosis nor age alone is reliable enough to predict driver safety or crashes or to revoke the driving privileges of these individuals. Driving research utilizes tools such as questionnaires about driving habits and history, driving simulators, standardized road tests utilizing instrumented vehicles, and state driving records. Research challenges include outlining the evolution of driving safety, understanding the mechanisms of driving impairment, and developing a reliable and efficient standardized test battery for prediction of driver safety in neurodegenerative disorders. This information will enable healthcare providers to advise their patients with neurodegenerative disorders with more certainty, affect policy, and help develop rehabilitative measures for driving. PMID:18713573

  14. Associated Markers for Adult-onset Allergic Asthma.

    PubMed

    Bedolla-Barajas, Martín; Morales-Romero, Jaime; Ramses-Bedolla-Pulido, Tonatiuh; Fabiola-García-Padilla, Lourdes; Hernández-Colín, Dante

    2015-10-01

    The clinical behavior of asthma varies with age at onset. This study was undertaken to identify associated markers of adult-onset allergic asthma (age ≥20 years).This cross-sectional study compared two groups: 58 patients with asthma onset at ≥20 years and 66 with onset at ≥20 years. They were compared depending on results of clinical history, and body mass index (BMI), aeroallergen sensitization, total serum IgE, eosinophil count, asthma control test, and asthma severity level.Ages at first asthma episode were 10.0 ± 6.6 and 33.4 ± 10.5 (p<0.001) in the <20 and ≥20 group, respectively. BMI was higher in adult asthmatic subjects (29.8 versus 27.1, P=0.017), but BMI ≥30 kg/m(2) was not associated with asthma onset in ≥20 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 0.759 to 3.211; p= 0.227). After multivariate analysis, allergic rhinitis and IgE ≥150 IU/mL were negatively correlated with asthma onset in ≥20 years old (OR adjusted [ORa] = 0.255, 95% CI 0.078 to 0.837, P= 0.024, and ORa =0.385, 95% CI 0.175 to 0.849, p= 0.018, respectively).Adult-onset allergic asthma was not different from early-onset asthma. PMID:26742445

  15. Coats’ disease of adult-onset in 48 eyes

    PubMed Central

    Rishi, Ekta; Rishi, Pukhraj; Appukuttan, Bindu; Uparkar, Mahesh; Sharma, Tarun; Gopal, Lingam

    2016-01-01

    Background: Coats’ disease diagnosed in adulthood is an idiopathic, retinal exudative vascular disease without an inciting factor and has retinal features different from the childhood disease. Aim: To describe clinical features, treatment, and outcomes of eyes with Coats’ disease first diagnosed in patients 35 years or older. Materials and Methods: Retrospective chart review of patients first diagnosed with Coats’ disease at the age of 35 years or more at a tertiary eye care center between January 1995 and 2012. Eyes with retinal exudation or Coats’-like response from secondary causes were excluded. Results: Forty-five of 646 patients (7%) diagnosed with Coats’ disease had adult-onset disease. Mean age at presentation was 47 years. Systemic hypertension was the most common (22%) systemic association and decreased vision the predominant presenting feature (83%). Localized (<6 clock h) presentation (74%) was unique to adults as against diffuse involvement (69%) in children (P < 0.001). Eyes were treated with laser photocoagulation 29 (60%), cryotherapy (4%), or both (2%) with surgical intervention in three (6%) eyes. Following treatment eight (35%) eyes improved, 11 (48%) eyes were stable while four (12%) eyes worsened due to complications. Conclusion: Adult-onset Coats’ disease has less extensive involvement, more benign natural course, and a more favorable treatment outcome as against the childhood-onset disease. The bilateral presentation emphasizes the need for regular follow-up to detect possible future involvement of the fellow eye. PMID:27609165

  16. Associated Markers for Adult-onset Allergic Asthma.

    PubMed

    Bedolla-Barajas, Martín; Morales-Romero, Jaime; Ramses-Bedolla-Pulido, Tonatiuh; Fabiola-García-Padilla, Lourdes; Hernández-Colín, Dante

    2015-10-01

    The clinical behavior of asthma varies with age at onset. This study was undertaken to identify associated markers of adult-onset allergic asthma (age ≥20 years).This cross-sectional study compared two groups: 58 patients with asthma onset at ≥20 years and 66 with onset at ≥20 years. They were compared depending on results of clinical history, and body mass index (BMI), aeroallergen sensitization, total serum IgE, eosinophil count, asthma control test, and asthma severity level.Ages at first asthma episode were 10.0 ± 6.6 and 33.4 ± 10.5 (p<0.001) in the <20 and ≥20 group, respectively. BMI was higher in adult asthmatic subjects (29.8 versus 27.1, P=0.017), but BMI ≥30 kg/m(2) was not associated with asthma onset in ≥20 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 0.759 to 3.211; p= 0.227). After multivariate analysis, allergic rhinitis and IgE ≥150 IU/mL were negatively correlated with asthma onset in ≥20 years old (OR adjusted [ORa] = 0.255, 95% CI 0.078 to 0.837, P= 0.024, and ORa =0.385, 95% CI 0.175 to 0.849, p= 0.018, respectively).Adult-onset allergic asthma was not different from early-onset asthma.

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

    PubMed Central

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

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action. PMID:25914621

  18. Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

    PubMed Central

    Cornelius, Carolin; Dinkova-Kostova, Albena T.; Calabrese, Edward J.; Mattson, Mark P.

    2010-01-01

    Abstract Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose–response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling. Antioxid. Redox Signal. 13, 1763–1811. PMID:20446769

  19. Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

    PubMed Central

    Magen, Daniella; Georgopoulos, Costa; Bross, Peter; Ang, Debbie; Segev, Yardena; Goldsher, Dorit; Nemirovski, Alexandra; Shahar, Eli; Ravid, Sarit; Luder, Anthony; Heno, Bayan; Gershoni-Baruch, Ruth; Skorecki, Karl; Mandel, Hanna

    2008-01-01

    Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration. PMID:18571143

  20. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy.

    PubMed

    Magen, Daniella; Georgopoulos, Costa; Bross, Peter; Ang, Debbie; Segev, Yardena; Goldsher, Dorit; Nemirovski, Alexandra; Shahar, Eli; Ravid, Sarit; Luder, Anthony; Heno, Bayan; Gershoni-Baruch, Ruth; Skorecki, Karl; Mandel, Hanna

    2008-07-01

    Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

  1. Sleep in Neurodegenerative Diseases.

    PubMed

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. PMID:26972029

  2. Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders.

    PubMed

    Kovacs, Gabor G; Klöppel, Stefan; Fischer, Ingeborg; Dorner, Suzanne; Lindeck-Pozza, Elisabeth; Birner, Peter; Bötefür, Ingolf C; Pilz, Peter; Volk, Benedikt; Budka, Herbert

    2003-01-20

    Neurodegenerative diseases share symptoms suggested to be related to the serotonergic system. To evaluate the involvement of serotonergic raphe nuclei, we compared the percentage of neurons synthesizing serotonin in the nucleus centralis superior (NCS), raphe obscurus and pallidus (NROP) in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Parkinson's disease (PD), multiple system atrophy (MSA), and control brains. We used immunohistochemistry for tryptophan hydroxylase (TpOH), phosphorylated tau, and alpha-synuclein. We observed a significant decrease in the NCS in the NROP in AD, but a significant increase in PSP and MSA. Cytoskeletal pathology was present in the NCS and NROP to a variable degree. We conclude that there is disease- and nucleus-specific alteration of serotonin synthesis in the raphe.

  3. Cannabinoids and value-based decision making: implications for neurodegenerative disorders

    PubMed Central

    Lee, Angela M.; Oleson, Erik B.; Diergaarde, Leontien; Cheer, Joseph F.; Pattij, Tommy

    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 in patients with PD, but also shares neural substrates with PD in basal ganglia structures and the dopamine system. Interestingly, the endogenous cannabinoid system modulates dopamine function and subsequently value-based decision making. This review will provide an overview of the interdisciplinary research that has influenced our understanding of value-based decision making and the role of dopamine, particularly in the context of reinforcement learning theories, as well as recent animal and human studies that demonstrate the modulatory role of activation of cannabinoid receptors by exogenous agonists or their naturally occurring ligands. The implications of this research for the symptomatology of and potential treatments for PD are also discussed. PMID:23162787

  4. Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome: implications for normal aging and age-dependent neurodegenerative disorders.

    PubMed

    Graziotto, John J; Cao, Kan; Collins, Francis S; Krainc, Dimitri

    2012-01-01

    While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogues of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases.

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

    PubMed

    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. PMID:17431424

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

    PubMed

    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.

  7. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders.

    PubMed

    Slavin, Shimon; Kurkalli, Basan G S; Karussis, Dimitrios

    2008-11-01

    No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

  8. Adult onset Still's disease accompanied by acute respiratory distress syndrome: A case report

    PubMed Central

    Xi, Xiao-Tu; Wang, Mao-Jie; Huang, Run-Yue; Ding, Bang-Han

    2016-01-01

    Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fever and arthralgia/arthritis. The most common pulmonary manifestations associated with AOSD are pulmonary infiltrates and pleural effusion. The present study describes a 40-year-old male with AOSD who developed fever, sore throat and shortness of breath. Difficulty breathing promptly developed, and the patient was diagnosed with acute respiratory distress syndrome (ARDS). The patient did not respond to antibiotics, including imipenem, vancomycin, fluconazole, moxifloxacin, penicillin, doxycycline and meropenem, but was sensitive to glucocorticoid treatment, including methylprednisolone sodium succinate. ARDS accompanied by AOSD has been rarely reported in the literature. In conclusion, in a patient with ARDS who does not respond to antibiotic treatment, the involvement of AOSD should be considered. PMID:27588099

  9. Adult-onset Still's disease with myocarditis and hemophagocytic lymphohistiocytosis: Rare manifestation with fatal outcome.

    PubMed

    Gupta, Devika; Jagani, Rajat; Mendonca, Satish; Rathi, Khushi Ram

    2016-01-01

    Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology characterized by fever, evanescent pink salmon rash, arthritis, and multiorgan involvement. Here, we report an unusual manifestation of AOSD in a 40-year-old male who presented to our hospital with pyrexia of unknown origin and rash of 3 weeks duration. All his serological investigations and imaging studies were unremarkable. He was fulfilling clinical and laboratory criteria as per Yamaguchi for AOSD and was managed for the same. Our patient did not respond well to the treatment, had a downhill course, and succumbed to his illness. Autopsy confirmed myocarditis and florid bone marrow reactive hemophagocytosis as the cause of his death. PMID:26960645

  10. Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases

    PubMed Central

    Edelmann, Mariola J.; Nicholson, Benjamin; Kessler, Benedikt M.

    2011-01-01

    Recent advances in the development and discovery of pharmacological interventions within the ubiquitin–proteasome system (UPS) have uncovered an enormous potential for possible novel treatments of neurodegenerative disease, cancer, immunological disorder and microbial infection. Interference with proteasome activity, although initially considered unlikely to be exploitable clinically, has already proved to be very effective against haematological malignancies, and more specific derivatives that target subsets of proteasomes are emerging. Recent small-molecule screens have revealed inhibitors against ubiquitin-conjugating and -deconjugating enzymes, many of which have been evaluated for their potential use as therapeutics, either as single agents or in synergy with other drugs. Here, we discuss recent advances in the characterisation of novel UPS modulators (in particular, inhibitors of ubiquitin-conjugating and -deconjugating enzymes) and how they pave the way towards new therapeutic approaches for the treatment of proteotoxic disease, cancer and microbial infection. PMID:22088887

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2010-12-01

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

  13. Anti-Viral Agents in Neurodegenerative Disorders: New Paradigm for Targeting Alzheimer's Disease.

    PubMed

    Faldu, Khushboo G; Shah, Jigna S; Patel, Snehal S

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease affecting geriatric populations for which several causes have been proposed. These include a relationship with known pathogens although the exact nature of such a relationship remains uncertain. Herpes simplex virus-1 has been proposed as potential cause of AD because of its ability to form ß amyloid(Aß) and neurofibrillary tangles due to tau hyperphosphorylation and action of beta & gamma secretase on amyloid precursor protein(APP) together with genetic association with apolipoprotein-E4(ApoE-Ɛ4), which points out to latent Herpes Simplex virus-1 as an agent causing AD. There are numerous studies that linked HSV-1 with AD like anti-HSV-1 IgM antibodies, nectin-2, heme oxygenase-1, phosphorylated eukaryotic initiation factor-2A, caspase-8 and nucleus-specific alteration of raphe neurons. Various possible mechanisms by which HSV-1 might lead to development of AD such as ApoE, ß-amyloid, tau phosphorylation, inflammation and oxidative stress are also discussed. Thus, this review discusses patent information and a strong relationship between latent HSV-1 and AD and also proposes antiviral therapy for AD. PMID:25963683

  14. The Changing Landscape of Voltage-Gated Calcium Channels in Neurovascular Disorders and in Neurodegenerative Diseases

    PubMed Central

    Cataldi, Mauro

    2013-01-01

    It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca2+ in neurons. Also, some of them as L-type channels are essential for Ca2+-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the “harmless” VGCCs may become “toxic” for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca2+ when: a) their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca2+-dependent action potentials carry high Ca2+ loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca2+. This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca2+-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia. PMID:24179464

  15. Cellular and biochemical actions of melatonin which protect against free radicals: role in neurodegenerative disorders.

    PubMed

    Ortiz, Genaro G; Benítez-King, Gloria A; Rosales-Corral, Sergio A; Pacheco-Moisés, Fermín P; Velázquez-Brizuela, Irma E

    2008-09-01

    Molecular oxygen is toxic for anaerobic organisms but it is also obvious that oxygen is poisonous to aerobic organisms as well, since oxygen plays an essential role for inducing molecular damage. Molecular oxygen is a triplet radical in its ground-stage (.O-O.) and has two unpaired electrons that can undergoes consecutive reductions of one electron and generates other more reactive forms of oxygen known as free radicals and reactive oxygen species. These reactants (including superoxide radicals, hydroxyl radicals) possess variable degrees of toxicity. Nitric oxide (NO*) contains one unpaired electron and is, therefore, a radical. NO* is generated in biological tissues by specific nitric oxide synthases and acts as an important biological signal. Excessive nitric oxide production, under pathological conditions, leads to detrimental effects of this molecule on tissues, which can be attributed to its diffusion-limited reaction with superoxide to form the powerful and toxic oxidant, peroxynitrite.Reactive oxygen and nitrogen species are molecular "renegades"; these highly unstable products tend to react rapidly with adjacent molecules, donating, abstracting, or even sharing their outer orbital electron(s). This reaction not only changes the target molecule, but often passes the unpaired electron along to the target, generating a second free radical, which can then go on to react with a new target amplifying their effects.This review describes the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases and the roles of melatonin as free radical scavenger and neurocytoskeletal protector. PMID:19506721

  16. Optogenetics for neurodegenerative diseases

    PubMed Central

    Vann, Kiara T; Xiong, Zhi-Gang

    2016-01-01

    Neurodegenerative diseases are devastating conditions that lead to progressive degeneration of neurons. Neurodegeneration may result in ataxia, dementia, and muscle atrophies, etc. Despite enormous research efforts that have been made, there is lack of effective therapeutic interventions for most of these diseases. Optogenetics is a recently developed novel technique that combines optics and genetics to modulate the activity of specific neurons. Optogenetics has been implemented in various studies including neuropsychiatric disorders and neurodegenerative diseases. This review focuses on the recent advance in using this technique for the studies of common neurodegenerative diseases. PMID:27186317

  17. Axial mitochondrial myopathy in a patient with rapidly progressive adult-onset scoliosis.

    PubMed

    Hiniker, Annie; Wong, Lee-Jun; Berven, Sigurd; Truong, Cavatina K; Adesina, Adekunle M; Margeta, Marta

    2014-01-01

    Axial myopathy can be the underlying cause of rapidly progressive adult-onset scoliosis; however, the pathogenesis of this disorder remains poorly understood. Here we present a case of a 69-year old woman with a family history of scoliosis affecting both her mother and her son, who over 4 years developed rapidly progressive scoliosis. The patient had a history of stable scoliosis since adolescence that worsened significantly at age 65, leading to low back pain and radiculopathy. Paraspinal muscle biopsy showed morphologic evidence of a mitochondrial myopathy. Diagnostic deficiencies of electron transport chain enzymes were not detected using standard bioassays, but mitochondrial immunofluorescence demonstrated many muscle fibers totally or partially deficient for complexes I, III, IV-I, and IV-IV. Massively parallel sequencing of paraspinal muscle mtDNA detected multiple deletions as well as a 40.9% heteroplasmic novel m.12293G > A (MT-TL2) variant, which changes a G:C pairing to an A:C mispairing in the anticodon stem of tRNA Leu(CUN). Interestingly, these mitochondrial abnormalities were not detected in the blood of either the patient or her son, suggesting that the patient's rapidly progressive late onset scoliosis was due to the acquired paraspinal mitochondrial myopathy; the cause of non-progressive scoliosis in the other two family members currently remains unexplained. Notably, this case illustrates that isolated mitochondrial myopathy can underlie rapidly-progressive adult-onset scoliosis and should be considered in the differential diagnosis of the primary axial myopathy.

  18. Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation

    PubMed Central

    Ikeda, S; Yazaki, M; Takei, Y; Ikegami, T; Hashikura, Y; Kawasaki, S; Iwai, M; Kobayashi, K; Saheki, T

    2001-01-01

    OBJECTIVE—Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to.
METHODS—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member.
RESULTS—There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work.
CONCLUSIONS—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.

 PMID:11606680

  19. Does impairment of the ubiquitin-proteasome system or the autophagy-lysosome pathway predispose individuals to neurodegenerative disorders such as Parkinson's disease?

    PubMed

    Matsuda, Noriyuki; Tanaka, Keiji

    2010-01-01

    About twenty years ago, an abnormal enrichment of ubiquitin in the inclusion bodies of various neurodegenerative disorders was reported. To date, this phenotype has been a diagnostic feature of many neurodegenerative disorders including Alzheimer's and Parkinson's diseases (PD). Because ubiquitin tags proteins that must be eliminated from cells, thereby targeting them for proteasomal degradation, many scientists believed that the ubiquitin-proteasome system (UPS) was inactivated in these neurodegenerative disorders. This inactivation would lead to an accumulation of ubiquitylated proteins with their concomitant aggregation into inclusion bodies and subsequent neuronal death. This hypothesis was further fuelled by the discovery that parkin, the causal gene of autosomal recessive juvenile Parkinsonism, functions as a ubiquitin ligase. However, recent findings by several groups demonstrated that ubiquitylation is also relevant to the autophagy system, with parkin promoting autophagy of dysfunctional mitochondria following the loss of mitochondrial membrane potential. These novel topics do not necessarily mean that the proteasome is involved in neurodegeneration of PD. In this review, we describe current evidence and controversies regarding the relationship between UPS and neurodegenerative disorders such as PD, and discuss several scientific discrepancies that await further clarification.

  20. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  1. Comparing illness presentation, treatment and functioning between patients with adolescent- and adult-onset psychosis.

    PubMed

    Hui, Christy Lai-Ming; Li, Adrienne Wing-Yee; Leung, Chung-Ming; Chang, Wing-Chung; Chan, Sherry Kit-Wa; Lee, Edwin Ho-Ming; Chen, Eric Yu-Hai

    2014-12-30

    Studies have shown that early- and adult-onset schizophrenia patients differ in pre-morbid traits, illness presentation, psychopathology, and prognosis. We aimed to compare adult-onset patients (age range 26-55 years) with an adolescent-onset cohort (15-25 years) in demographics, illness presentation and functioning at baseline. Participants were from two territory-wide early intervention services for adolescent-onset (n=671) and adult-onset psychosis patients (n=360) in Hong Kong. The adolescent-onset cohort had their initial psychotic episode from 2001-2003; retrospective data collection was done through systematic case note review. The adult-onset cohort was recruited for a larger interventional study from 2009-2011; information was collected via face-to-face interviews. Adult-onset psychosis was significantly associated with more females, more smokers, more non-local birth, more full-time employment, better functioning, poorer medication adherence, more psychiatric hospitalization and fewer with schizophrenia than adolescent-onset psychosis (mean age: 20.4). The effect sizes were small, except for medication adherence where a robust effect was found. No group difference in DUP was found. The finding that adult-onset patients had better functioning challenges the view that adolescent- and adult-onset psychoses share a similar prognostic trajectory. Implications for adapting intervention processes for adolescent- and adult-onset psychosis are discussed.

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

    PubMed

    Castorina, Alessandro; Szychlinska, Marta Anna; Marzagalli, Rubina; Musumeci, Giuseppe

    2015-06-01

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

  3. Adult-onset hypothyroidism in a lynx (Lynx canadensis).

    PubMed

    Greer, Leah L; Troutman, Mitchell; McCracken, Malcolm D; Ramsay, Edward C

    2003-09-01

    A 19-yr-old female lynx (Lynx canadensis) presented for an acute onset of anorexia and reluctance to move. Physical examination, radiography, hematology, and serum biochemistry revealed evidence of renal failure, presumptive uremic gastritis, chronic intervertebral disk disease at T13-L1, and markedly low serum levels of total thyroxine (1.54 nmol/L) and total triixodothyronine (0.55 nmol/L). Twenty-five hours after its original presentation, the lynx exhibited horizontal nystagmus, which has been suggested as a clinical sign associated with hypothyroidism in domestic dogs. The lynx was euthanatized because of poor prognosis, and medical management concerns related to its chronic renal failure. Necropsy examination substantiated that the lynx had true hypothyroidism with 60-90% of the thyroid gland replaced with adipose tissue. Although feline adult-onset hypothyroidism may have low incidence, it should still be considered as a cause of nonspecific signs of disease in cats, as well as signs suggestive of hypothyroidism. Routine monitoring of baseline exotic felid thyroid levels throughout life would help to identify normal values and diagnose a potential disease that has obscure clinical signs.

  4. Vaccination with heat-shocked mononuclear cells as a strategy for treating neurodegenerative disorders driven by microglial inflammation.

    PubMed

    McCarty, Mark F; Al-Harbi, Saleh A

    2013-11-01

    Naturally occurring T regulatory cells targeting epitopes derived from various heat shock proteins escape thymic negative selection and can be activated by vaccination with heat shock proteins; hence, vaccination with such proteins has exerted favorable effects on rodent models of autoimmune disorders. A more elegant way to achieve such vaccination, first evaluated clinically by Al-Harbi in the early 1990s, is to subject mononuclear cells to survivable heat shock ex vivo, incubate them at physiological temperature for a further 24-48 h, and then inject them subcutaneously; anecdotally, beneficial effects were observed with this strategy in a wide range of autoimmune and inflammatory conditions. There is growing evidence that M1-activated microglia play a primary or secondary role in the pathogenesis of numerous neurodegenerative diseases, as well as in major depression. T regulatory cells, by polarizing microglial toward a reparative M2 phenotype, have the potential to aid control of such disorders. It would be appropriate to test the heat-shocked mononuclear cell vaccination strategy in animal models of neurodegeneration and major depression, and to evaluate this approach clinically if such studies yield encouraging results. PMID:23968572

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

    PubMed Central

    Holvoet, Bryan; De Waele, Liesbeth; Quattrocelli, Mattia; Gheysens, Olivier; Sampaolesi, Maurillio; Verfaillie, Catherine M.; Deroose, Christophe M.

    2016-01-01

    Numerous neurodegenerative and neuromuscular disorders are associated with cell-specific depletion in the human body. This imbalance in tissue homeostasis is in healthy individuals repaired by the presence of endogenous stem cells that can replace the lost cell type. However, in most disorders, a genetic origin or limited presence or exhaustion of stem cells impairs correct cell replacement. During the last 30 years, methods to readily isolate and expand stem cells have been developed and this resulted in a major change in the regenerative medicine field as it generates sufficient amount of cells for human transplantation applications. Furthermore, stem cells have been shown to release cytokines with beneficial effects for several diseases. At present however, clinical stem cell transplantations studies are struggling to demonstrate clinical efficacy despite promising preclinical results. Therefore, to allow stem cell therapy to achieve its full potential, more insight in their in vivo behavior has to be achieved. Different methods to noninvasively monitor these cells have been developed and are discussed. In some cases, stem cell monitoring even reached the clinical setting. We anticipate that by further exploring these imaging possibilities and unraveling their in vivo behavior further improvement in stem cell transplantations will be achieved. PMID:26997958

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

    PubMed

    Holvoet, Bryan; De Waele, Liesbeth; Quattrocelli, Mattia; Gheysens, Olivier; Sampaolesi, Maurillio; Verfaillie, Catherine M; Deroose, Christophe M

    2016-01-01

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

  7. Scientific and ethical issues related to stem cell research and interventions in neurodegenerative disorders of the brain.

    PubMed

    Barker, Roger A; de Beaufort, Inez

    2013-11-01

    Should patients with Parkinson's disease participate in research involving stem cell treatments? Are induced pluripotent stem cells (iPSC) the ethical solution to the moral issues regarding embryonic stem cells? How can we adapt trial designs to best assess small numbers of patients in receipt of invasive experimental therapies? Over the last 20 years there has been a revolution in our ability to make stem cells from different sources and use them for therapeutic gain in disorders of the brain. These cells, which are defined by their capacity to proliferate indefinitely as well as differentiate into selective phenotypic cell types, are viewed as being especially attractive for studying disease processes and for grafting in patients with chronic incurable neurodegenerative disorders of the CNS such as Parkinson's disease (PD). In this review we briefly discuss and summarise where our understanding of stem cell biology has taken us relative to the clinic and patients, before dealing with some of the major ethical issues that work of this nature generates. This includes issues to do with the source of the cells, their ownership and exploitation along with questions about patient recruitment, consent and trial design when they translate to the clinic for therapeutic use.

  8. Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders.

    PubMed

    Bauer, M; Alda, M; Priller, J; Young, L T

    2003-11-01

    Bipolar disorder is increasingly recognized as an illness that may progress to impairment in neurocognitive functioning and cell loss in cortical and limbic brain regions. Glutamatergic damage and/or damage due to high glucocorticoid levels that inhibit adult neurogenesis are likely contributing mechanisms. Drug treatments with possible neuroprotective effects are becoming increasingly important both clinically and as research tools. Mood stabilizing drugs and lithium in particular may act to prevent neuronal damage and tissue loss that may occur in the brain of patients with bipolar disorders. Lithium has been shown to exert neuroprotective effects in vitro and to stimulate neurogenesis in the hippocampus. Animal studies have demonstrated pharmacological effects of lithium suggestive of its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of signal transduction intermediates such as myo-inositol, protein kinase C, phosphotidylinositol-3 kinase (PI-3K)/protein kinase B (Akt), ras-mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3alpha and -3beta and calcium. It remains to be established whether lithium treatment protects against possible cell damage in the same manner as it protects against recurrences of the illness. We propose to examine the effect of long-term lithium treatment on neurocognitive functioning of bipolar patients and the use of lithium in the treatment of chronic neuropsychiatric disorders.

  9. Beyond the cherry-red spot: Ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders.

    PubMed

    Chen, Hui; Chan, Annie Y; Stone, Donald U; Mandal, Nawajes A

    2014-01-01

    Sphingolipids are a ubiquitous membrane lipid present in every cell and found most abundantly in neural tissues. Disorders such as Tay-Sachs or Niemann-Pick disease are the most familiar examples of dysfunction in sphingolipid metabolism and are typically associated with neurodegeneration and ocular findings such as blindness. More recently, the role of bioactive sphingolipids has been established in a multitude of cellular events, including cell survival, growth, senescence and apoptosis, inflammation, and neovascularization. We discuss our current knowledge and understanding of sphingolipid metabolism and signaling in the pathogenesis of ocular diseases. PMID:24011710

  10. Inflammatory mediators leading to protein misfolding and uncompetitive/fast off-rate drug therapy for neurodegenerative disorders.

    PubMed

    Lipton, Stuart A; Gu, Zezong; Nakamura, Tomohiro

    2007-01-01

    Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which

  11. Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease.

    PubMed Central

    Huggins, M; Bloch, M; Kanani, S; Quarrell, O W; Theilman, J; Hedrick, A; Dickens, B; Lynch, A; Hayden, M

    1990-01-01

    The goal of predictive testing is to modify the risk for currently healthy individuals to develop a genetic disease in the future. Such testing using polymorphic DNA markers has had major application in Huntington disease. The Canadian Collaborative Study of Predictive Testing for Huntington Disease has been guided by major principles of medical ethics, including autonomy, beneficence, confidentiality, and justice. Numerous ethical and legal dilemmas have arisen in this program, challenging these principles and occasionally casting them into conflict. The present report describes these dilemmas and offers our approach to resolving them. These issues will have relevance to predictive-testing programs for other adult-onset disorders. PMID:1971997

  12. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease

    PubMed Central

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María.L.; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A.; Hernández, María V.; Sifuentes-Giraldo, Walter A.; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R.; Moreno, Mireia; Fiter, Jordi; Riscos, Marina de los; Carreira, Patricia; Rodriguez-Valls, María J.; González-Vela, M. Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A.

    2015-01-01

    Abstract Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2–6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3–47.5] mg/day at ANK onset to 5 [0–10] at 12 months. After a median [IQR] follow-up of 16 [5–50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations. PMID:26426623

  13. Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.

    PubMed

    Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-01-15

    Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism. PMID:26549647

  14. TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders

    PubMed Central

    Gupta, Vivek K.; You, Yuyi; Gupta, Veer Bala; Klistorner, Alexander; Graham, Stuart L.

    2013-01-01

    The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches. PMID:23670594

  15. Novel therapeutic strategies using nanodrug delivery, stem cells and combination therapy for CNS trauma and neurodegenerative disorders.

    PubMed

    Sharma, Hari S; Muresanu, Dafin F; Sharma, Aruna

    2013-10-01

    The 10th Global College of Neuroprotection and Neuroregeneration Annual Conference in collaboration with the 6th International Association of Neurorestoratology VI Intercontinental Hotel, Bucharest, Romania, 4-7 April 2013 The 10th Global College of Neuroproetction and Neuroregeneration Annual Conference together with the International Association of Neurorestoratology VI was held in Bucharest under the auspicious of the Society for the Study of Neuroprotection and Neuroplasticity during 4-7 April 2013. The focus of these unified societies meeting was on neurorestoration, neuroprotection and neuroregeneration in various clinical neurodegenerative diseases; for example, Alzheimer's, Parkinson's, Huntington's disease, stroke and brain or spinal cord injuries. The main aim to enhance healthcare was suggested by the use of stem cells, nanodrug delivery of drugs and stem cells, use of multimodal drugs as well as a combination of different approaches. The meeting was attended by more than 500 delegates including researches, policy makers and healthcare professionals along with several representatives from drug industries from Europe and USA. It appears that future of neuroprotection could be achieved by the use of stem cells and nanodrug delivery in chronic neurological disorders.

  16. Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

    PubMed

    Jana, Arundhati; Modi, Khushbu K; Roy, Avik; Anderson, John A; van Breemen, Richard B; Pahan, Kalipada

    2013-06-01

    This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

  17. Successful treatment of adult-onset erythromelalgia with steroid pulse and pregabalin.

    PubMed

    Kakizaki, Aya; Fujimura, Taku; Kambayashi, Yumi; Watabe, Akiko; Aiba, Setsuya

    2012-09-01

    Adult-onset erythromelalgia (EM) is a rare disease characterized by episodic bouts of burning pain and erythema for which the optimal therapy is unclear. In this report, we describe a 68-year-old Japanese woman with adult-onset EM. Intravenous administration of methylprednisolone sodium succinate 1,000 mg/day dramatically improved her pain as evaluated by the visual analog scale. Although the patient's pain gradually developed again, it could be controlled with pregabalin. Our present case might suggest a possible, optimal therapy for adult-onset EM. PMID:23275767

  18. Successful Treatment of Adult-Onset Erythromelalgia with Steroid Pulse and Pregabalin

    PubMed Central

    Kakizaki, Aya; Fujimura, Taku; Kambayashi, Yumi; Watabe, Akiko; Aiba, Setsuya

    2012-01-01

    Adult-onset erythromelalgia (EM) is a rare disease characterized by episodic bouts of burning pain and erythema for which the optimal therapy is unclear. In this report, we describe a 68-year-old Japanese woman with adult-onset EM. Intravenous administration of methylprednisolone sodium succinate 1,000 mg/day dramatically improved her pain as evaluated by the visual analog scale. Although the patient's pain gradually developed again, it could be controlled with pregabalin. Our present case might suggest a possible, optimal therapy for adult-onset EM. PMID:23275767

  19. Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes.

    PubMed

    Calabrese, Vittorio; Boyd-Kimball, Debra; Scapagnini, Giovanni; Butterfield, D Allan

    2004-01-01

    Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries, brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70 and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Increasing evidence suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of oxidative and

  20. Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes.

    PubMed

    Calabrese, Vittorio; Guagliano, Eleonora; Sapienza, Maria; Panebianco, Mariangela; Calafato, Stella; Puleo, Edoardo; Pennisi, Giovanni; Mancuso, Cesare; Butterfield, D Allan; Stella, Annamaria Giuffrida

    2007-01-01

    Reduced expression and/or activity of antioxidant proteins lead to oxidative stress, accelerated aging and neurodegeneration. However, while excess reactive oxygen species (ROS) are toxic, regulated ROS play an important role in cell signaling. Perturbation of redox status, mutations favoring protein misfolding, altered glyc(osyl)ation, overloading of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, HNE) or cholesterol oxidation, can disrupt redox homeostasis. Collectively or individually these effects may impose stress and lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia are major neurological disorders associated with production of abnormally aggregated proteins and, as such, belong to the so-called "protein conformational diseases". The pathogenic aggregation of proteins in non-native conformation is generally associated with metabolic derangements and excessive production of ROS. The "unfolded protein response" has evolved to prevent accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to new insights into the diverse processes that are regulated by cellular stress responses. The brain detects and overcomes oxidative stress by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat-shock proteins are highly conserved and facilitate correct protein folding. Heme oxygenase-1, an inducible and redox-regulated enzyme, has having an important role in cellular antioxidant defense. An emerging concept is neuroprotection afforded by heme oxygenase by its heme degrading activity and tissue-specific antioxidant effects, due to its products carbon monoxide and biliverdin, which is then reduced by biliverdin reductase in bilirubin. There is increasing interest in dietary compounds that can

  1. Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

    PubMed Central

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

  2. Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination.

    PubMed

    Rasband, Matthew N; Kagawa, Tetsushi; Park, Eunice W; Ikenaka, Kazuhiro; Trimmer, James S

    2003-08-15

    Demyelination results in conduction block through changes in passive cable properties of an axon and in the expression and localization of axonal ion channels. We show here that adult-onset chronic demyelination, such as occurs in demyelinating disorders and after nerve injury, alters the complement of axonal voltage-dependent Na+ (Nav) channel isoforms and their localization. As a model, we used heterozygous transgenic mice with two extra copies of the proteolipid protein gene (Plp/-). Retinal ganglion cell axons in these mice myelinate normally, with young Plp/- and wild-type mice expressing Nav1.2 at low levels, whereas Nav1.6 is clustered in high densities at nodes of Ranvier. At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1.2. We conclude that myelin is crucial not only for node of Ranvier formation, but also to actively maintain the proper localization and complement of distinct axonal Nav channel isoforms throughout life. The altered Nav channel isoform localization and complement induced by demyelination may contribute to the pathophysiology of demyelinating disorders and nerve injury. PMID:12898531

  3. Genetics Home Reference: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

    MedlinePlus

    ... it causes a severe decline in thinking and reasoning abilities (dementia). Over time, motor skills are affected, ... Schmahmann JD. Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol. 2009 Jan; ...

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

    PubMed

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

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10-15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

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

    PubMed Central

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

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10–15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer’s disease or Parkinson’s disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

  6. Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art

    PubMed Central

    Walsh, M J; Cooper-Knock, J; Dodd, J E; Stopford, M J; Mihaylov, S R; Kirby, J; Shaw, P J; Hautbergue, G M

    2015-01-01

    Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and noncoding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may coexist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins – and how these lead to neurodegeneration – remain unknown. The field of RNA biology research faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterization of pathological mechanisms that trigger disease onset and progression. PMID:25319671

  7. Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening

    PubMed Central

    Lazzeri, L.; Cammi, A.; Dragoni, F.

    2016-01-01

    Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P = 0.04; OR 0.4), stress at onset (P = 0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P = 0.003; OR = 0.23), and thyroid nodules (P = 0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P = 0.003; OR = 2.87) and Koebner phenomenon (P < 0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P = 0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients. PMID:27747240

  8. Inflammatory mediators leading to protein misfolding and uncompetitive/fast off-rate drug therapy for neurodegenerative disorders.

    PubMed

    Lipton, Stuart A; Gu, Zezong; Nakamura, Tomohiro

    2007-01-01

    Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which

  9. Health-related quality of life in sporadic adult-onset ataxia.

    PubMed

    Abele, Michael; Klockgether, Thomas

    2007-02-15

    Despite progressive disability in sporadic adult-onset ataxia (SAOA), little is known about patients' assessment of their ataxic disorder and its impact on health-related quality of life (Hr-QoL). This study investigated Hr-QoL by means of the following self-administered scales: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory (BDI), and the Medical Outcome Study Short Form (SF-36). Twenty-two unselected ataxia patients were included. Sleep-related complaints were found in 9 (41%) of 22 and symptoms of depression in 6 (38%) of 16 patients. Compared to a large german control group, SAOA patients had lower scores in all SF-36 dimensions except for bodily pain. The greatest impairment was found in the domain physical functioning, followed by the domains social functioning and role limitations (emotional problems). There was a significant negative correlation of all nonmotor SF-36 dimensions with the BDI score. Walking aid dependency was significantly correlated with poorer health status perception in several motor and nonmotor domains. In addition, impaired sleep quality was correlated with an impaired general health perception and with bodily pain. The study demonstrates a great impact of SAOA on Hr-QoL. Adequate treatment of depression, motor disability, and impaired sleep quality is essential to improve Hr-QoL in ataxic patients. PMID:17149704

  10. Adult-Onset Familial Mediterranean Fever in Northwestern Iran; Clinical Feature and Treatment Outcome

    PubMed Central

    Nobakht, H; Zamani, F; Ajdarkosh, H; Mohamadzadeh, Z; Fereshtehnejad, SM; Nassaji, M

    2011-01-01

    BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by sporadic, paroxysmal attacks of fever and serosal inflammation. Although the disease usually begins before the age of 20 years, we aimed to evaluate the demography, clinical features and treatment outcome of familial Mediterranean fever in Iranian adult patients above 20 years old. METHODS In this cross-sectional study, adult patients (first attack at the age of >20 years) with a diagnosis of FMF who referred to the gastroenterology and rheumatology Clinics of Ardebil University of Medical Science (situated in north west of Iran) over the period of 2004-2009 were enrolled. FMF diagnosis was based on clinical criteria. RESULTS Forty four FMF patients (30 male and 14 female) with the mean [± Standard Deviation (SD)] age of first attack of 29 ± 7.8 years were enrolled. Abdominal pain (95.5%) and fever (91%) were the most common clinical findings. All of the patients had satisfactorily responded to therapy. Response was complete in 76.7% and partial in 23.3% of the patients. There was no clinical or laboratory evidence of amyloidosis at the time of diagnosis or during follow-up. CONCLUSION Our findings demonstrated that adult-onset FMF in Iran has different characteristics (more common in males, lesser prevalence of arthritis and erysipelas-like erythema, less delay in diagnosis) and treatment outcome (favorable response even to low-dose colchicine) in comparison with the previous data on early onset patients. PMID:25197532

  11. Adult-onset familial mediterranean Fever in northwestern iran; clinical feature and treatment outcome.

    PubMed

    Nobakht, H; Zamani, F; Ajdarkosh, H; Mohamadzadeh, Z; Fereshtehnejad, Sm; Nassaji, M

    2011-03-01

    BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by sporadic, paroxysmal attacks of fever and serosal inflammation. Although the disease usually begins before the age of 20 years, we aimed to evaluate the demography, clinical features and treatment outcome of familial Mediterranean fever in Iranian adult patients above 20 years old. METHODS In this cross-sectional study, adult patients (first attack at the age of >20 years) with a diagnosis of FMF who referred to the gastroenterology and rheumatology Clinics of Ardebil University of Medical Science (situated in north west of Iran) over the period of 2004-2009 were enrolled. FMF diagnosis was based on clinical criteria. RESULTS Forty four FMF patients (30 male and 14 female) with the mean [± Standard Deviation (SD)] age of first attack of 29 ± 7.8 years were enrolled. Abdominal pain (95.5%) and fever (91%) were the most common clinical findings. All of the patients had satisfactorily responded to therapy. Response was complete in 76.7% and partial in 23.3% of the patients. There was no clinical or laboratory evidence of amyloidosis at the time of diagnosis or during follow-up. CONCLUSION Our findings demonstrated that adult-onset FMF in Iran has different characteristics (more common in males, lesser prevalence of arthritis and erysipelas-like erythema, less delay in diagnosis) and treatment outcome (favorable response even to low-dose colchicine) in comparison with the previous data on early onset patients.

  12. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.

  13. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα. PMID:25533124

  14. Glutamate and Neurodegenerative Disease

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

    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

  16. Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders.

    PubMed

    Roncarati, Renza; Scali, Carla; Comery, Thomas A; Grauer, Steven M; Aschmi, Suzan; Bothmann, Hendrick; Jow, Brian; Kowal, Dianne; Gianfriddo, Marco; Kelley, Cody; Zanelli, Ugo; Ghiron, Chiara; Haydar, Simon; Dunlop, John; Terstappen, Georg C

    2009-05-01

    The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.

  17. Ceruloplasmin in neurodegenerative diseases.

    PubMed

    Vassiliev, Vadim; Harris, Zena Leah; Zatta, Paolo

    2005-11-01

    For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.

  18. Generation of a novel mouse model that recapitulates early and adult onset glycogenosis type IV.

    PubMed

    Akman, H Orhan; Sheiko, Tatiana; Tay, Stacey K H; Finegold, Milton J; Dimauro, Salvatore; Craigen, William J

    2011-11-15

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen branching enzyme (GBE). The diagnostic feature of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age of disease onset. Absence of enzyme activity is lethal in utero or in infancy affecting primarily muscle and liver. However, residual enzyme activity (5-20%) leads to juvenile or adult onset of a disorder that primarily affects muscle as well as central and peripheral nervous system. Here, we describe two mouse models of GSD IV that reflect this spectrum of disease. Homologous recombination was used to insert flippase recognition target recombination sites around exon 7 of the Gbe1 gene and a phosphoglycerate kinase-Neomycin cassette within intron 7, leading to a reduced synthesis of GBE. Mice bearing this mutation (Gbe1(neo/neo)) exhibit a phenotype similar to juvenile onset GSD IV, with wide spread accumulation of PG. Meanwhile, FLPe-mediated homozygous deletion of exon 7 completely eliminated GBE activity (Gbe1(-/-)), leading to a phenotype of lethal early onset GSD IV, with significant in utero accumulation of PG. Adult mice with residual GBE exhibit progressive neuromuscular dysfunction and die prematurely. Differently from muscle, PG in liver is a degradable source of glucose and readily depleted by fasting, emphasizing that there are structural and regulatory differences in glycogen metabolism among tissues. Both mouse models recapitulate typical histological and physiological features of two human variants of branching enzyme deficiency. PMID:21856731

  19. Mutations in CIZ1 cause adult-onset primary cervical dystonia

    PubMed Central

    Xiao, Jianfeng; Uitti, Ryan J.; Zhao, Yu; Vemula, Satya R.; Perlmutter, Joel S.; Wszolek, Zbigniew K.; Maraganore, Demetrius M.; Auburger, Georg; Leube, Barbara; Lehnhoff, Katja; LeDoux, Mark S.

    2012-01-01

    Objective Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult-onset, primary cervical dystonia. Methods Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult-onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult-onset cervical dystonia and matching controls for sequence variants in this mutant gene. Results Exome sequencing led to the identification of an exonic splicing enhancer mutation in Exon 7 of CIZ1 (c.790A>G, p.S264G) which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21Cip1/Waf1-interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified two additional CIZ1 missense mutations (p.P47S and p.R672M). Interpretation Mutations in CIZ1 may cause adult-onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system. PMID:22447717

  20. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy.

    PubMed Central

    Thomas, P K; Young, E; King, R H

    1989-01-01

    A 32 year old male is described with an onset of upper limb postural tremor in adolescence followed by muscle cramps. Progressive proximal amyotrophy and weakness in the limbs developed late in the third decade. Examination disclosed, in addition, bilateral facial weakness and mild dysarthria. Enzyme studies revealed hexosaminidase A and B deficiency, indicating a diagnosis of Sandhoff disease. Intra-axonal membranocytoplasmic bodies were present in a rectal biopsy. The presentation, which resembled that of X-linked bulbospinal neuronopathy, widens the clinical spectrum for disorders related to G(M2) gangliosidosis. Images PMID:2795083

  1. Adult onset Hallervorden-Spatz disease with psychotic symptoms.

    PubMed

    del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

    2011-01-01

    Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia. PMID:21769749

  2. Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism.

    PubMed

    Tufekcioglu, Zeynep; Cakar, Arman; Bilgic, Basar; Hanagasi, Hasmet; Gurvit, Hakan; Emre, Murat

    2016-06-01

    Phenylketonuria (PKU) is an autosomal recessive metabolic disorder due to mutations in the phenylalanine hydroxylase (PAH) gene, which converts phenylalanine (PHE) to tyrosine. Although it is principally a childhood disorder, in rare cases, the first signs of PKU may develop in late adulthood resembling common neurological diseases. Here we report a 59-year-old, previously normal functioning man who was admitted with blurred vision, cognitive problems, and gait difficulty that began 8 months before. He had brisk reflexes and left side dominant parkinsonism. His Mini-Mental State Examination (MMSE) score was 25/30, and neuropsychological evaluation revealed a dysexecutive syndrome with simultanagnosia and constructional apraxia. His Clinical Dementia Rating score (CDR) was 1. Cranial MRI revealed bilateral diffuse hyperintense lesions in parietal and occipital white matter in T2, fluid-attenuated inversion recovery, and diffusion weighted images. Diagnostic workup for rapidly progressive dementias was all normal except PHE level which was found to be highly elevated (1075 μmol/L, normal 39-240 μmol/L) with normal tyrosine level (61.20 μmol/L, normal 35-100 μmol/L). Three months after PHE-restricted diet, his cognitive impairment and signs of parkinsonism significantly improved, with MRI scan unchanged. This case demonstrates that late-onset PKU is a rare, treatable cause of rapidly progressive dementia and parkinsonism with certain constellations such as consanguinity and white matter abnormalities (WMAs) in imaging. PMID:26962957

  3. Adult onset Hallervorden-Spatz disease with psychotic symptoms.

    PubMed

    del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

    2011-01-01

    Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

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

    PubMed

    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.

  5. Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Barešová, Veronika; Ivánek, Robert; Hůlková, Helena; Jahnová, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynelä, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav

    2011-01-01

    Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID:21820099

  6. DNA damage in neurodegenerative diseases.

    PubMed

    Coppedè, Fabio; Migliore, Lucia

    2015-06-01

    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, Parkinson's disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans. PMID:26255941

  7. Glycoproteomics in Neurodegenerative Diseases

    PubMed Central

    Hwang, Hyejin; Zhang, Jianpeng; Chung, Kathryn A.; Leverenz, James B.; Zabetian, Cyrus P.; Peskind, Elaine R.; Jankovic, Joseph; Su, Zhen; Hancock, Aneeka M.; Pan, Catherine; Montine, Thomas J.; Pan, Sheng; Nutt, John; Albin, Roger; Gearing, Marla; Beyer, Richard P.; Shi, Min; Zhang, Jing

    2009-01-01

    Protein glycosylation regulates protein function and cellular distribution. Additionally, aberrant protein glycosylations have been recognized to play major roles in human disorders, including neurodegenerative diseases. Glycoproteomics, a branch of proteomics that catalogs and quantifies glycoproteins, provides a powerful means to systematically profile the glycopeptides or glycoproteins of a complex mixture that are highly enriched in body fluids, and therefore, carry great potential to be diagnostic and/or prognostic markers. Application of this mass spectrometry-based technology to the study of neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease) is relatively new, and is expected to provide insight into the biochemical pathogenesis of neurodegeneration, as well as biomarker discovery. In this review, we have summarized the current understanding of glycoproteins in biology and neurodegenerative disease, and have discussed existing proteomic technologies that are utilized to characterize glycoproteins. Some of the ongoing studies, where glycoproteins isolated from cerebrospinal fluid and human brain are being characterized in Parkinson's disease at different stages versus controls, are presented, along with future applications of targeted validation of brain specific glycoproteins in body fluids. PMID:19358229

  8. Adult-Onset Antisocial Behavior Trajectories: Associations with Adolescent Family Processes and Emerging Adulthood Functioning

    ERIC Educational Resources Information Center

    Mata, Andrea D.; van Dulmen, Manfred H. M.

    2012-01-01

    Guided by conceptual and empirical work on emerging adulthood, this study investigated the role of closeness to mother and father and behavioral autonomy during adolescence on the development of adult-onset antisocial behavior. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we identified four aggressive…

  9. Is Adolescent-Onset First-Episode Psychosis Different from Adult Onset?

    ERIC Educational Resources Information Center

    Ballageer, Trevor; Malla, Ashok; Manchanda, Rahul; Takhar, Jatinder; Haricharan, Raj

    2005-01-01

    Objective: To examine whether first-episode psychosis patients with onset during adolescence (ages 15-18) differ significantly from those with young-adult onset (ages 19-30). Method: Consecutive patients presenting with first-episode psychosis (N = 242) were assessed for demographic and illness characteristics such as duration of untreated…

  10. Epidemiology and outcome of articular complications in adult onset Still's disease.

    PubMed

    Mahfoudhi, Madiha; Shimi, Rafik; Turki, Sami; Kheder, Adel

    2015-01-01

    The adult onset Still's disease is a rare inflammatory pathology of unknown pathogeny. The clinical features are variable. The diagnosis is difficult since exclusion of infectious, systemic and tumoral pathologies should be done. The articular complications are frequent and can be revelatory of this pathology. The articular prognosis depends on the diagnosis delay and the treatment efficiency. Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. It was a cross-sectional study concerning 18 cases of adult onset Still disease diagnosed from 1990 to 2014 in the internal medicine A department of Charles Nicolle Hospital in Tunis, meeting Yamaguchi criteria. We identified clinical, radiological, evolving and therapeutic profile of the articular manifestations occurred in these patients. There were 11 women and 7 men. The average age was 27 years. The arthralgias were reported in all cases; while, the arthritis interested thirteen patients. A hand deformation was found in four patients. A wrist ankylosis was noted in one case and a flexion elbow in one patient. The Standard articular radiographs were normal in ten cases. The treatment associated essentially non-steroidal anti-inflammatory and/or corticosteroids and/or methotrexate. Concerning the evolving profile, the monocyclic form was present in 25% of the cases, the intermittent form in 40% and the chronic articular form in 35% of our patients. The adult onset Still's disease is rare and heterogeneous. The articular disturbances are frequent and have various outcomes.

  11. A multi-hit endocrine model of intrinsic adult-onset asthma.

    PubMed

    Atwood, Craig S; Bowen, Richard L

    2008-04-01

    Epidemiological studies indicate that adult-onset asthma is initiated by stress (anxiety and depression), obesity and menopause. Ironically, despite our understanding of the various stressors that promote chronic adult-onset asthma, most of which are known to elevate cortisol production via the hypothalamic-pituitary-adrenal (HPA) axis, inhaled and systemic corticosteroids are the mainstay for the treatment of chronic asthma. This implicates other endocrine or cellular changes independent of cortisol synthesis in non-allergic adult-onset asthma. The mechanism by which corticosteroids are thought to modulate bronchial tone in relieving asthma is via corticosteroid-responsive genes that increase PGE(2) and cAMP production which promote muscle relaxation. Therefore, any physiological condition that suppresses intracellular PGE(2) and cAMP production would counter cortisol-induced muscle relaxation and potentially trigger non-allergic adult-onset asthma. Stress, obesity and menopause act on three interrelated endocrine pathways, the serotonergic, leptinergic and hypothalamic pathways, all of which operate through receptors to modulate cAMP and Ca(2+) metabolism in smooth muscle cells (SMCs). We propose that the level of SMC cAMP, as determined by overall signaling through corticosteroid receptors, leptin receptors and the GPCRs of the HPG and serotonergic pathways, will regulate bronchial tone (i.e. the 'Multi-Hit Endocrine Model of Adult-Onset Asthma'). Thus, decreases in HPG (menopause) and serotonergic (depression) signaling and increases in leptinergic (obesity) signaling relative to HPA signaling would decrease cellular SMC cAMP and promote muscle contraction. This model can explain the discrepant epidemiological data associating stress, obesity, depression and menopause with adult-onset asthma and is supported by basic and clinical data. Treatment of depressed or menopausal asthmatics with selective serotonin reuptake inhibitors or hormone replacement therapy

  12. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson's disease.

    PubMed

    Campos, Helineide Cristina; da Rocha, Miguel Divino; Viegas, Flávia Pereira Dias; Nicastro, Patrícia Carolina; Fossaluzza, Poliana Calve; Fraga, Carlos Alberto Manssour; Barreiro, Eliezer J; Viegas, Claudio

    2011-03-01

    Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. Although the clinical and neuropathological aspects of these debilitating disorders are distinct, they share a pattern of neurodegeneration in anatomically or functionally related regions. For each disease, presently available treatments only address symptoms and do not alter the course or progression of the underlying diseases. In this context, the search for new effective chemical entities, capable of acting on diverse biochemical targets, with new mechanisms of action and low toxicity are genuine challenges to research groups and the pharmaceutical industry. This medical need has led to the reemerging of modern natural products chemistry that has yielded sophisticated and complex new lead molecules for drug discovery and development. In this review we discuss some of the main contributions of the natural products chemistry that covers multiple and varied plant species. Advances in the discovery of active constituents of plants, herbs, and extracts prescribed by traditional medicine practices for the treatment of senile neurodegenerative disorders, especially for PD, in the period after the 2000s is reviewed. The most important contributions from the 1990s are also discussed. The review also focuses on the pharmacological mechanisms of action that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuroprotection. It is concluded that natural product chemistry brings tremendous diversity and historical precedent to a huge area of unmet medical need.

  13. The Role of Uric Acid and Methyl Derivatives in the Prevention of Age-Related Neurodegenerative Disorders.

    PubMed

    Cutler, Roy G; Camandola, Simonetta; Malott, Kelli F; Edelhauser, Maria A; Mattson, Mark P

    2015-01-01

    High uric acid (UA levels have been correlated with a reduced risk of many neurodegenerative diseases through mechanisms involving chelating Fenton reaction transitional metals, antioxidant quenching of superoxide and hydroxyl free radicals, and as an electron donor that increases antioxidant enzyme activity (e.g. SOD. However, the clinical usefulness of UA is limited by its' low water solubility and propensity to form inflammatory crystals at hyperuricemic levels. This review focuses on the role of UA in neuroprotection, as well as potential strategies aimed at increasing UA levels in the soluble range, and the potential therapeutic use of more water-soluble methyl-UA derivatives from the natural catabolic end-products of dietary caffeine, theophylline, and theobromine. PMID:26059354

  14. Etiologic Framework for the Study of Neurodegenerative Disorders as Well as Vascular and Metabolic Comorbidities on the Grounds of Shared Epidemiologic and Biologic Features

    PubMed Central

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

    2016-01-01

    Background: During the last two decades, protein aggregation at all organismal levels, from viruses to humans, has emerged from a neglected area of protein science to become a central issue in biology and biomedicine. This article constitutes a risk-based review aimed at supporting an etiologic scenario of selected, sporadic, protein-associated, i.e., conformational, neurodegenerative disorders (NDDs), and their vascular- and metabolic-associated ailments. Methods: A rationale is adopted, to incorporate selected clinical data and results from animal-model research, complementing epidemiologic evidences reported in two prior articles. Findings: Theory is formulated assuming an underlying conformational transmission mechanism, mediated either by horizontal transfer of mammalian genes coding for specific aggregation-prone proteins, or by xeno-templating between bacterial and host proteins. We build a few population-based and experimentally-testable hypotheses focusing on: (1) non-disposable surgical instruments for sporadic Creutzfeldt-Jakob disease (sCJD) and other rapid progressive neurodegenerative dementia (sRPNDd), multiple system atrophy (MSA), and motor neuron disease (MND); and (2) specific bacterial infections such as B. pertussis and E. coli for all forms, but particularly for late-life sporadic conformational, NDDs, type 2 diabetes mellitus (T2DM), and atherosclerosis where natural protein fibrils present in such organisms as a result of adaptation to the human host induce prion-like mechanisms. Conclusion: Implications for cohort alignment and experimental animal research are discussed and research lines proposed. PMID:27378910

  15. REM Sleep Behavior Disorder: Updated Review of the Core Features, the RBD-Neurodegenerative Disease Association, Evolving Concepts, Controversies, and Future Directions

    PubMed Central

    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

  16. Opening Pandora’s jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders

    PubMed Central

    Khanna, Rajesh; Wilson, Sarah M; Brittain, Joel M; Weimer, Jill; Sultana, Rukhsana; Butterfield, Allan; Hensley, Kenneth

    2012-01-01

    CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions. PMID:23308041

  17. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Kramer, P.L.

    1997-02-01

    Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-on-set primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C. 57 refs., 3 figs., 3 tabs.

  18. Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease

    PubMed Central

    Lee, Hajeong; Yoo, Kyung Don; Oh, Yun Kyu; Kim, Dong Ki; Oh, Kook-Hwan; Joo, Kwon Wook; Kim, Yon Su; Ahn, Curie; Han, Jin Suk; Lim, Chun Soo

    2016-01-01

    Abstract Minimal change disease (MCD) is a well-known benign primary glomerulonephritis because of its distinct rare tendency to progress to end-stage renal disease. However, factors associated with relapse in adults are not well known. We aimed to identify predictors of relapse in adult-onset MCD patients. A retrospective cohort of 195 patients with adult-onset primary MCD with nephritic syndrome and disease onset between 1979 and 2013 was followed up for >12 months. The number of relapses was counted and predictors of relapse were analyzed. A total of 195 patients were included. Median age at diagnosis was 38 years (IQR, 23–53 years) and 113 (57.9%) were men. During 81 months (IQR, 44–153 months) of follow-up, 92% of patients achieved remission after initial treatment. However, only 60 (32.8%) did not experience a relapse and 11 patients failed to remit. Among the remaining 124 patients, 65 experienced a relapse once or twice and 59 experienced a relapse more than twice. Younger onset age, increased severity of nephrotic features such as lower serum albumin levels and higher cholesterol level were associated with relapse. Interestingly, the grade of mesangial proliferation was lower in patients who experienced a relapse. Initial combined treatment with corticosteroids (CS) and cyclophosphamide reduced the number of relapses. In addition, patients with shorter treatment duration tended to experience relapse more often. Multivariate analysis showed that younger onset age, combined mesangial proliferation, initial treatment regimen, and treatment duration were independent risk factors for relapse. Progression to end-stage renal disease was developed in only a patient. In conclusion, more than two-thirds of adult-onset nephrotic MCD patients experienced relapse, although their renal progression was rare. Younger onset age, CS without cyclophosphamide treatment, and shorter treatment duration were independent risk factors for relapse in adult-onset MCD patients

  19. Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease.

    PubMed

    Lee, Hajeong; Yoo, Kyung Don; Oh, Yun Kyu; Kim, Dong Ki; Oh, Kook-Hwan; Joo, Kwon Wook; Kim, Yon Su; Ahn, Curie; Han, Jin Suk; Lim, Chun Soo

    2016-03-01

    Minimal change disease (MCD) is a well-known benign primary glomerulonephritis because of its distinct rare tendency to progress to end-stage renal disease. However, factors associated with relapse in adults are not well known. We aimed to identify predictors of relapse in adult-onset MCD patients.A retrospective cohort of 195 patients with adult-onset primary MCD with nephritic syndrome and disease onset between 1979 and 2013 was followed up for >12 months. The number of relapses was counted and predictors of relapse were analyzed.A total of 195 patients were included. Median age at diagnosis was 38 years (IQR, 23-53 years) and 113 (57.9%) were men. During 81 months (IQR, 44-153 months) of follow-up, 92% of patients achieved remission after initial treatment. However, only 60 (32.8%) did not experience a relapse and 11 patients failed to remit. Among the remaining 124 patients, 65 experienced a relapse once or twice and 59 experienced a relapse more than twice. Younger onset age, increased severity of nephrotic features such as lower serum albumin levels and higher cholesterol level were associated with relapse. Interestingly, the grade of mesangial proliferation was lower in patients who experienced a relapse. Initial combined treatment with corticosteroids (CS) and cyclophosphamide reduced the number of relapses. In addition, patients with shorter treatment duration tended to experience relapse more often. Multivariate analysis showed that younger onset age, combined mesangial proliferation, initial treatment regimen, and treatment duration were independent risk factors for relapse. Progression to end-stage renal disease was developed in only a patient.In conclusion, more than two-thirds of adult-onset nephrotic MCD patients experienced relapse, although their renal progression was rare. Younger onset age, CS without cyclophosphamide treatment, and shorter treatment duration were independent risk factors for relapse in adult-onset MCD patients.

  20. Childhood- and adult-onset lupus: an update of similarities and differences.

    PubMed

    Papadimitraki, Eva D; Isenberg, David A

    2009-07-01

    Systemic lupus erythematosus (SLE) is a multifactorial autoimmune rheumatic disease. Although its highest prevalence is among women of childbearing age, the disease is not confined within this population. A total of 15-20% of cases of SLE are diagnosed in children younger than 16 years (childhood-onset lupus). Although there have been few studies directly comparing childhood- to adult-onset lupus, there is substantial evidence to suggest that pediatric lupus patients display some differences in their disease profile compared with adult-onset populations. Overall, an increased male-to-female ratio, a higher prevalence of nephritis and CNS involvement necessitating a more sustained need for steroids and immnosuppressive drugs, and a higher prevalence of progression to end-stage renal disease are distinguishing features of childhood-onset lupus. In contrast, a higher prevalence of pulmonary involvement, arthritis and discoid lupus are reported in adult-onset SLE patients. Furthermore, childhood-onset lupus patients may experience a serious negative impact on their psychosocial and physical development, issues that pose extra challenges to healthcare providers. Growth delay, osteoporosis, the psychological effect of steroid-induced alterations of the physical image, and often poor treatment compliance are the issues that need to be addressed in pediatric lupus populations. In this review, we compare the epidemiological, clinical and laboratory features, and treatment options of childhood- and adult-onset lupus, and comment on the applicability of the instruments that measure activity, severity and cumulative disease damage in childhood-onset disease. In addition, we highlight special issues of concern for pediatric lupus patients, discussing the significance in the transition from pediatric to adult rheumatology care.

  1. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database.

  2. Intra-arterial Chemotherapy for Adult Onset Retinoblastoma in a 32-Year-Old Man.

    PubMed

    Magan, Tejal; Khoo, Chloe T L; Jabbour, Pascal M; Fuller, Dwain G; Shields, Carol L

    2016-01-01

    A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.]. PMID:27486894

  3. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database. PMID:27581317

  4. Urticaria and dermographism in patients with adult-onset Still's disease.

    PubMed

    Criado, Paulo Ricardo; de Carvalho, Jozélio Freire; Ayabe, Liliane Akemi; Brandt, Hebert Roberto Clivati; Romiti, Ricardo; Maruta, Celina W

    2012-08-01

    Adult-onset Still's disease (AOSD) patients typically present with arthralgia, fever, lymphadenopathy and a transient salmon maculopapular rash. Only approximately 25 cases of AOSD with urticaria were described in the literature. In this article, the authors report three additional cases of AOSD with urticarial and dermographic lesions who had a good clinical response to glucocorticoid and antihistamines. A review of the literature concerning this issue is also herein written.

  5. Epidemiology and outcome of articular complications in adult onset still's disease

    PubMed Central

    Mahfoudhi, Madiha; Shimi, Rafik; Turki, Sami; Kheder, Adel

    2015-01-01

    The adult onset Still's disease is a rare inflammatory pathology of unknown pathogeny. The clinical features are variable. The diagnosis is difficult since exclusion of infectious, systemic and tumoral pathologies should be done. The articular complications are frequent and can be revelatory of this pathology. The articular prognosis depends on the diagnosis delay and the treatment efficiency. Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. It was a cross-sectional study concerning 18 cases of adult onset Still disease diagnosed from 1990 to 2014 in the internal medicine A department of Charles Nicolle Hospital in Tunis, meeting Yamaguchi criteria. We identified clinical, radiological, evolving and therapeutic profile of the articular manifestations occurred in these patients. There were 11 women and 7 men. The average age was 27 years. The arthralgias were reported in all cases; while, the arthritis interested thirteen patients. A hand deformation was found in four patients. A wrist ankylosis was noted in one case and a flexion elbow in one patient. The Standard articular radiographs were normal in ten cases. The treatment associated essentially non-steroidal anti-inflammatory and/or corticosteroids and/or methotrexate. Concerning the evolving profile, the monocyclic form was present in 25% of the cases, the intermittent form in 40% and the chronic articular form in 35% of our patients. The adult onset Still's disease is rare and heterogeneous. The articular disturbances are frequent and have various outcomes. PMID:26834930

  6. What can pluripotent stem cells teach us about neurodegenerative diseases?

    PubMed

    Wichterle, Hynek; Przedborski, Serge

    2010-07-01

    Neurodegenerative diseases represent a growing public health challenge. Current medications treat symptoms, but none halt or retard neurodegeneration. The recent advent of pluripotent cell biology has opened new avenues for neurodegenerative disease research. The greatest potential for induced pluripotent cells derived from affected individuals is likely to be their utility for modeling and understanding the mechanisms underlying neurodegenerative processes, and for searching for new treatments, including cell replacement therapies. However, much work remains to be done before pluripotent cells can be used for preclinical and clinical applications. Here we discuss the challenges of generating specific neural cell subtypes from pluripotent stem cells, the use of pluripotent stem cells to model both cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration, whether adult-onset neurodegeneration can be emulated in short-term cultures and the hurdles of cell replacement therapy. Progress in these four areas will substantially accelerate effective application of pluripotent stem cells.

  7. The need for improved detection and management of adult-onset hearing loss in australia.

    PubMed

    McMahon, Catherine M; Gopinath, Bamini; Schneider, Julie; Reath, Jennifer; Hickson, Louise; Leeder, Stephen R; Mitchell, Paul; Cowan, Robert

    2013-01-01

    Adult-onset hearing loss is insidious and typically diagnosed and managed several years after onset. Often, this is after the loss having led to multiple negative consequences including effects on employment, depressive symptoms, and increased risk of mortality. In contrast, the use of hearing aids is associated with reduced depression, longer life expectancy, and retention in the workplace. Despite this, several studies indicate high levels of unmet need for hearing health services in older adults and poor use of prescribed hearing aids, often leading to their abandonment. In Australia, the largest component of financial cost of hearing loss (excluding the loss of well-being) is due to lost workplace productivity. Nonetheless, the Australian public health system does not have an effective and sustainable hearing screening strategy to tackle the problem of poor detection of adult-onset hearing loss. Given the increasing prevalence and disease burden of hearing impairment in adults, two key areas are not adequately met in the Australian healthcare system: (1) early identification of persons with chronic hearing impairment; (2) appropriate and targeted referral of these patients to hearing health service providers. This paper reviews the current literature, including population-based data from the Blue Mountains Hearing Study, and suggests different models for early detection of adult-onset hearing loss. PMID:23710184

  8. Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans.

    PubMed

    Langille, Megan M; Islam, Talat; Burnett, Margaret; Amezcua, Lilyana

    2016-07-01

    Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis.

  9. Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

    PubMed Central

    Song, Gyu; Napoli, Eleonora; Wong, Sarah; Hagerman, Randi; Liu, Siming; Tassone, Flora; Giulivi, Cecilia

    2016-01-01

    A 55–200 expansion of the CGG nucleotide repeat in the 5’-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the “premutation” as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with age- and sex-matched controls (n = 25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals’ scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier- specific. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset. PMID:27385396

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    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

    2014-01-01

    Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusions and Implications 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. PMID:25117211

  12. The Vitamin D, Ionised Calcium and Parathyroid Hormone Axis of Cerebral Capillary Function: Therapeutic Considerations for Vascular-Based Neurodegenerative Disorders

    PubMed Central

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

    2015-01-01

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

  13. Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D2 concept

    PubMed Central

    Uversky, Vladimir N

    2010-01-01

    Many biologically active proteins, which are usually called intrinsically disordered or natively unfolded proteins, lack stable tertiary and/or secondary structure under physiological conditions in vitro. Their functions complement the functional repertoire of ordered proteins, with intrinsically disordered proteins (IDPs) often being involved in regulation, signaling and control. Their amino acid sequences and compositions are very different from those of ordered proteins, making reliable identification of IDPs possible at the proteome level. IDPs are highly abundant in various human diseases, including neurodegeneration and other protein dysfunction maladies and, therefore, represent attractive novel drug targets. Some of the aspects of IDPs, as well as their roles in neurodegeneration and protein dysfunction diseases, are discussed in this article, together with the peculiarities of IDPs as potential drug targets. PMID:20653509

  14. Mitochondrial Dysfunction in Neurodegenerative Diseases

    PubMed Central

    Johri, Ashu

    2012-01-01

    Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron. PMID:22700435

  15. Inferior olivary nucleus involvement in pediatric neurodegenerative disorders: does it play a role in neuroimaging pattern-recognition approach?

    PubMed

    Mirabelli-Badenier, Marisol; Morana, Giovanni; Bruno, Claudio; Di Rocco, Maja; Striano, Pasaquale; De Grandis, Eusa; Veneselli, Edvige; Rossi, Andrea; Biancheri, Roberta

    2015-04-01

    The diagnostic work up of neurometabolic/degenerative disorders is complex. In such context, identification of neuroradiological features suggestive of specific diagnoses is useful to prompt further diagnostic tests. Involvement of the inferior olivary nucleus (ION) has been reported in several pathologic conditions, either as a primary manifestation of disease or secondary to hypertrophic olivary degeneration (HOD). In this study, we analyzed a cohort of 95 children with different neurometabolic/degenerative diseases involving the brainstem and cerebellum, with the aim to evaluate whether ION involvement plays a role in a neuroimaging-based pattern-recognition approach. A total of 13 patients (13.7%) showed bilateral high-signal intensity and enlargement of the ION on T2-weighted images, while 16 (16.8%) had ION T2-hyperintensity without olivary nucleus enlargement. Our study demonstrates that ION involvement is not rare in children with neurometabolic/degenerative disorders. Two main neuroradiological patterns, that is, "T2-hyperintense signal" and "T2-hyperintense signal with enlargement" are found. These patterns can be related to different etiologies, and do not suggest specific diagnoses. Primary ION lesion can be characterized by olivary swelling, and the differentiation from typical secondary HOD may be difficult.

  16. Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.

    PubMed

    Manikkam, Mohan; Haque, M Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E; Skinner, Michael K

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.

  17. Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline

    PubMed Central

    Manikkam, Mohan; Haque, M. Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E.; Skinner, Michael K.

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. PMID:25057798

  18. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications.

    PubMed

    Tezcan, Kamer; Louie, Kristal T; Qu, Yong; Velasquez, Jorge; Zaldivar, Frank; Rioseco-Camacho, Natalia; Camacho, José Angel

    2012-01-01

    The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency.

  19. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications.

    PubMed

    Tezcan, Kamer; Louie, Kristal T; Qu, Yong; Velasquez, Jorge; Zaldivar, Frank; Rioseco-Camacho, Natalia; Camacho, José Angel

    2012-01-01

    The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency. PMID:23430880

  20. Bartonella henselae infection presenting with a picture of adult-onset Still's disease.

    PubMed

    Durey, Areum; Kwon, Hea Yoon; Im, Jae-Hyoung; Lee, Sun Myoung; Baek, JiHyeon; Han, Seung Baik; Kang, Jae-Seung; Lee, Jin-Soo

    2016-05-01

    We report a patient with a clinical picture of suggestive for adult-onset Still's Disease (ASOD) due to Bartonella infection. A 42-year-old immunocompetent man was admitted with fever, rash, arthralgia and sore throat. As his clinical picture suggested ASOD except unusual skin manifestation, we treated him on steroid and ibuprofen. His fever and constitutional symptoms responded immediately within 24hrs of commencing therapy, yet rash and leukocytosis remained. Meanwhile, Bartonella infection was proved by culture of bone marrow. Minocyclin treatment started combined with hydroxychloroquine sulfate and the patient discharged with overall improvement. PMID:27000538

  1. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options.

    PubMed

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  2. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease

    PubMed Central

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  3. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options

    PubMed Central

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  4. The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome

    PubMed Central

    Canetta, Pietro A. A.; Radhakrishnan, Jai

    2015-01-01

    Adult-onset nephrotic syndrome (NS) differs from its pediatric counterpart in several important ways. Most importantly, NS in adults is more etiologically heterogeneous compared to children, and thus treatment approaches rely heavily on the histological diagnosis provided by renal biopsy. The evidence-based approach to treatment of adult NS has been critically examined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in glomerulonephritis, published in 2012. Here, we examine the strengths and limits of those guidelines and review recent work that expands the evidence-based approach. PMID:26442238

  5. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease.

    PubMed

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  6. Depressive symptoms in neurodegenerative diseases

    PubMed Central

    Baquero, Miquel; Martín, Nuria

    2015-01-01

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

  7. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

    PubMed

    Bowman, Elizabeth A; Walterfang, Mark; Abel, Larry; Desmond, Patricia; Fahey, Michael; Velakoulis, Dennis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function. PMID:26092521

  8. Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders.

    PubMed

    Hobson, Adrian D; Harris, Christopher M; van der Kam, Elizabeth L; Turner, Sean C; Abibi, Ayome; Aguirre, Ana L; Bousquet, Peter; Kebede, Tegest; Konopacki, Donald B; Gintant, Gary; Kim, Youngjae; Larson, Kelly; Maull, John W; Moore, Nigel S; Shi, Dan; Shrestha, Anurupa; Tang, Xiubo; Zhang, Peng; Sarris, Kathy K

    2015-12-10

    S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis. PMID:26509640

  9. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders

    PubMed Central

    Daniele, Stefano G.; Béraud, Dawn; Davenport, Connor; Cheng, Kui; Yin, Hang; Maguire-Zeiss, Kathleen A.

    2015-01-01

    Synucleinopathies, such as Parkinson’s disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded α-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric α-synuclein causes proinflammatory responses in the brain parenchyma by triggering microglial activation, which may exacerbate pathogenic processes by establishing a chronic neuroinflammatory milieu. Here, we found that higher-ordered oligomeric α-synuclein induced a proinflammatory microglial phenotype by directly engaging the heterodimer TLR1/2 (Toll-like receptor 1 and 2) at the cell membrane, leading to the nuclear translocation of NF-κB (nuclear factor κB) and the increased production of the proinflammatory cytokines TNF-α and IL-1β in a MyD88-dependent manner. Blocking signaling by the TLR1/2 heterodimer with the small molecule inhibitor, CU-CPT22, reduced the expression and secretion of these inflammatory cytokines from cultured primary mouse microglia. Candesartan cilexetil, a drug approved for treating hypertension and that inhibits the expression of TLR2, reversed the activated proinflammatory phenotype of primary microglia exposed to oligomeric α-synuclein, supporting the possibility of repurposing this drug for synucleinopathies. PMID:25969543

  10. A functional SNP catalog of overlapping miRNA-binding sites in genes implicated in prion disease and other neurodegenerative disorders.

    PubMed

    Saba, Reuben; Medina, Sarah J; Booth, Stephanie A

    2014-10-01

    The involvement of SNPs in miRNA target sites remains poorly investigated in neurodegenerative disease. In addition to associations with disease risk, such genetic variations can also provide novel insight into mechanistic pathways that may be responsible for disease etiology and/or pathobiology. To identify SNPs associated specifically with degenerating neurons, we restricted our analysis to genes that are dysregulated in CA1 hippocampal neurons of mice during early, preclinical phase of Prion disease. The 125 genes chosen are also implicated in other numerous degenerative and neurological diseases and disorders and are therefore likely to be of fundamental importance. We predicted those SNPs that could increase, decrease, or have neutral effects on miRNA binding. This group of genes was more likely to possess DNA variants than were genes chosen at random. Furthermore, many of the SNPs are common within the human population, and could contribute to the growing awareness that miRNAs and associated SNPs could account for detrimental neurological states. Interestingly, SNPs that overlapped miRNA-binding sites in the 3'-UTR of GABA-receptor subunit coding genes were particularly enriched. Moreover, we demonstrated that SNP rs9291296 would strengthen miR-26a-5p binding to a highly conserved site in the 3'-UTR of gamma-aminobutyric acid receptor subunit alpha-4.

  11. Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis

    PubMed Central

    Yang, Yi; Lynch, David R.; Lukas, Thomas; Ahmeti, Kreshnik; Sleiman, Patrick M.A.; Ryan, Eanna; Schadt, Kimberly A.; Newman, Jordan H.; Deng, Han-Xiang; Siddique, Nailah

    2016-01-01

    Objective: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. Methods: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. Results: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. Conclusions: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial. PMID:27123479

  12. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions.

  13. The social behavior of male rats administered an adult-onset calorie restriction regimen.

    PubMed

    Govic, Antonina; Levay, Elizabeth A; Kent, Stephen; Paolini, Antonio G

    2009-03-23

    The behavioral outcomes of a calorie restricted diet are often neglected in favour of a more physiological examination of the consequences of calorie restriction (CR). This is especially the case with social behavior. A few findings within the maternal CR literature suggest that adult male social behavior is altered by this regimen. Despite the paucity of findings within the maternal CR literature, a systematic investigation of the behavioral phenotype of males administered an adult-onset CR is completely lacking and was the focus of the current study. Adult male hooded Wistar rats were administered a three week CR, with one group receiving a 25% CR and another group receiving a 50% CR before male-to-male social behavior was examined and compared with ad libitium fed males. Various behavioral elements were modulated by CR, both the CR25% and 50% group initiated contact sooner and engaged in greater social activity compared to the ad libitum fed controls. The CR25% group also demonstrated less non-social (self-grooming) behavior and a greater frequency of walkovers compared to all groups, indicating a propensity towards dominance. The CR50% group demonstrated greater environmental assessment/exploration, as measured by the frequency of rearing. As with the maternal CR literature, an adult-onset chronic CR induces a more socially active behavioral phenotype and reduces interest in non-social behavior in the moderately CR group. Taken together, the social behavioral phenotype can be modulated by a CR initiated and maintained during adulthood.

  14. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions. PMID:24842077

  15. Similarities in speech and white matter characteristics in idiopathic developmental stuttering and adult-onset stuttering

    PubMed Central

    Chang, Soo-Eun; Synnestvedt, Anna; Ostuni, John

    2009-01-01

    Adult-onset stuttering (AS) typically occurs following neurological and/or psychological trauma, considered different from developmental stuttering (DS), which starts during early childhood with few if any new cases reported after adolescence. Here we report four cases of AS, two with apparent psychological trigger and two without, none with evidence of neurological injury, and none conforming to previously reported characteristics of psychogenic stuttering. We asked whether this group of AS would have similar speech and neuroanatomical characteristics to those with DS. We conducted blinded analyses of speech samples in both AS cases and 14 cases of DS on type, frequency, and loci of disfluencies. Diffusion tensor imaging (DTI) was conducted to compare white matter tracts using fractional anisotropy (FA). We found that AS did not differ significantly from DS in any of the speech characteristics measured. On DTI, DS had significantly increased FA relative to controls in the right superior longitudinal tract. AS cases showed a similar trend for increases in these regions when compared to controls. The results of this study suggest that symptoms of idiopathic stuttering can begin during adulthood, and that similar neuroanatomical differences from controls may be associated with both developmental and adult onset idiopathic stuttering. PMID:20640049

  16. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer's disease.

    PubMed

    da Rocha, Miguel Divino; Viegas, Flávia Pereira Dias; Campos, Helineide Cristina; Nicastro, Patrícia Carolina; Fossaluzza, Poliana Calve; Fraga, Carlos Alberto Manssour; Barreiro, Eliezer J; Viegas, Claudio

    2011-03-01

    The present review is part II in a series (part I focuses on Parkinson's Disease) that addresses the value of natural product chemistry in the discovery of medicines for the treatment of neurodegenerative disorders. Data reviewed document that a host of products from plant species and derivatives have neuroprotectant effects in vitro and in vivo. In addition, besides neuroprotection, natural products also demonstrate biological effects that target biochemical pathways underlying associated symptoms of neurdegnerative disorders that include cognitive impairments, energy/fatigue, mood, and anxiety. This part of the review series focuses specifically upon Alzheimer's Disease (AD). AD is postulated to result from extracellular formation of amyloid plaques and intracellular deposits of neurofibrilary tangles in the hippocampus, cerebral cortex and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition β-amyloid (Aβ), a peptide derived from the amyloid precursor protein (APP). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorilated tau protein, a microtubule-associated protein. In addition, environmental factors can engender the production of cytokines that are closely related to the installation of an inflammatory process that contributes to neuronal death and the development and the progression of AD. In this review we focus on the recent main contribuitions of natural products chemistry to the discovery of new chemical entities usefull to the control and prevention of AD installation and progression. More than sixteen plant species, including Ginseng, Celastrus paniculatus, Centella asiatica, Curcuma longa, Ginkgo biloba, Huperzia serrata, Lycoris radiate, Galanthus nivalis, Magnolia officinalis, Polygala tenuifolia, Salvia lavandulaefolia, Salvia miltiorrhiza, Coptis chinensis, Crocus sativus, Evodia rutaecarpa, Sanguisorba officinalis, Veratrum grandiflorum and

  17. Biology of Mitochondria in Neurodegenerative Diseases

    PubMed Central

    Martin, Lee J.

    2012-01-01

    Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS. PMID:22482456

  18. Meditation and neurodegenerative diseases.

    PubMed

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

    2014-01-01

    Neurodegenerative diseases pose a significant problem for the healthcare system, doctors, and patients. With an aging population, more and more individuals are developing neurodegenerative diseases and there are few treatment options at the present time. Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform. There is increasing research evidence to support the application of meditation techniques to help improve cognition and memory in patients with neurodegenerative diseases. This review discusses the current data on meditation, memory, and attention, and the potential applications of meditation techniques in patients with neurodegenerative diseases.

  19. Case report: An adult-onset type II citrin deficiency patient in the emergency department

    PubMed Central

    TANG, LUJIA; CHEN, LIANG; WANG, HAIRONG; DAI, LIHUA; PAN, SHUMING

    2016-01-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown. PMID:27347070

  20. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism.

    PubMed

    Nakamura, R K; Russell, N J; Shelton, G D

    2012-06-01

    A nine-year-old neutered female mixed breed dog presented for evaluation following a five-day history of lethargy, inappetence, weakness, abdominal distension and generalised muscle atrophy. Persistent vatrial standstill with a junctional rhythm was identified on electrocardiogram. Echocardiogram identified moderate dilation of all cardiac chambers and mild thickening of the mitral and tricuspid valves. Serology was negative for Neospora caninum and Toxoplasma gondii. Permanent pacemaker implantation was performed in addition to endomyocardial and skeletal muscle biopsies. Cryosections from the biceps femoris muscle showed numerous nemaline rod bodies while endomyocardial biopsies were possibly consistent with end-stage myocarditis. Rod bodies have rarely been reported in the veterinary literature. To the authors' knowledge, this is the first report of adult-onset nemaline rod myopathy and hypothyroidism with concurrent cardiac disease in a dog. PMID:22647214

  1. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy

    PubMed Central

    de Swart, B J M; van Engelen, B G M; van de Kerkhof, J P B M; Maassen, B

    2004-01-01

    Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy. Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed. Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur. Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production. PMID:15377703

  2. A mouse model of adult-onset anaemia due to erythropoietin deficiency.

    PubMed

    Yamazaki, Shun; Souma, Tomokazu; Hirano, Ikuo; Pan, Xiaoqing; Minegishi, Naoko; Suzuki, Norio; Yamamoto, Masayuki

    2013-01-01

    Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells. PMID:23727690

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

    PubMed Central

    Zueva, Marina V.

    2015-01-01

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

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

    PubMed

    Zueva, Marina V

    2015-01-01

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

  5. Assignment of the gene coding for the human high-affinity glutamate transporter EAAC1 to 9p24: Potential role in dicarboxylic aminoaciduria and neurodegenerative disorders

    SciTech Connect

    Smith, C.P.; Kanai, Y.; Stelzner, M.; Hediger, M.A.; Weremowicz, S.; Morton, C.C. )

    1994-03-15

    Functional defects of high-affinity glutamate transporters have been implicated in the pathophysiology of neurodegenerative diseases such as amyotrophic lateral sclerosis. In small intestine and kidney, in which the high-affinity glutamate transporter mediates net absorption of glutamate and aspartate across epithelial cells, an inborn error of glutamate transport is thought to cause dicarboxylic aminoaciduria. This disorder is characterized by increased urinary excretion of glutamate and aspartate and is, in general, associated with neurologic and developmental abnormalities. Recently, the authors isolated a cDNA encoding a high-affinity glutamate transporter (EAAC1) that also transports aspartate but not other amino acids. EAAC1 is ubiquitously expressed throughout the body, particularly in brain (neurons), intestine, and kidney. Here, the authors present mapping of the chromosome location of EAAC1 using Southern analysis of a panel of human/rodent somatic cell hybrids and fluorescence in situ hybridization (FISH). Southern analysis of EcoRI-digested DNA gave bands at 6.5, 5.6, 5.1, and 1.2 kb for human genomic DNA; 7.5 kb for mouse genomic DNA; and 7.3, 3.2, and 1 kb for hamster genomic DNA. All four human EAAC1-specific bands were observed in the lane corresponding to the human/Chinese hamster hybrid containing chromosome 9 but not in lanes corresponding to any other hybrid. Because the human/Chinese hamster hybrid is the only one retaining chromosome 9, this result unambiguously assigns human EAAC1 to chromosome 9. For precise chromosome assignment of the human EAAC1 gene, they employed FISH. Map position of the EAAC1 probe was assigned by visual inspection of the fluorescent signal on the DAPI-stained metaphase chromosomes. The human EAAC1 gene was assigned to 9p24.

  6. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Caused by a Novel R782G Mutation in CSF1R.

    PubMed

    Foulds, Nicola; Pengelly, Reuben J; Hammans, Simon R; Nicoll, James A R; Ellison, David W; Ditchfield, Adam; Beck, Sarah; Ennis, Sarah

    2015-05-15

    We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled "hereditary diffuse leukencephalopathy with axonal spheroids" (HDLS) and "pigmentary orthochromatic leukodystrophy" (POLD), disorders which now appear to form a disease continuum. The term "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.

  7. Liver transplantation versus conservative treatment for adult-onset type II citrullinemia: our experience and a review of the literature.

    PubMed

    Kimura, N; Kubo, N; Narumi, S; Toyoki, Y; Ishido, K; Kudo, D; Umehara, M; Yakoshi, Y; Hakamada, K

    2013-11-01

    Adult-onset type II citrullinemia (CTLN2), an autosomal recessive disorder caused by a mutation in the SLC25A13 gene, is characterized by increased serum citrulline and ammonia levels. Patients with CTLN2 also display various neuropsychiatric symptoms. Many individuals with CTLN2 are fond of protein-rich and/or lipid-rich foods with an aversion to carbohydrate-rich foods. We herein report two cases of CTLN2 treated with living donor liver transplantation (LDLT) and provide a review of the pertinent literature. Case 1 was a 43-year-old man admitted to our hospital for repetitive episodes of consciousness disturbance. Case 2 was a 37-year-old man admitted to our hospital because of abnormal behavior associated with hyperammonemia. A definitive diagnosis of CTLN2 was accomplished by DNA analysis in both patients, who successfully underwent LDLT using liver segments from donor siblings with confirmed heterozygous gene expression. Case 2 also underwent conservative therapy with arginine and a high-fat, carbohydrate-restricted diet prior to LDLT. Postoperative recovery was uneventful and food was unrestricted in both patients. We also identified 77 cases of CTLN2 in the literature and reviewed them in terms of outcome of both liver transplantation and conservative therapy. The survival rate in patients treated by liver transplantation was 100%, whereas that in patients treated by conservative treatment showed improvement from 39.5% to 76.5% over the years. Liver transplantation is a practical treatment that fundamentally improves patient quality of life after transplantation. However, recent studies have suggested that arginine and sodium pyruvate administration combined with intensive nutritional support is also an effective therapy for CTLN2. Further development of conservative therapy may provide a safer, more affordable alternative to liver transplantation in the near future.

  8. Omental transplantation for neurodegenerative diseases

    PubMed Central

    Rafael, Hernando

    2014-01-01

    Up to date, almost all researchers consider that there is still no effective therapy for neurodegenerative diseases (NDDs) and therefore, these diseases are incurable. However, since May 1998, we know that a progressive ischemia in the medial temporal lobes and subcommissural regions can cause Alzheimer’s disease; because, in contrast to this, its revascularization by means of omental tissue can cure or improve this disease. Likewise we observed that the aging process, Huntington’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis; all of them are of ischemic origin caused by cerebral atherosclerosis, associated with vascular anomalies and/or environmental chemicals. On the contrary, an omental transplantation on the affected zone can stop and improve these diseases. For these reasons, I believe that NDDs, are wrongly classified as neurodegenerative disorders. PMID:25232510

  9. Drosophila Models of Neurodegenerative Diseases

    PubMed Central

    Lu, Bingwei; Vogel, Hannes

    2011-01-01

    Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases. PMID:18842101

  10. Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson’s disease

    PubMed Central

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

    2009-01-01

    (MAO) -A and -B enzymes (IC50 2.5 and 2.0 nM, and 25 and 20 µM, respectively), and (−)-epicatechin (8) and (−)-procyanidin B2 (9) showed potent antioxidant and moderate MAO-B inhibitory activities (IC50 <0.13 and 0.57 µg/mL, and 65 and 35 µM). 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. Analysis of regular/commercial B. caapi dried stems showed a similar qualitative HPLC pattern, but relatively low content of dominant markers 1, 2, 7, and 9, which led to decreased MAO inhibitory and antioxidant potency. Conclusion Collectively, these results give additional basis to the existing claim of B. caapi stem extract for the treatment of Parkinsonism, including other neurodegenerative disorders. PMID:19879939

  11. Humoral Activity of Cord Blood-Derived Stem/Progenitor Cells: Implications for Stem Cell-Based Adjuvant Therapy of Neurodegenerative Disorders

    PubMed Central

    Paczkowska, Edyta; Kaczyńska, Katarzyna; Pius-Sadowska, Ewa; Rogińska, Dorota; Kawa, Miłosz; Ustianowski, Przemysław; Safranow, Krzysztof; Celewicz, Zbigniew; Machaliński, Bogusław

    2013-01-01

    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. PMID:24391835

  12. Adult onset sinonasal rhabdomyosarcoma - a rare case report with cytohistological features.

    PubMed

    Sood, N; Sehrawat, N

    2016-08-01

    Rhabdomyosarcoma (RMS) is a fast growing, malignant tumour arising from immature mesenchymal cells, committed to skeletal muscle differentiation. It is more often seen in the paediatric population and constitutes less than 1% of all malignancies and less than 3% of all soft tissue tumours. RMS of the paranasal sinuses constitutes 10-15% of adult head and neck RMS, ethmoidal and maxillary sinuses being the most common. We report a 56-year-oldman presenting with left nasal obstruction, epistaxis on and off and left cheek swelling. Nasal endoscopy revealed a reddish friable mass, bleeding on touch, in the left nasal cavity. CECT scan showed a heterogeneous growth in the left maxillary sinus eroding the medial orbital wall and lateral nasal wall. FNAC of the left cheek swelling yielded highly cellular smears showing predominantly singly scattered round to ovoid neoplastic cells with scanty cytoplasm and indistinct nucleoli. Few of the cells had eccentric nuclei with moderate amount of eosinophilic cytoplasm. Attempted pseudorossette formation was seen. An impression of round cell tumour was given. A diagnosis of an adult onset sinonasal rhabdomyosarcoma was made on histopathological examination of the nasal biopsy, supported by immunohistochemistry (IHC) showing strong myogenin positivity, focal positivity for PAX8 and negativity for CK, LCA, S-100 and CD99. Parameningeal RMS is rare in adults especially the elderly. However, it needs to be considered whenever a poorly-differentiated neoplasm is seen in this age and IHC is a useful aid. PMID:27568676

  13. Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.

    PubMed

    Santín, Sheila; García-Maset, Rafael; Ruíz, Patricia; Giménez, Isabel; Zamora, Isabel; Peña, Antonia; Madrid, Alvaro; Camacho, Juan A; Fraga, Gloria; Sánchez-Moreno, Ana; Cobo, Maria Angeles; Bernis, Carmen; Ortiz, Alberto; de Pablos, Augusto Luque; Pintos, Guillem; Justa, Maria Luisa; Hidalgo-Barquero, Emilia; Fernández-Llama, Patricia; Ballarín, José; Ars, Elisabet; Torra, Roser

    2009-12-01

    Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.

  14. Patterns and correlates of multiple risk factors for adult-onset cancer among adolescents

    PubMed Central

    MAYS, DARREN; PESHKIN, BETH N.; WALKER, LESLIE R.; ABRAHAM, ANISHA A.; HAWKINS, KIRSTEN B.; TERCYAK, KENNETH P.

    2012-01-01

    We investigated patterns and correlates of multiple, adult-onset cancer risk factors (MCRFs) among adolescents. Baseline data from an intervention efficacy trial were analyzed to examine patterns of co-occurring MCRFs and sociodemographic and theoretical (e.g., prevention self-efficacy) correlates of MCRFs among adolescents (N = 50) age 13 – 21. The mean total MCRFs was 4.6 (SD = 1.6; range 0–9). The most common risk factors were intentions to use alcohol (n = 40, 80%), < 5 daily servings of fruits/vegetables (n = 40, 80%), and lifetime alcohol use (n = 38, 76%). MCRFs commonly co-occurred, suggesting a clustered risk profile. Greater age (B = 0.19 95% CI 0.01, 0.38) and lower prevention self-efficacy (B = −0.16, 95% CI −0.02, −0.30) were significantly (p < 0.05) associated with MCRFs. Multiple health behavior change interventions are needed to prevent accumulation of risk factors as youth mature. Self-efficacy may be an important target for prevention interventions. PMID:22363044

  15. The distinction between juvenile and adult-onset primary open-angle glaucoma

    SciTech Connect

    Wiggs, J.L.; Haines, J.L.; Damji, K.F.

    1996-01-01

    Because of the significant differences between the juvenile and adult forms of open-angle glaucoma, especially with regard to inheritance, prevalence, severity, and age of onset, we read with interest the recent publication by Morissette et al., describing a pedigree with a phenotype that overlaps the distinctive features of juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (usually abbreviated as POAG or COAG). These authors conclude that a gene mapped to human chromosome 1q21-q31 (GLC1A) can be responsible for both juvenile and adult forms of open-angle glaucoma. The implications of such a result could be extremely important, in light of the high prevalence of the adult form of the disease. However, while the data presented in this report suggest that variable expressivity of the GLC1A gene may lead to a broader range of onset for this form of juvenile glaucoma, these data do not identify the GLC1A gene as an important cause of POAG. To prevent misleading interpretations of this and similar studies, we wish to clarify the distinction between the juvenile and adult forms of open-angle glaucoma. 8 refs.

  16. Effect size of memory deficits in mice with adult-onset P301L tau expression.

    PubMed

    Hunsberger, Holly C; Rudy, Carolyn C; Weitzner, Daniel S; Zhang, Chong; Tosto, David E; Knowlan, Kevin; Xu, Ying; Reed, Miranda N

    2014-10-01

    Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer's disease.

  17. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  18. Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions

    PubMed Central

    Cardin, Velia

    2016-01-01

    Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID:27242405

  19. A search for the primary abnormality in adult-onset type II citrullinemia

    SciTech Connect

    Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori ); Kumashiro, Ryukichi; Tanikawa, Kyuichi ); O'Brien, W.E.; Beaudet, A.L. )

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.

  20. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD

    PubMed Central

    van der Zee, Julie; Mariën, Peter; Crols, Roeland; Van Mossevelde, Sara; Dillen, Lubina; Perrone, Federica; Engelborghs, Sebastiaan; Verhoeven, Jo; D'aes, Tine; Ceuterick-De Groote, Chantal; Sieben, Anne; Versijpt, Jan; Cras, Patrick; Martin, Jean-Jacques

    2016-01-01

    Objective: To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD). Methods: Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing. Results: We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype. Conclusions: A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms.

  1. Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene.

    PubMed

    Antunes, Ana Patrícia; Nogueira, Célia; Rocha, Hugo; Vilarinho, Laura; Evangelista, Teresinha

    2013-12-01

    Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is an autosomal recessive disease. Most common phenotypes occur in the neonatal period or in childhood with cardiomyopathy, hepatomegaly, and hypoketogenic hypoglycemia. Juvenile/adult-onset is characterized by exercise intolerance and recurrent rhabdomyolysis triggered by prolonged exercise or fasting. This article reports a patient with the homozygous mutation c.1097G>A (p.R366H) in the ACADVL gene. In Portugal, VLCAD deficiency became part of the neonatal screening plan in 2004, and as of 2012, 8 early-onset cases have been diagnosed, giving an incidence rate of 1:97.238 per 737.902 newborns. This patient was diagnosed outside of the neonatal screening plan. Beta-oxidation defects pose a diagnostic challenge because of their transient clinical and laboratorial manifestations and the absence of morphological changes in muscle biopsy further complicate matters, especially in the late-onset forms of the disease. The adult phenotype of VLCAD deficiency is highlighted, emphasizing the need for a high suspicion index and the value of tandem mass spectrometry for the diagnosis. PMID:24263034

  2. Juvenile versus adult-onset ankylosing spondylitis -- clinical, radiographic, and social outcomes. a systematic review.

    PubMed

    Jadon, Deepak R; Ramanan, Athimalaipet V; Sengupta, Raj

    2013-11-01

    Ankylosing spondylitis (AS) has 2 main modes of onset: juvenile-onset AS (JoAS) and adult-onset AS (AoAS). It is not known whether JoAS is a subtype of AS, or AS modulated by early age of onset and longer disease duration. We performed a systematic review of the literature, identifying 12 articles and 1 abstract directly comparing JoAS and AoAS cohorts, with observational study design. Patients with JoAS appear to have more peripheral joint involvement both clinically and radiographically (especially knees and ankles) and more root joint involvement (hips and shoulders); they are more likely to proceed to hip arthroplasty and often initially present with peripheral rather than axial symptoms. Patients with AoAS appear to have more axial symptoms and radiographic disease, particularly in the lumbar spine, and worse axial metrology. In terms of other characteristics, more evidence is needed to confidently state whether JoAS and AoAS are different.

  3. Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease Successfully Treated with Anakinra

    PubMed Central

    Kato, Hiroshi

    2016-01-01

    Macrophage activation syndrome (MAS) is a potentially fatal complication of Adult-Onset Still's disease (Still's disease). Whereas an increasing body of evidence supports interleukin-1 (IL-1) blockade as a promising treatment for Still's disease, whether it is therapeutic for MAS associated with Still's disease remains unclear. We report a 34-year-old Caucasian man with one-decade history of TNF-blockade-responsive seronegative arthritis who presented with abrupt onset of fever, serositis, bicytopenia, splenomegaly, hepatitis, and disseminated intravascular coagulation. Striking hyperferritinemia was noted without evidence of infection, malignancy, or hemophagocytosis on bone marrow biopsy. NK cells were undetectable in the peripheral blood, whereas soluble IL-2 receptor was elevated. His multiorgan disease resolved in association with methylprednisolone pulse therapy, Anakinra, and a tapering course of prednisone. This case reinforces the notion that Still's disease is inherently poised to manifest MAS as one of the clinical phenotypes by shedding light on the role of IL-1 underlying both Still's disease and related MAS.

  4. Neural regulation of acid maltase in an unusual adult onset deficiency.

    PubMed

    Meola, G; Sansone, V; Rotondo, G; Radice, S; Sterlicchio, M; Mauri, M; Bresolin, N; Moggio, M

    1994-01-01

    In a 48-year-old female, the first symptoms apparently manifested themselves 18 years before, with occasional tripping and weakness in both legs. During the next 18 years, weakness progressed and the patient developed a waddling gait; she became unable to rise from a lying or seated position unassisted and the shoulder girdle also became affected. Neurological examination revealed limb and shoulder girdle predominantly involving the lower extremities. We established cell cultures from muscle biopsy specimens obtained from our patient and carried out morphological analysis which, although aspecific, demonstrated clear signs of neurogenic suffering. This was confirmed in EMG studies performed. Biochemical analysis revealed very low acid maltase residual activity. We describe an unusual case of adult-onset acid maltase deficiency (AMD) with neurogenic atrophy and low residual activity. Innervated myofibres prepared by co-culturing the patient's myoblasts, with spinal cord foetal mouse explants were not associated with an abnormal in vitro maturation of the innervated myofibres as expected by the very low residual enzymatic activity found both in the muscle biopsy specimens and in the muscle cultures. There is strong suggestion that factors other than the amount of residual activity must be involved to determine the clinical manifestation of this disease.

  5. Autophagy, inflammation and neurodegenerative disease

    PubMed Central

    Alirezaei, Mehrdad; Kemball, Christopher C.; Whitton, J. Lindsay

    2010-01-01

    Autophagy is emerging as a central regulator of cellular health and disease and, in the central nervous system (CNS), this homeostatic process appears to influence synaptic growth and plasticity. Herein, we review the evidence that dysregulation of autophagy may contribute to several neurodegenerative diseases of the CNS. Up-regulation of autophagy may prevent, delay or ameliorate at least some of these disorders, and – based on recent findings from our laboratory – we speculate that this goal may be achieved using a safe, simple, and inexpensive approach. PMID:21138487

  6. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study

    PubMed Central

    Hoppin, Jane A.; Umbach, David M.; London, Stephanie J.; Henneberger, Paul K.; Kullman, Greg J.; Coble, Joseph; Alavanja, Michael C.R.; Beane Freeman, Laura E.; Sandler, Dale P.

    2010-01-01

    Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. We used data from 19,704 male farmers in the Agricultural Health Study to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after age 20. We categorized asthma cases as allergic (N=127) and non-allergic (N=314) based on their history of eczema or hayfever. We used polytomous logistic regression controlling for age, state, smoking, and body mass to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and non-allergic asthma. For ever use, 12 individual pesticides were associated with allergic asthma and four with non-allergic asthma. For allergic asthma, coumaphos (odds ratio (OR) =2.34, 95% Confidence Interval (CI) =1.49,3.70), heptachlor (OR=2.01, 95%CI=1.30,3.11), parathion (OR=2.05, 95%CI=1.21,3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR=2.15, 95%CI=1.23,3.76) and ethylene dibromide (OR=2.07, 95%CI=1.02,4.20), all had odds ratios greater than 2.0 and significant exposure-response trends. For non-allergic asthma, DDT had the strongest association (OR=1.41, 95%CI=1.09,1.84) but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. We saw little evidence that allergy alone was driving these associations. Pesticides may be an overlooked contributor to asthma risk among farmers. PMID:19541724

  7. Parental smoking in pregnancy and the risks of adult-onset hypertension.

    PubMed

    de Jonge, Layla L; Harris, Holly R; Rich-Edwards, Janet W; Willett, Walter C; Forman, Michele R; Jaddoe, Vincent W V; Michels, Karin B

    2013-02-01

    Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33086 participants of the Nurses' Health Study II and the Nurses' Mothers' Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8575 (25.9%) mothers and 18874 (57.0%) fathers smoked during pregnancy. During follow-up, 7825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥ 15 cigarettes/d during pregnancy were associated with increased risks of hypertension (rate ratio, 1.19; 95% CI, 1.09-1.29; and rate ratio, 1.18; 95% CI, 1.12-1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, whereas additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (rate ratio, 1.07; 95% CI, 0.98-1.16; and rate ratio, 1.06; 95% CI, 1.01-1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.

  8. Characterisation of a syndrome of autoimmune adult onset focal epilepsy and encephalitis.

    PubMed

    Ramanathan, Sudarshini; Bleasel, Andrew; Parratt, John; Orr, Carolyn; Dale, Russell C; Vincent, Angela; Fung, Victor S C

    2014-07-01

    We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of "autoimmune adult onset focal epilepsy and encephalitis" is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-D-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome. PMID:24518268

  9. PARENTAL SMOKING IN PREGNANCY AND THE RISKS OF ADULT ONSET HYPERTENSION

    PubMed Central

    De Jonge, Layla L.; Harris, Holly R.; Rich-Edwards, Janet W.; Willett, Walter C.; Forman, Michele R.; Jaddoe, Vincent W.V.; Michels, Karin B.

    2013-01-01

    Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33,086 participants of the Nurses’ Health Study II and the Nurses’ Mothers’ Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8,575 (25.9%) mothers and 18,874 (57.0%) fathers smoked during pregnancy. During follow-up, 7,825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥15 cigarettes/day during pregnancy were associated with increased risks of hypertension (RR 1.19, 95% CI 1.09 to 1.29, and RR 1.18, 95% CI 1.12 to 1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, while additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (RR 1.07, 95% CI 0.98 to 1.16, and RR 1.06, 95% CI 1.01 to 1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms. PMID:23266542

  10. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice.

    PubMed

    Pan, Weihong; Hsuchou, Hung; He, Yi; Sakharkar, Amul; Cain, Courtney; Yu, Chuanhui; Kastin, Abba J

    2008-06-01

    The agouti viable yellow (A vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, (125)I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young A vy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A vy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) A vy and B6 mice. Higher ObRb mRNA was seen in the A vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the A vy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

  11. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD

    PubMed Central

    van der Zee, Julie; Mariën, Peter; Crols, Roeland; Van Mossevelde, Sara; Dillen, Lubina; Perrone, Federica; Engelborghs, Sebastiaan; Verhoeven, Jo; D'aes, Tine; Ceuterick-De Groote, Chantal; Sieben, Anne; Versijpt, Jan; Cras, Patrick; Martin, Jean-Jacques

    2016-01-01

    Objective: To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD). Methods: Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing. Results: We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype. Conclusions: A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms. PMID:27668283

  12. Muscle MRI Findings in Childhood/Adult Onset Pompe Disease Correlate with Muscle Function

    PubMed Central

    Figueroa-Bonaparte, Sebastián; Segovia, Sonia; Llauger, Jaume; Belmonte, Izaskun; Pedrosa, Irene; Alejaldre, Aída; Mayos, Mercè; Suárez-Cuartín, Guillermo; Gallardo, Eduard; Illa, Isabel; Díaz-Manera, Jordi

    2016-01-01

    Objectives Enzyme replacement therapy has shown to be effective for childhood/adult onset Pompe disease (AOPD). The discovery of biomarkers useful for monitoring disease progression is one of the priority research topics in Pompe disease. Muscle MRI could be one possible test but the correlation between muscle MRI and muscle strength and function has been only partially addressed so far. Methods We studied 34 AOPD patients using functional scales (Manual Research Council scale, hand held myometry, 6 minutes walking test, timed to up and go test, time to climb up and down 4 steps, time to walk 10 meters and Motor Function Measure 20 Scale), respiratory tests (Forced Vital Capacity seated and lying, Maximun Inspiratory Pressure and Maximum Expiratory Pressure), daily live activities scales (Activlim) and quality of life scales (Short Form-36 and Individualized Neuromuscular Quality of Life questionnaire). We performed a whole body muscle MRI using T1w and 3-point Dixon imaging centered on thighs and lower trunk region. Results T1w whole body muscle MRI showed a homogeneous pattern of muscle involvement that could also be found in pre-symptomatic individuals. We found a strong correlation between muscle strength, muscle functional scales and the degree of muscle fatty replacement in muscle MRI analyzed using T1w and 3-point Dixon imaging studies. Moreover, muscle MRI detected mild degree of fatty replacement in paraspinal muscles in pre-symptomatic patients. Conclusion Based on our findings, we consider that muscle MRI correlates with muscle function in patients with AOPD and could be useful for diagnosis and follow-up in pre-symptomatic and symptomatic patients under treatment. Take home message Muscle MRI correlates with muscle function in patients with AOPD and could be useful to follow-up patients in daily clinic. PMID:27711114

  13. Metal attenuating therapies in neurodegenerative disease.

    PubMed

    Mot, Alexandra I; Wedd, Anthony G; Sinclair, Layla; Brown, David R; Collins, Steven J; Brazier, Marcus W

    2011-12-01

    The clinical and pathological spectrum of neurodegenerative diseases is diverse, although common to many of these disorders is the accumulation of misfolded proteins, with oxidative stress thought to be an important contributing mechanism to neuronal damage. As a corollary, transition metal ion dyshomeostasis appears to play a key pathogenic role in a number of these maladies, including the most common of neurodegenerative diseases. In this review, studies spanning a wide variety of neurodegenerative disorders are presented with their involvement of transition metals compared and contrasted, including more detailed treatise in relation to Alzheimer's disease, Parkinson's disease and prion diseases. For each of these diseases, a discussion of the evolving scientific rationale for the development of therapies aimed at ameliorating the detrimental effects of transition metal dysregulation, including results from various human trials, is then provided.

  14. Chorea and related disorders

    PubMed Central

    Bhidayasiri, R; Truong, D

    2004-01-01

    Chorea refers to irregular, flowing, non-stereotyped, random, involuntary movements that often possess a writhing quality referred to as choreoathetosis. When mild, chorea can be difficult to differentiate from restlessness. When chorea is proximal and of large amplitude, it is called ballism. Chorea is usually worsened by anxiety and stress and subsides during sleep. Most patients attempt to disguise chorea by incorporating it into a purposeful activity. Whereas ballism is most often encountered as hemiballism due to contralateral structural lesions of the subthalamic nucleus and/or its afferent or efferent projections, chorea may be the expression of a wide range of disorders, including metabolic, infectious, inflammatory, vascular, and neurodegenerative, as well as drug induced syndromes. In clinical practice, Sydenham's chorea is the most common form of childhood chorea, whereas Huntington's disease and drug induced chorea account for the majority of adult onset cases. The aim of this review is to provide an up to date discussion of this disorder, as well as a practical approach to its management. PMID:15356354

  15. Exclusion of one pedigree affected by adult onset primary open angle glaucoma from linkage to the juvenile glaucoma locus on chromosome 1q21-q31.

    PubMed Central

    Avramopoulos, D; Kitsos, G; Economou-Petersen, E; Grigoriadou, M; Vassilopoulos, D; Papageorgiou, C; Psilas, K; Petersen, M B

    1996-01-01

    A locus for autosomal dominant juvenile onset primary open angle glaucoma (POAG) was recently assigned to chromosome region 1q21-q31. In the present study, a large Greek family with autosomal dominant adult onset POAG was investigated using microsatellite markers. Exclusion of linkage of the adult onset POAG gene to the region D1S194-D1S191 was obtained in this pedigree. Therefore, the data provide evidence that juvenile and adult onset POAG are genetically distinct disease entities. PMID:9004141

  16. Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns

    PubMed Central

    Sanchez-Mut, J V; Heyn, H; Vidal, E; Moran, S; Sayols, S; Delgado-Morales, R; Schultz, M D; Ansoleaga, B; Garcia-Esparcia, P; Pons-Espinal, M; de Lagran, M M; Dopazo, J; Rabano, A; Avila, J; Dierssen, M; Lott, I; Ferrer, I; Ecker, J R; Esteller, M

    2016-01-01

    Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies. PMID:26784972

  17. 18F-FDG PET/CT in patients with adult-onset Still's disease.

    PubMed

    Dong, Meng-Jie; Wang, Cai-Qin; Zhao, Kui; Wang, Guo-Lin; Sun, Mei-Ling; Liu, Zhen-Feng; Xu, Liqin

    2015-12-01

    (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has become useful for the detection and diagnosis of inflammatory conditions, including rheumatic diseases, immunoglobulin (Ig) G4-related disease and giant cell arteritis. However, few articles based on small sample sizes (n = 7) diagnosed as adult-onset Still's disease (AOSD) have been published. The study aim was to observe the reliable characteristics and usefulness of (18)F-FDG PET/CT for the evaluation of consecutive patients with AOSD. Eligible patients were selected from among those who had undergone (18)F-FDG PET/CT between May 2007 and June 2014. Twenty-six consecutive AOSD patients were recruited retrospectively according to criteria set by Yamaguchi et al. All patients underwent evaluation by (18)F-FDG PET/CT. The characteristics and usefulness of (18)F-FDG PET/CT for evaluation of consecutive patients with AOSD were evaluated. All 26 patients had (18)F-FDG-avid lesion(s) related to their particular disease. Diffuse and homogeneous accumulation of (18)F-FDG was seen in the bone marrow (26/26; 100 %; maximum standardized uptake (SUVmax), 2.10-6.73) and spleen (25/26; 96.15 %). The SUVmax of affected lymph nodes was 1.3-9.53 (mean ± SD, 4.12 ± 2.24). The SUVmax and size factors (maximum diameter and areas) of affected lymph nodes were significantly different (P = 0.033 and P = 0.012, respectively). (18)F-FDG PET/CT showed the general distribution of (18)F-FDG accumulation. This factor helped to exclude malignant disease and aided the diagnosis of AOSD (42.3 %) in 11 cases when combined with clinical features and aided decisions regarding appropriate biopsy sites, such as the lymph nodes (n = 9) and bone marrow (n = 13). (18)F-FDG PET/CT is a unique imaging method for the assessment of metabolic activity throughout the body in subjects with AOSD. Characteristics or patterns of AOSD observed on (18)F-FDG PET/CT can be used for the

  18. An increased incidence of Hodgkin's lymphoma in patients with adult-onset sarcoma

    PubMed Central

    2012-01-01

    Background Sarcomas are rare, often fatal malignancies of connective tissues that can occur in genetic predisposition syndromes or result from carcinogen exposure. Hodgkin's lymphoma (HL) is not known to contribute to any recognised familial cancer syndrome comprising sarcomas, but is known to be associated with a variety of second cancers, including sarcomas. This study describes the prevalence of HL in families affected by sarcoma. Methods The International Sarcoma Kindred Study (ISKS) is a prospective cohort of 561 families ascertained via a proband with adult-onset sarcoma. Cancer-specific standardised incidence ratios (SIR) for multiple primary malignancies in probands were estimated. Clinical characteristics of individuals reporting both sarcoma and HL were described. Standardised incidence ratios for the occurrence of cancer in ISKS families were also estimated. Results Multiple primary cancers were reported in 16% of probands, significantly higher than in the general population. The risk of HL in probands was increased 15.8-fold (95%CI 7.9-31.6) and increased risks were also seen for breast cancer (SIR 2.9, 95%CI 1.9-4.4) and thyroid cancer (SIR 8.4, 95%CI 4.2-16.8). In 8 probands with both HL and sarcoma, the diagnosis of HL preceded that of sarcoma in 7 cases, and occurred synchronously in one case. Only 3 cases of sarcoma occurred in or close to prior radiotherapy fields. The overall incidence of HL in the ISKS cohort was not significantly increased by comparison with age- and gender-specific population estimates (SIR 1.63, 95%CI 1.05-2.43), suggesting that the association between HL and sarcomas did not extend to other family members. The age of onset of non-sarcoma, non-HL cancers in families affected by both HL and sarcoma was younger than the general population (56.2 y vs 65.6 y, P < 0.0001). Conclusions The basis for the association between HL and sarcomas may include the carcinogenic effects of therapy combined with excellent survival rates for HL

  19. Oxidative stress in neurodegenerative diseases.

    PubMed

    Chen, Xueping; Guo, Chunyan; Kong, Jiming

    2012-02-15

    Reactive oxygen species are constantly produced in aerobic organisms as by-products of normal oxygen metabolism and include free radicals such as superoxide anion (O2 (-)) and hydroxyl radical (OH(-)), and non-radical hydrogen peroxide (H2O2). The mitochondrial respiratory chain and enzymatic reactions by various enzymes are endogenous sources of reactive oxygen species. Exogenous reactive oxygen species -inducing stressors include ionizing radiation, ultraviolet light, and divergent oxidizing chemicals. At low concentrations, reactive oxygen species serve as an important second messenger in cell signaling; however, at higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death. Oxidative stress is a condition of imbalance between reactive oxygen species formation and cellular antioxidant capacity due to enhanced ROS generation and/or dysfunction of the antioxidant system. Biochemical alterations in these macromolecular components can lead to various pathological conditions and human diseases, especially neurodegenerative diseases. Neurodegenerative diseases are morphologically featured by progressive cell loss in specific vulnerable neuronal cells, often associated with cytoskeletal protein aggregates forming inclusions in neurons and/or glial cells. Deposition of abnormal aggregated proteins and disruption of metal ions homeostasis are highly associated with oxidative stress. The main aim of this review is to present as much detailed information as possible that is available on various neurodegenerative disorders and their connection with oxidative stress. A variety of therapeutic strategies designed to address these pathological processes are also described. For the future therapeutic direction, one specific pathway that involves the transcription factor nuclear factor erythroid 2-related factor 2 is receiving considerable attention.

  20. Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

    SciTech Connect

    Paw, B.H.; Kaback, M.M.; Neufeld, E.F. )

    1989-04-01

    Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

  1. Catalpol: a potential therapeutic for neurodegenerative diseases.

    PubMed

    Jiang, B; Shen, R F; Bi, J; Tian, X S; Hinchliffe, T; Xia, Y

    2015-01-01

    Neurodegenerative disorders, e.g., Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the progressive loss of neurons and subsequent cognitive decline. They are mainly found in older populations. Due to increasing life expectancies, the toll inflicted upon society by these disorders continues to become heavier and more prominent. Despite extensive research, however, the exact etiology of these disorders is still unknown, though the pathophysiological mechanisms have been attributed to oxidative, inflammatory and apoptotic injury in the brain. Moreover, there is currently no promising therapeutic agent against these neurodegenerative changes. Catalpol, an iridoid glucoside contained richly in the roots of the small flowering plant species Rehmannia glutinosa Libosch, has been shown to have antioxidation, anti-inflammation, anti-apoptosis and other neuroprotective properties and plays a role in neuroprotection against hypoxic/ischemic injury, AD and PD in both in vivo and in vitro models. It may therefore represent a potential therapeutical agent for the treatment of hypoxic/ischemic injury and neurodegenerative diseases. Based on our studies and those of others in the literature, here we comprehensively review the role of Catalpol in neuroprotection against pathological conditions, especially in neurodegenerative states and the potential mechanisms involved.

  2. Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.

    PubMed

    Nguyen, K Hoa; Ande, Sudharsana R; Mishra, Suresh

    2016-01-29

    The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.

  3. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    SciTech Connect

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; Gasparini, L.; Ferrera, D.; Canale, C.; Guipponi, M.; Pennacchio, L. A.; Antonarakis, S. E.; Brussino, A.; Brusco, A.

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

  4. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    DOE PAGES

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; et al

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in amore » postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.« less

  5. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    PubMed Central

    Giorgio, Elisa; Robyr, Daniel; Spielmann, Malte; Ferrero, Enza; Di Gregorio, Eleonora; Imperiale, Daniele; Vaula, Giovanna; Stamoulis, Georgios; Santoni, Federico; Atzori, Cristiana; Gasparini, Laura; Ferrera, Denise; Canale, Claudio; Guipponi, Michel; Pennacchio, Len A.; Antonarakis, Stylianos E.; Brussino, Alessandro; Brusco, Alfredo

    2015-01-01

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes. PMID:25701871

  6. Spinocerebellar ataxia type 1 and Machado-Joseph disease: Incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia

    SciTech Connect

    Ranum, L.P.W.; Gomez, C.; Orr, H.T.

    1995-09-01

    The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia, we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% have SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively. 30 refs., 1 fig., 3 tabs.

  7. Adult-onset nemaline rods in a patient treated for suspected dermatomyositis: study with two-dimensional electrophoresis

    SciTech Connect

    Danon, M.J.; Giometti, C.S.; Manaligod, J.R.; Perurena, O.H.; Skosey, J.L.

    1981-12-01

    A 65-year-old woman with progressive muscle weakness and a diffuse rash of three years' duration was examined. Muscle tissue was studied with histochemical techniques, phase-contrast microscopy, electron microscopy, and two-dimensional electrophoresis. Histochemical studies showed numerous nemaline rods, with a normal ratio of types I and II fibers. Two-dimensional electrophoresis revealed abnormalities in the myosin light chain and tropomyosin protein patterns when compared with normal and diseased muscle biopsy samples, including those from two patients with adult-onset dermatomyositis.

  8. Aquaporins and Neurodegenerative Diseases

    PubMed Central

    Foglio, Eleonora; Rodella, Luigi Fabrizio

    2010-01-01

    Aquaporins (AQPs) are a family of widely distributed membrane-inserted water channel proteins providing a pathway for osmotically-driven water, glycerol, urea or ions transport through cell membranes and mechanisms to control particular aspects of homeostasis. Beside their physiological expression patterns in Central Nervous System (CNS), it is conceivable that AQPs are also abnormally expressed in some pathological conditions interesting CNS (e.g. neurodegenerative diseases) in which preservation of brain homeostasis is at risk. The purpose of this review was to take in consideration those neurodegenerative diseases in whose pathogenetic processes it was possible to hypothesize some alterations in CNS AQPs expression or modulation leading to damages of brain water homeostasis. PMID:21119882

  9. Curcumin and neurodegenerative diseases

    PubMed Central

    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

  10. Circulating microRNAs in Neurodegenerative Diseases.

    PubMed

    Grasso, Margherita; Piscopo, Paola; Crestini, Alessio; Confaloni, Annamaria; Denti, Michela A

    2015-01-01

    Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by a combination of events that impair normal neuronal function. Although they are considered different disorders, there are overlapping features among them from the clinical, pathological, and genetic points of view. Synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities such as axonal transport defects normally precede the neuronal loss that is a relatively late event. The diagnosis of many neurodegenerative diseases is mainly based on patient's cognitive function analysis, and the development of diagnostic methods is complicated by the brain's capacity to compensate for neuronal loss over a long period of time. This results in the late clinical manifestation of symptoms, a time when successful treatment is no longer feasible. Thus, a noninvasive diagnostic method based on early events detection is particularly important. In the last years, some biomarkers expressed in human body fluids have been proposed. microRNAs (miRNAs), with their high stability, tissue- or cell type-specific expression, lower cost, and shorter time in the assay development, could constitute a good tool to obtain an early disease diagnosis for a wide number of human pathologies, including neurodegenerative diseases. The possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative disorders is a highly promising approach for developing minimally invasive screening tests and to identify new therapeutic targets.

  11. Neuronal Network Oscillations in Neurodegenerative Diseases.

    PubMed

    Nimmrich, Volker; Draguhn, Andreas; Axmacher, Nikolai

    2015-09-01

    Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker. PMID:25920466

  12. Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.

    PubMed

    Vasilopoulou, Catherine G; Constantinou, Caterina; Giannakopoulou, Dimitra; Giompres, Panagiotis; Margarity, Marigoula

    2016-10-01

    Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner. PMID:27317840

  13. Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.

    PubMed

    Vasilopoulou, Catherine G; Constantinou, Caterina; Giannakopoulou, Dimitra; Giompres, Panagiotis; Margarity, Marigoula

    2016-10-01

    Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner.

  14. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    PubMed Central

    Martin, Lee J.

    2010-01-01

    Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal 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. PMID:21258649

  15. Stem cells and neurodegenerative diseases.

    PubMed

    Hou, LingLing; Hong, Tao

    2008-04-01

    Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington' disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease.

  16. Endocytic membrane trafficking and neurodegenerative disease.

    PubMed

    Schreij, Andrea M A; Fon, Edward A; McPherson, Peter S

    2016-04-01

    Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology. PMID:26721251

  17. Synthetic prions and other human neurodegenerative proteinopathies.

    PubMed

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

    2015-09-01

    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.

  18. Wiki-Based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma: A New Paradigm in Sarcoma Evidence

    PubMed Central

    Neuhaus, S. J.; Thomas, D.; Desai, J.; Vuletich, C.; von Dincklage, J.; Olver, I.

    2015-01-01

    In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. PMID:25784832

  19. Sporadic adult-onset neuronal intranuclear inclusion disease with the main presentation of repeated cerebellar ataxia: a case study.

    PubMed

    Sakurai, Takeo; Harada, Seiko; Wakida, Kenji; Yoshida, Mari; Nishida, Hiroshi

    2016-06-22

    A 66-year-old woman suddenly experienced unsteadiness while walking; she had experienced the same symptom before, but it had resolved immediately. Her neurological findings showed cerebellar ataxia, absence of tendon reflex in the extremities, and orthostatic hypotension. MRI with DWI of the brain showed linear high-intensity areas at the white matter just below the cerebral cortex. Therefore, we suspected neuronal intranuclear inclusion disease (NIID). In her cutaneous skin biopsy, intranuclear inclusion bodies, which tested positive for an anti-ubiquitin antibody and anti-p62 antibody, were observed in sweat gland cells and fibroblasts; therefore, we diagnosed her with NIID. As no one in her family had similar symptoms, this was a case of sporadic NIID. Adult-onset NIID with the main presentation of cerebellar ataxia is rare; in our case, this repeated acute-onset symptom was a unique manifestation of the condition. PMID:27181748

  20. Adult Onset of BRAFV600E-Mutated Langerhans Cell Histiocytosis with Cutaneous Involvement Successfully Diagnosed by Immunohistochemical Staining

    PubMed Central

    Tono, Hisayuki; Fujimura, Taku; Kakizaki, Aya; Furudate, Sadanori; Ishibashi, Masaya; Aiba, Setsuya

    2015-01-01

    Langerhans cell histiocytosis (LCH) is characterized by the clonal proliferation of Langerhans cells; it is categorized as a single-system disease with single or multifocal lesions, and as a multi-system disease with or without the risk of organ involvement. Although the skin is not categorized as a risk organ, the precise diagnosis of skin lesions is necessary to determine the protocol for the treatment of LCH. In this report, we describe a 28-year-old Japanese man with adult onset of BRAFV600E-mutated LCH with cutaneous involvement successfully diagnosed by immunohistochemical staining. Our report suggests that immunohistochemical staining for the BRAFV600E gene could be a diagnostic tool to determine the clinical type of LCH. PMID:26500535

  1. An unusual manifestation in a patient with adult-onset Still’s disease: Minimal glomerular lesion

    PubMed Central

    El Mezouar, Imane; Abourazzak, Fatima Zahra; Ghani, Najoua; Harzy, Taoufik

    2014-01-01

    Adult-onset Still’s disease (AOSD) is a multisystem inflammatory disease of unknown etiology. It is characterized by arthritis, hectic fever, transient rash and visceral lesions such as pleuropericarditis, lymphadenopathy and hepato splenomegaly. Although kidney involvement may appear in some cases of AOSD, minimal glomerular lesion (MGL) has not been described. We describe a female patient, who presented with multisystemic manifestations, including high spiking fever, arthralgias, striking hyperferritinemia, and proteinuria. Renal biopsy showed classic MGL. A diagnosis of AOSD was made on the basis of Yamaguchi’s criteria. The patient was treated with steroids, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria, thereby strongly suggesting a causative link between AOSD and MGL in this patient. Renal involvement in the AOSD was rarely reported in the literature. MGL may be a cause of unexplained proteinuria in AOSD. In this situation, renal biopsy is necessary to establish a definitive diagnosis.

  2. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region

    SciTech Connect

    Stoilova, D.; Trifan, O.C.; Sarfarazi, M.

    1996-08-15

    Primary open angle glaucoma (GLC1) is a common ocular disorder with a characteristic degeneration of the optic nerve and visual field defects that is often associated with an elevated intraocular pressure. The severe but rare juvenile-onset type has previously been mapped to 1q21-q31, and its genetic heterogeneity has been established. Herein, we present a new locus (GLC1B) for one form of GLC1 on chromosome 2cen-q13 with a clinical presentation of low to moderate intraocular pressure, onset in late 40s, and a good response to medical treatment. Two-point and haplotype analyses of affected and unaffected meioses in six families provided maximum linkage information with D2S417, GATA112EO3, D2S113, D2S373, and D2S274 (lod scores ranging from 3.11 to 6.48) within a region of 8.5 cM that is flanked by D2S2161 and D2S2264. Analysis of affected meioses alone revealed no recombination with an additional two markers (D2S2264 and D2S135) in a region of 11.2 cM that is flanked by D2S2161 and D2S176. Analysis of unaffected meioses identified only one healthy 86-year-old male who has inherited the entire affected haplotype and, hence, is a gene carrier for this condition. Eight additional families with similar and/or different clinical presentation did not show any linkage to this region and, therefore, provided evidence for genetic heterogeneity of adult-onset primary open angle glaucoma. 63 refs., 2 figs., 2 tabs.

  3. Intrauterine protein restriction combined with early postnatal overfeeding was not associated with adult-onset obesity but produced glucose intolerance by pancreatic dysfunction

    PubMed Central

    2013-01-01

    We investigated if whether intrauterine protein restriction in combination with overfeeding during lactation would cause adult-onset obesity and metabolic disorders. After birth, litters from dams fed with control (17% protein) and low protein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CC and LC groups, respectively) pups. All of the offspring were fed a diet containing 12% protein from the time of weaning until they were 90 d old. Compared to the CC and LC groups, the CO and LO groups had higher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lower brown adipose tissue weight and lipid content and greater weight gain and absolute and relative white adipose tissue weight and absolute lipid content. Compared with the CO and CC rats, the LC and LO rats exhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygen consumption, carbon dioxide production and spontaneous activity, increased relative retroperitoneal adipose tissue weight and unaltered absolute white adipose tissue weight and lipid content. The fasting serum glucose was similar among the groups. The area under the glucose curve was higher in the LO and CO rats than in the LC and CC rats. The basal insulinemia and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in the LO group than in the other groups. The total area under the insulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats. Kitt was higher in the LO, LC and CO groups than in the CC group. Thus, intrauterine protein restriction followed by overfeeding during lactation did not induce obesity, but produced glucose intolerance by impairing pancreatic function in adulthood. PMID:23305533

  4. Intrauterine protein restriction combined with early postnatal overfeeding was not associated with adult-onset obesity but produced glucose intolerance by pancreatic dysfunction.

    PubMed

    Coutinho, Grazielle Vitória Ponti; Coutinho, Felipe Rodrigues; Faiad, Jaline Zandonato; Taki, Marina Satie; de Lima Reis, Silvia Regina; Ignácio-Souza, Letícia Martins; Paiva, Adriene Alexandra; Latorraca, Márcia Queiroz; Gomes-da-Silva, Maria Helena Gaíva; Martins, Maria Salete Ferreira

    2013-01-01

    We investigated if whether intrauterine protein restriction in combination with overfeeding during lactation would cause adult-onset obesity and metabolic disorders. After birth, litters from dams fed with control (17% protein) and low protein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CC and LC groups, respectively) pups. All of the offspring were fed a diet containing 12% protein from the time of weaning until they were 90 d old. Compared to the CC and LC groups, the CO and LO groups had higher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lower brown adipose tissue weight and lipid content and greater weight gain and absolute and relative white adipose tissue weight and absolute lipid content. Compared with the CO and CC rats, the LC and LO rats exhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygen consumption, carbon dioxide production and spontaneous activity, increased relative retroperitoneal adipose tissue weight and unaltered absolute white adipose tissue weight and lipid content. The fasting serum glucose was similar among the groups. The area under the glucose curve was higher in the LO and CO rats than in the LC and CC rats. The basal insulinemia and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in the LO group than in the other groups. The total area under the insulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats. Kitt was higher in the LO, LC and CO groups than in the CC group. Thus, intrauterine protein restriction followed by overfeeding during lactation did not induce obesity, but produced glucose intolerance by impairing pancreatic function in adulthood. PMID:23305533

  5. Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency

    PubMed Central

    Stender, Stefan; Chakrabarti, Rima S.; Xing, Chao; Gotway, Garrett; Cohen, Jonathan C.; Hobbs, Helen H.

    2016-01-01

    Background The etiology of liver disease remains elusive in some adults presenting with severe hepatic dysfunction. Methods and results Here we describe a woman of Pakistani descent who had elevated aminotransferases at age 23. She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29. She died without a diagnosis at age 32 after having a liver transplant. Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase. SAH hydrolase catalyzes the final step in conversion of methionine to homocysteine and inactivating mutations in this enzyme cause a rare autosomal recessive disorder, SAH hydrolase deficiency, that typically presents in infancy. An asymptomatic 7-year old son of the proband is also homozygous for the AHCY-R49H mutation and has elevated serum aminotransferase levels, as well as markedly elevated serum levels of SAH, S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH hydrolase deficiency. Conclusion This report reveals several new aspects of SAH hydrolase deficiency. Affected women with SAH hydrolase deficiency can give birth to healthy children. SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma. The measurement of serum amino acids should be considered in patients with liver disease or hepatocellular carcinoma of unknown etiology. PMID:26527160

  6. Molecular imaging of stem cell transplantation for neurodegenerative diseases.

    PubMed

    Wang, Ping; Moore, Anna

    2012-01-01

    Cell replacement therapy with stem cells holds tremendous therapeutic potential for treating neurodegenerative diseases. Over the last decade, molecular imaging techniques have proven to be of great value in tracking transplanted cells and assessing the therapeutic efficacy. This current review summarizes the role and capabilities of different molecular imaging modalities including optical imaging, nuclear imaging and magnetic resonance imaging in the field of stem cell therapy for neurodegenerative disorders. We discuss current challenges and perspectives of these techniques and encompass updated information such as theranostic imaging and optogenetics in stem cell-based treatment of neurodegenerative diseases.

  7. Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease.

    PubMed

    Abeliovich, Asa; Doege, Claudia A

    2009-02-12

    The recent description of somatic cell reprogramming to an embryonic stem (ES) cell-like phenotype, termed induced pluripotent stem (iPS) cell technology, presents an exciting potential venue toward cell-based therapeutics and disease models for neurodegenerative disorders. Two recent studies (Dimos et al. and Ebert et al.) describe the initial characterization of neurodegenerative disease patient-derived iPS cell cultures as proof of concept for the utility of this technology.

  8. Adult-Onset Fatal Neurohepatopathy in a Woman Caused by MPV17 Mutation.

    PubMed

    Mendelsohn, Bryce A; Mehta, Neil; Hameed, Bilal; Pekmezci, Melike; Packman, Seymour; Ralph, Jeffrey

    2014-01-01

    Hepatocerebral mitochondrial DNA depletion syndromes are classically considered diseases of early childhood, typically affecting the liver, peripheral, and central nervous systems with a rapidly progressive course. Evidence is emerging that initial symptom onset can extend into adulthood, though few such cases have been reported. We describe a 25-year-old woman who presented initially with secondary amenorrhea, followed by a megaloblastic anemia, lactic acidosis, leukoencephalopathy, progressive peripheral neuropathy, and liver cirrhosis. An apparently homozygous P98L mutation was identified in MPV17, a gene associated with a lethal infantile neurohepatopathy. Homozygosity for the same allele was recently reported in a man with a similar hepatic and neurologic phenotype. This is the first clinical report of an adult female with this disorder, and the first to describe amenorrhea and megaloblastic anemia as likely associated symptoms. PMID:24190800

  9. Delineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging

    PubMed Central

    Yu, Hongjun; Nie, Binbin; Li, Na; Luo, Chunrong; Li, Haijun; Liu, Fang; Bai, Yan; Shan, Baoci; Xu, Lin; Xu, Xiufeng

    2014-01-01

    Background Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD. Method In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 18–45 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms. Results Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (18–29 years old) and LO (30–45 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms. Conclusion Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance. Trial Registration ClinicalTrials.gov NCT00703742 PMID:25393297

  10. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies

    PubMed Central

    Valera, Elvira; Masliah, Eliezer

    2013-01-01

    Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer’s disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson’s disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (Aβ) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, α-synuclein (α-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of α-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting Aβ, α-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on α-synucleinopathies. PMID:23384597

  11. Resveratrol: A Focus on Several Neurodegenerative Diseases

    PubMed Central

    Tellone, Ester; Galtieri, Antonio; Russo, Annamaria; Giardina, Bruno; Ficarra, Silvana

    2015-01-01

    Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong. PMID:26180587

  12. Sporadic early adult-onset distal myopathy with rimmed vacuoles: immunohistochemistry and electron microscopy.

    PubMed

    Ceuterick, C; Martin, J J

    1996-08-01

    We report the histoenzymology, immunohistochemistry and electron microscopy of the tibialis anterior muscle of a 50-year-old male patient affected by a sporadic distal myopathy with onset during adolescence. There was no family history of muscle disorder and no clinical signs of cardiomyopathy. Extremely large variations in muscle fibre diameter (the size of some fibres exceeding 200-250 microns), rimmed vacuoles, necrotic fibres invaded by macrophages, atrophic fibres and perimysial fibrosis were observed. Using a wide range of antibodies raised against membrane- and cytoskeletal muscle proteins, granular desmin immunoreactivity was observed in muscle fibre lesions. There were no inflammatory parameters. Of special interest was the occurrence of autophagic vacuoles without 18-20 nm thick sarcoplasmic filaments and the presence of small aggregates of intermediate desmin-like filaments among a great diversity of ultrastructural findings. The morphological differential diagnosis is discussed. Our results stress the importance of combined immunohistochemistry and electron microscopy in the delineation of distal myopathies. DNA defects, however, still have to be identified which would improve the present classifications of distal myopathies.

  13. Inflammation in neurodegenerative diseases--an update.

    PubMed

    Amor, Sandra; Peferoen, Laura A N; Vogel, Daphne Y S; Breur, Marjolein; van der Valk, Paul; Baker, David; van Noort, Johannes M

    2014-06-01

    Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases. PMID:24329535

  14. Inflammation in neurodegenerative diseases--an update.

    PubMed

    Amor, Sandra; Peferoen, Laura A N; Vogel, Daphne Y S; Breur, Marjolein; van der Valk, Paul; Baker, David; van Noort, Johannes M

    2014-06-01

    Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases.

  15. Stem cell-based models and therapies for neurodegenerative diseases.

    PubMed

    Iyer, Shilpa; Alsayegh, Khaled; Abraham, Sheena; Rao, Raj R

    2009-01-01

    Multiple neurodegenerative disorders typically result from irrevocable damage and improper functioning of specialized neuronal cells or populations of neuronal cells. These disorders have the potential to contribute to an already overburdened health care system unless the progression of neurodegeneration can be altered. Progress in understanding neurodegenerative cell biology has been hampered by a lack of predictive and, some would claim, relevant cellular models. Additionally, the research needed to develop new drugs and determine methods for repair or replacement of damaged neurons is severely hampered by the lack of an adequate in vitro human neuron cell-based model. In this context, pluripotent stem cells and neural progenitors and their properties including unlimited proliferation, plasticity to generate other cell types, and a readily available source of cells--pose an excellent alternative to ex vivo primary cultures or established immortalized cell lines in contributing to our understanding of neurodegenerative cell biology and our ability to analyze the therapeutic or cytotoxic effects of chemicals, drugs, and xenobiotics. Many questions that define the underlying "genesis" of the neuronal death in these disorders also remain unanswered, with evidence suggesting a key role for mitochondrial dysfunction. The assessment of stem cells, neural progenitors, and engineered adult cells can provide useful insights into neuronal development and neurodegenerative processes. Finally, the potential for a combination of cell- and gene-based therapeutics for neurodegenerative disorders is also discussed.

  16. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  17. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

    PubMed

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole; Perrier, Anselme L; Humbert, Sandrine

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

  18. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

    PubMed Central

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

    2013-01-01

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

  19. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes.

    PubMed

    Luque, Raul M; Lin, Qing; Córdoba-Chacón, José; Subbaiah, Papasani V; Buch, Thorsten; Waisman, Ari; Vankelecom, Hugo; Kineman, Rhonda D

    2011-01-19

    Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre(+/-),iDTR(+/-) offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre(-/-),iDTR(+/-) mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes.

  20. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.

    PubMed

    Kim, Eun-Joo; Shin, Jin-Hong; Lee, Jeong Hee; Kim, Jong Hun; Na, Duk L; Suh, Yeon-Lim; Hwang, Sun Jae; Lee, Jae-Hyeok; Lee, Young Min; Shin, Myung-Jun; Lee, Myung Jun; Kim, Seong-Jang; Yoon, Uicheul; Park, Do Youn; Jung, Dae Soo; Ahn, Jae Woo; Sung, Suk; Huh, Gi Yeong

    2015-02-15

    We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

  1. Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

    PubMed

    Sugai, Fuminobu; Baba, Kousuke; Toyooka, Keiko; Liang, Wen-Chen; Nishino, Ichizo; Yamadera, Misaki; Sumi, Hisae; Fujimura, Harutoshi; Nishikawa, Yoshiro

    2012-02-01

    We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content. PMID:21907580

  2. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review.

    PubMed

    Watanabe, Eri; Sugawara, Hitoshi; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  3. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  4. The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia

    PubMed Central

    Zhang, Qifeng; Smethurst, Elizabeth; Segonds-Pichon, Anne; Schrewe, Heinrich; Wakelam, Michael J. O.

    2016-01-01

    Phospholipase D2 (PLD2) is an enzyme that produces phosphatidic acid (PA), a lipid messenger molecule involved in a number of cellular events including, through its membrane curvature properties, endocytosis. The PLD2 knock out (PLD2KO) mouse has been previously reported to be protected from insult in a model of Alzheimer's disease. We have further analysed a PLD2KO mouse using mass spectrophotometry of its lipids and found significant differences in PA species throughout its brain. We have examined the expression pattern of PLD2 which allowed us to define which region of the brain to analyse for defect, notably PLD2 was not detected in glial-rich regions. The expression pattern lead us to specifically examine the mitral cells of olfactory bulbs, the Cornus Amonis (CA) regions of the hippocampus and the Purkinje cells of the cerebellum. We find that the change to longer PA species correlates with subtle architectural defect in the cerebellum, exemplified by ectopic Purkinje cells and an adult-onset deficit of olfaction. These observations draw parallels to defects in the reelin heterozygote as well as the effect of high fat diet on olfaction. PMID:27658289

  5. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.

  6. Adult-onset Kawasaki disease (mucocutaneous lymph node syndrome) and concurrent Coxsackievirus A4 infection: a case report

    PubMed Central

    Ueda, Yuki; Kenzaka, Tsuneaki; Noda, Ayako; Yamamoto, Yu; Matsumura, Masami

    2015-01-01

    Introduction Kawasaki disease (KD) most commonly develops in infants, although its specific cause is still unclear. We report here a rare case of adult-onset KD which revealed to be concurrently infected by Coxsackievirus A4. Case presentation The patient was a 37-year-old Japanese man who presented with fever, exanthema, changes in the peripheral extremities, bilateral non-exudative conjunctival injection, and changes in the oropharynx, signs that meet the diagnostic criteria for KD defined by the Centers for Disease Control and Prevention. In this case, the patient had a significantly high antibody titer for Coxsackievirus A4, which led us to presume that the occurrence of KD was concurrent Coxsackievirus A4 infection. Conclusion We reported a very rare case of KD which suggests that the disease can be concurrent Coxsackievirus A4 infection. Although KD is an acute childhood disease, with fever as one of the principal features, KD should also be considered in the differential diagnosis when adult patients present with a fever of unknown cause associated with a rash. PMID:26491373

  7. Relationship between neuropsychological impairment and grey and white matter changes in adult-onset myotonic dystrophy type 1.

    PubMed

    Baldanzi, Sigrid; Cecchi, Paolo; Fabbri, Serena; Pesaresi, Ilaria; Simoncini, Costanza; Angelini, Corrado; Bonuccelli, Ubaldo; Cosottini, Mirco; Siciliano, Gabriele

    2016-01-01

    Myotonic dystrophy type 1 (DM1) has a wide phenotypic spectrum and potentially may affect central nervous system with mild to severe involvement. Our aim was to investigate grey matter (GM) and white matter (WM) structural alterations in a sample of adult-onset DM1 patients and to evaluate relationship with clinical and cognitive variables. Thirty DM1 patients underwent neuropsychological investigation and 3T-MRI protocol. GM and WM changes were evaluated calculating brain parenchymal fraction (BPF), voxel-based morphometry (VBM), white matter lesion load (LL% and Fazekas scale) and tract based spatial statistical (TBSS). Patients showed main impairment in tests exploring executive and mnesic domains with visuo-spatial involvement, significantly related to BPF. VBM revealed clusters of widespread GM reduction and TBSS revealed areas of decreased fractional anisotropy (FA) and increased radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD) in patients compared to a group of matched healthy controls. Multiple regression analyses showed areas of significant negative relationship between left temporal atrophy and verbal memory, between RD and mnesic and visuo-spatial cognitive domains, and between AD and verbal memory. TBSS results indicate that the involvement of normal appearance WM, beyond the signal changes detected with conventional MR imaging (Fazekas scale and LL%), was associated with neuropsychological deficit. These data suggest that disrupted complex neuronal networks can underlie cognitive-behavioural dysfunctions in DM1. PMID:27437180

  8. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

    PubMed Central

    Gao, Hui-Ming; Hong, Jau-Shyong

    2016-01-01

    Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. PMID:18599350

  9. Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

    PubMed Central

    Rama Rao, Kakulavarapu V.; Kielian, Tammy

    2015-01-01

    Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron–astrocyte cross-talk in the context of select neurodegenerative diseases. PMID:26543505

  10. Indian Herbs for the Treatment of Neurodegenerative Disease.

    PubMed

    Mannangatti, Padmanabhan; Naidu, Kamalakkannan Narasimha

    2016-01-01

    Ayurveda, an ancient system of medicine that is indigenous to India, is believed to be the world's oldest comprehensive health-care system and is now one of the most recognized and widely practiced disciplines of alternative medicine in the world. Medicinal herbs have been in use for treating diseases since ancient times in India. Ayurvedic therapies with medicinal herbs and herbomineral products generally provide relief without much adverse effects even after prolonged administration. Neurodegenerative disorders are a major cause of mortality and disability, and increasing life spans represent one of the key challenges of medical research. Ayurvedic medicine describes most neurodegenerative diseases and has defined a number of plants with therapeutic benefits for the treatment of neurodegenerative diseases having antioxidant activities. In this chapter, the role of four important Ayurvedic medicinal plants, viz., Withania somnifera (ashwagandha), Bacopa monnieri (brahmi), Centella asiatica (gotu kola), and Mucuna pruriens (velvet bean), on neurodegenerative diseases are discussed. PMID:27651261

  11. Neurodegenerative disease high-field imaging

    PubMed Central

    van der Grond, J.; van Buchem, M.A.; van Zijl, P.; Webb, A.G.

    2012-01-01

    High field magnetic resonance imaging is showing potential for imaging of neurodegenerative diseases. 7 T MRI is beginning to be used in a clinical research setting and the theoretical benefits, i.e. higher signal-to-noise, sensitivity to iron, improved MRA and increased spectral resolution in spectroscopy are being confirmed. Despite the limited number of studies to date, initial results in patients with multiple sclerosis, Alzheimer’s disease and Huntington’s disease show promising additional features in contrast that may assist in better diagnosis of these disorders. PMID:22548926

  12. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q

    SciTech Connect

    Morissette, J.; Plante, M.; Raymond, V.

    1995-06-01

    Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members >35 years of age, except for three obligatory carriers. Key combination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years. 49 refs., 4 figs., 2 tabs.

  13. Prolonged remission state of refractory adult onset Still's disease following CD34-selected autologous peripheral blood stem cell transplantation.

    PubMed

    Lanza, F; Dominici, M; Govoni, M; Moretti, S; Campioni, D; Corte, R L; Latorraca, A; Tieghi, A; Castagnari, B; Trotta, F; Castoldi, G

    2000-06-01

    We report a 38-year-old patient affected by refractory adult onset Still's disease who achieved a prolonged remission following CD34-selected ABMT. The conditioning regimen was based on the use of CY and anti-thymocyte globulin. A 3.0 and 2.0 log reduction of T (CD3+) and B (CD19+) lymphocytes, respectively, was obtained using a Ceprate device to select CD34+ cells from PBSC. In the pre-transplant period (1994-1998) the patient had a chronic persistent disease course with frequent and recurrent systemic articular flares and loss of some functional abilities, despite daily prednisone, pulses of CY and immunosuppressive therapy (CYA or MTX). At the time of ABMT the patient had become non-ambulatory. Within 3 weeks of ABMT the patient showed a marked decrease in joint swelling, and morning stiffness. Joint pain and systemic symptoms disappeared, the patient was able to walk and run and gained general well being. ESR, C-reactive protein and WBC count were significantly decreased, while Hb level increased. This partial remission persisted for at least 1 year after ABMT, although at 15 months of follow-up a reappearance of moderate synovitis in the knees and wrists was noted. Our data further showed that both patient BM microenvironment and stem-progenitor cell function (as assessed by LTC-IC assay) were damaged even 1 year after CD34-selected ABMT, suggesting that the persistence of these alterations could have facilitated the favorable outcome of the disease following ABMT. Bone Marrow Transplantation (2000) 25, 1307-1310. PMID:10871738

  14. Parenchymal lung involvement in adult-onset Still disease: A STROBE-compliant case series and literature review.

    PubMed

    Gerfaud-Valentin, Mathieu; Cottin, Vincent; Jamilloux, Yvan; Hot, Arnaud; Gaillard-Coadon, Agathe; Durieu, Isabelle; Broussolle, Christiane; Iwaz, Jean; Sève, Pascal

    2016-07-01

    Parenchymal lung involvement (PLI) in adult-onset Still's disease (AOSD) has seldom, if ever, been studied. We examine here retrospective cohort AOSD cases and present a review of the literature (1971-2014) on AOSD-related PLI cases.Patients with PLI were identified in 57 AOSD cases. For inclusion, the patients had to fulfill Yamaguchi or Fautrel classification criteria, show respiratory symptoms, and have imaging evidence of pulmonary involvement, and data allowing exclusion of infectious, cardiogenic, toxic, or iatrogenic cause of PLI should be available. This AOSD + PLI group was compared with a control group (non-PLI-complicated AOSD cases from the same cohort).AOSD + PLI was found in 3 out of the 57 patients with AOSD (5.3%) and the literature mentioned 27 patients. Among these 30 AOSD + PLI cases, 12 presented an acute respiratory distress syndrome (ARDS) and the remaining 18 another PLI. In the latter, a nonspecific interstitial pneumonia computed tomography pattern prevailed in the lower lobes, pulmonary function tests showed a restrictive lung function, the alveolar differential cell count was neutrophilic in half of the cases, and the histological findings were consistent with bronchiolitis and nonspecific interstitial pneumonia. Corticosteroids were fully efficient in all but 3 patients. Ten out of 12 ARDS cases occurred during the first year of the disease course. All ARDS-complicated AOSD cases received corticosteroids with favorable outcomes in 10 (2 deceased). Most PLIs occurred during the systemic onset of AOSD.PLI may occur in 5% of AOSDs, of which ARDS is the most severe. Very often, corticosteroids are efficient in controlling this complication. PMID:27472698

  15. Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

    PubMed Central

    Ren, Hong; Liu, Jian; Zhang, Weijia; Wei, Chengguo; Xu, Jing; Zhang, Wen; Li, Xiao; Wang, Weiming; Lv, Danfeng; He, John Cijiang; Chen, Nan

    2015-01-01

    Objective To search for biomarkers to differentiate primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Methods We isolated glomeruli from kidney biopsies of 6 patients with adult-onset steroid sensitiveFSGS and 5 patients with MCD, and compared the profiles of glomerular transcriptomes between the two groups of patients using microarray analysis. Results Analysis of differential expressed genes (DEGs) revealed that up-regulated DEGs in FSGS patients compared with MCD patients were primarily involved in spermatogenesis, gamete generation, regulation of muscle contraction, response to unfolded protein, cell proliferation and skeletal system development. The down-regulated DEGs were primarily related to metabolic process, intracellular transport, oxidation/reduction andestablishment of intracellular localization. We validated the expression of the top 6 up-regulated and top 6 down-regulated DEGs using real-time PCR. Membrane metallo-endopeptidase (MME) is a down-regulated gene that was previously identified as a key gene for kidney development. Immunostaining confirmed that the protein expression of MME decreased significantly in FSGS kidneys compared with MCD kidneys. Conclusions This report was the first study to examine transcriptomes in Chinese patients with various glomerular diseases. Expressions of MME both in RNA and protein level decreased significantly in glomeruli of FSGS kidneys compared with MCD kidneys. Our data suggested that MME might play a role in the normal physiological function of podocytes and a decrease in MME expression might be related to podocyte injury. We also identified genes and pathways specific for FSGS versus MCD, and our data could help identify potential new biomarkers for the differential diagnosis between these two diseases. PMID:26536600

  16. Apraxias in Neurodegenerative Dementias

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Abbas, Mirza Masoom

    2015-01-01

    Background: Apraxia is a state of inability to carry out a learned motor act in the absence of motor, sensory or cerebellar defect on command processed through the Praxis circuit. Breakdown in default networking is one of the early dysfunction in cortical dementias and result in perplexity, awkwardness, omission, substitution errors, toying behavior and unrecognizable gestures in response to command with voluntary reflex dissociation where, when unobserved patient will carry out reflex movements normally. Awareness into the organicity of these phenomenas will help in early diagnosis, which will help in initiating appropriate treatment and slowing down the progression of the disease. Aims and Objectives: The aim was to look for the various kinds of apraxias in patients with dementia using appropriate simple tests. Patients and Methods: Three hundred patients satisfying Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia were evaluated in detail with mandatory investigations for dementia followed by testing for ideational, ideomotor, limb-kinetic, buccopharyngeal, dressing apraxia, constructional apraxia and gait apraxias in addition to recording of rare apraxias when present. Results: Alzheimer's disease showed maximum association with apraxias in all the phases of the disease ideational, ideomotor, dressing and constructional apraxias early and buccopharyngeal and gait apraxia late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxias late into the disease. Cortical basal ganglionic degeneration showed limb apraxias and diffuse Lewy body disease showed more agnosias and less apraxias common apraxias seen was Ideational and Ideomotor. Conclusion: Recognition of the apraxias help in establishing organicity, categorization, caregiver education, early strategies for treatment, avoiding anti-psychotics and introducing disease modifying pharmacotherapeutic agents and also prognosticating. PMID:25722511

  17. Solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment

    PubMed Central

    Cohen, Philip R.

    2016-01-01

    Background: Mastocytosis is either cutaneous (with skin-limited proliferation of mast cells) or systemic (with mast cells in extracutaneous sites). The onset of solitary mastocytoma in an adult is rare. Purpose: A woman with the new onset of solitary mastocytoma is described. The clinical features of patients with adult-onset solitary mastocytoma are summarized. Recommendations for the evaluation and treatment of individuals with adult-onset solitary mastocytoma are proposed. Methods: PubMed was searched with the key words: adult, CD2, CD25, cell, cutaneous, disease, KIT, KIT D816V, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, and urticarial. The papers generated by the search, and their references, were reviewed. Results: A 38-year-old Taiwanese woman presented with an asymptomatic brown patch, which morphologically mimicked a dysplastic nevus, on her right abdomen; biopsy demonstrated a solitary mastocytoma. Comprehensive evaluation (including serologic and bone marrow examination) excluded systemic mastocytosis and her residual mastocytoma is being monitored. Adult-onset solitary mastocytoma has been described in 16 patients. Lesions were either on the head and neck (5/14), torso (5/14) or extremities (4/14). Urtication following lesion rubbing was noted in 79% (11/14) of patients. Excision of the mastocytoma [75% (9/12)] was the most common treatment. Other management approaches included corticosteroids (topical or intralesional), antihistamines (systemic) or observation. Systemic symptoms were noted in 5 patients: flushing (3 women) and pruritus (3 women); gastrointestinal symptoms and headaches, flushing and/or anaphylaxis were each noted in one woman. None of the patients with adult-onset solitary mastocytoma had systemic mastocytosis; however, only 3 women were evaluated for systemic mastocytosis. Conclusions: Systemic mastocytosis is common in adults with new onset cutaneous mastocytosis. Therefore, a conservative work up for new onset

  18. Solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment

    PubMed Central

    Cohen, Philip R.

    2016-01-01

    Background: Mastocytosis is either cutaneous (with skin-limited proliferation of mast cells) or systemic (with mast cells in extracutaneous sites). The onset of solitary mastocytoma in an adult is rare. Purpose: A woman with the new onset of solitary mastocytoma is described. The clinical features of patients with adult-onset solitary mastocytoma are summarized. Recommendations for the evaluation and treatment of individuals with adult-onset solitary mastocytoma are proposed. Methods: PubMed was searched with the key words: adult, CD2, CD25, cell, cutaneous, disease, KIT, KIT D816V, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, and urticarial. The papers generated by the search, and their references, were reviewed. Results: A 38-year-old Taiwanese woman presented with an asymptomatic brown patch, which morphologically mimicked a dysplastic nevus, on her right abdomen; biopsy demonstrated a solitary mastocytoma. Comprehensive evaluation (including serologic and bone marrow examination) excluded systemic mastocytosis and her residual mastocytoma is being monitored. Adult-onset solitary mastocytoma has been described in 16 patients. Lesions were either on the head and neck (5/14), torso (5/14) or extremities (4/14). Urtication following lesion rubbing was noted in 79% (11/14) of patients. Excision of the mastocytoma [75% (9/12)] was the most common treatment. Other management approaches included corticosteroids (topical or intralesional), antihistamines (systemic) or observation. Systemic symptoms were noted in 5 patients: flushing (3 women) and pruritus (3 women); gastrointestinal symptoms and headaches, flushing and/or anaphylaxis were each noted in one woman. None of the patients with adult-onset solitary mastocytoma had systemic mastocytosis; however, only 3 women were evaluated for systemic mastocytosis. Conclusions: Systemic mastocytosis is common in adults with new onset cutaneous mastocytosis. Therefore, a conservative work up for new onset

  19. Adult-Onset Obesity Reveals Prenatal Programming of Glucose-Insulin Sensitivity in Male Sheep Nutrient Restricted during Late Gestation

    PubMed Central

    Rhodes, Philip; Craigon, Jim; Gray, Clint; Rhind, Stuart M.; Loughna, Paul T.; Gardner, David S.

    2009-01-01

    Background Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. Methods/Principal Findings Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1–65 days; LEE, n = 6) or late (65–128 days; LEL, n = 7) gestation (term ∼147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6–7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were ‘lean’ (1.5 years). Obesity revealed generalised metabolic ‘inflexibility’ and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulinAUC (from 133 to 341 [s.e.d. 26] ng.ml−1.120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml−1) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml−1; LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. Conclusions This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and ‘reveals’ programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young

  20. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Conclusion Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC. PMID:23050789

  1. Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study

    PubMed Central

    Schwingenschuh, Petra; Ruge, Diane; Edwards, Mark J; Terranova, Carmen; Katschnig, Petra; Carrillo, Fatima; Silveira-Moriyama, Laura; Schneider, Susanne A; Kägi, Georg; Dickson, John; Lees, Andrew J; Quinn, Niall; Mir, Pablo; Rothwell, John C; Bhatia, Kailash P

    2010-01-01

    different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs. PMID:20131394

  2. The role of mitochondria in inherited neurodegenerative diseases.

    PubMed

    Kwong, Jennifer Q; Beal, M Flint; Manfredi, Giovanni

    2006-06-01

    In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases. PMID:16805775

  3. Engineering enhanced protein disaggregases for neurodegenerative disease

    PubMed Central

    Jackrel, Meredith E; Shorter, James

    2015-01-01

    Abstract Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones. PMID:25738979

  4. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease.

    PubMed

    Hroudová, Jana; Singh, Namrata; Fišar, Zdeněk

    2014-01-01

    Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

  5. Contributions of isolated Pacific populations to understanding neurodegenerative diseases.

    PubMed

    Garruto, Ralph M; Yanagihara, Richard

    2009-01-01

    Isolated human populations have provided a natural experimental laboratory for the ongoing study of human disease. In the mid-20th century a number of high-incidence foci of neurodegenerative diseases were brought to medical attention including kuru, amyotrophic lateral sclerosis, and parkinsonism-dementia. These foci were discovered in Papua New Guinea, West New Guinea, the Kii Peninsula of Japan, and in the Mariana Islands. The study of these diseases in isolated human groups has significantly contributed to our understanding of the cause and mechanisms of pathogenesis of these and related neurodegenerative disorders globally. This paper is dedicated to D. Carleton Gajdusek, a pioneer in the study of neurodegenerative diseases, whose decades of fieldwork and laboratory studies have led to numerous scientific discoveries that have reshaped our thinking and understanding about neurodegeneration.

  6. Biomarker Discovery in Neurodegenerative Diseases: A Proteomic Approach

    PubMed Central

    Shi, Min; Caudle, W. Michael; Zhang, Jing

    2010-01-01

    Biomarkers for neurodegenerative disorders are essential to facilitate disease diagnosis, ideally at early stages, monitor disease progression, and assess response to existing and future treatments. Application of proteomics to the human brain, cerebrospinal fluid and plasma has greatly hastened the unbiased and high-throughput searches for novel biomarkers. There are many steps critical to biomarker discovery, whether for neurodegenerative or other diseases, including sample preparation, protein/peptide separation and identification, as well as independent confirmation and validation. In this review we have summarized current proteomics technologies involved in discovery of biomarkers for neurodegenerative diseases, practical considerations and limitations of several major aspects, as well as the current status of candidate biomarkers revealed by proteomics for Alzheimer and Parkinson diseases. PMID:18938247

  7. The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases

    PubMed Central

    Joshi, Gururaj; Johnson, Jeffrey A.

    2013-01-01

    Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer’s disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on targeted Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders. PMID:22742419

  8. Quantitative interaction proteomics of neurodegenerative disease proteins.

    PubMed

    Hosp, Fabian; Vossfeldt, Hannes; Heinig, Matthias; Vasiljevic, Djordje; Arumughan, Anup; Wyler, Emanuel; Landthaler, Markus; Hubner, Norbert; Wanker, Erich E; Lannfelt, Lars; Ingelsson, Martin; Lalowski, Maciej; Voigt, Aaron; Selbach, Matthias

    2015-05-19

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

  9. Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Donnelier, Julien; Braun, Samuel T.; Dolzhanskaya, Natalia; Ahrendt, Eva; Braun, Andrew P.; Velinov, Milen; Braun, Janice E. A.

    2015-01-01

    Cysteine string protein (CSPα) is a presynaptic J protein co-chaperone that opposes neurodegeneration. Mutations in CSPα (i.e., Leu115 to Arg substitution or deletion (Δ) of Leu116) cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly inherited neurodegenerative disease. We have previously demonstrated that CSPα limits the expression of large conductance, calcium-activated K+ (BK) channels in neurons, which may impact synaptic excitability and neurotransmission. Here we show by western blot analysis that expression of the pore-forming BKα subunit is elevated ~2.5 fold in the post-mortem cortex of a 36-year-old patient with the Leu116∆ CSPα mutation. Moreover, we find that the increase in BKα subunit level is selective for ANCL and not a general feature of neurodegenerative conditions. While reduced levels of CSPα are found in some postmortem cortex specimens from Alzheimer’s disease patients, we find no concomitant increase in BKα subunit expression in Alzheimer’s specimens. Both CSPα monomer and oligomer expression are reduced in synaptosomes prepared from ANCL cortex compared with control. In a cultured neuronal cell model, CSPα oligomers are short lived. The results of this study indicate that the Leu116∆ mutation leads to elevated BKα subunit levels in human cortex and extend our initial work in rodent models demonstrating the modulation of BKα subunit levels by the same CSPα mutation. While the precise sequence of pathogenic events still remains to be elucidated, our findings suggest that dysregulation of BK channels may contribute to neurodegeneration in ANCL. PMID:25905915

  10. Metal imaging in neurodegenerative diseases

    PubMed Central

    Bourassa, Megan W.

    2014-01-01

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

  11. Pulmonary arterial hypertension secondary to adult-onset Still's disease: Response to cyclosporine and sildenafil over 15 years of follow-up.

    PubMed

    Weatherald, Jason; Lategan, Johan; Helmersen, Doug

    2016-01-01

    Adult onset Still's disease (AOSD) is an autoimmune disease characterized by systemic inflammation and is a rarely reported cause of pulmonary arterial hypertension (PAH). We describe the clinical course of a 40-year-old woman who presented with PAH 19 months after a diagnosis of AOSD. Sildenafil and immunosuppressive therapy with cyclosporine resulted in clinical and hemodynamic improvement with long-term survival 15 years after her initial presentation of AOSD. We review the literature for published cases of PAH due to AOSD and discuss the potential mechanisms relating inflammatory diseases and PAH. PMID:27408785

  12. Adrenoleukodystrophy: new approaches to a neurodegenerative disease.

    PubMed

    Moser, Hugo W; Raymond, Gerald V; Dubey, Prachi

    2005-12-28

    X-linked adrenoleukodystrophy (X-ALD), which was first described in 1923, was viewed until 1976 as a rare and inexorably fatal neurodegenerative disorder that affected boys. The genetic defect and biochemical abnormalities have now been defined. Ongoing research has resulted in new findings: (1) there is a wide range of phenotypic expression. At least half of patients with X-ALD are adults with somewhat milder manifestations, and women who are carriers may become symptomatic. X-ALD is often misdiagnosed as attention-deficit/hyperactivity disorder in boys and as multiple sclerosis in men and women, and is not an uncommon cause of Addison disease; (2) the incidence of X-ALD, estimated to be 1:17,000 in all ethnic groups, approximates that of phenylketonuria; (3) noninvasive and presymptomatic diagnosis and prenatal diagnosis are available; family screening and genetic counseling are key to disease prevention; and (4) new therapies, applied early, show promise. Neonatal screening is likely to become available, and a wider awareness of X-ALD and its various modes of presentation permit new proactive approaches to this distressing disorder.

  13. Nocturnal hydration--an effective modality to reduce recurrent abdominal pain and recurrent pancreatitis in patients with adult-onset cystic fibrosis.

    PubMed

    Obideen, Kamil; Wehbi, Mohammad; Hoteit, Maarouf; Cai, Qiang

    2006-10-01

    Recurrent abdominal pain and recurrent pancreatitis are common problems associated with some patients with cystic fibrosis (CF). There is no known effective method to prevent recurrent abdominal pain and recurrent pancreatitis in such patients. The objective of this study was to determine whether nocturnal hydration (NH) prevents recurrent abdominal pain and recurrent acute pancreatitis in patients with adult-onset CF. Adult CF patients who were referred to our Pancreatic Diseases Clinic for recurrent abdominal pain and pancreatitis were enrolled in the study. Each patient was encouraged to drink plenty of water during the night and established a 6-month diary (3 months before and 3 months after NH was initiated), recording the frequency and severity of their abdominal pain, the amount of pain medication taken, and the volume of their water intake. We also reviewed the number of doctor's clinic visits, emergency room visits, and hospitalizations for about 1 year before and 1 year after the initiation of the NH. The frequency and the severity of abdominal pain in this group of patients were significantly reduced. The amount of pain medication and the number of emergency room visits and hospitalizations for abdominal pain and acute pancreatitis were reduced. NH is a simple and cost-effective method to prevent recurrent abdominal pain and pancreatitis in patients with adult-onset CF.

  14. An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene.

    PubMed

    Suzuki, Satoshi O; Iwaki, Toru; Arakawa, Kenji; Furuya, Hirokazu; Fujii, Naoki; Iwaki, Akiko

    2011-12-01

    We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin.

  15. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

    SciTech Connect

    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E.

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  16. Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy.

    PubMed

    Toyota, Tomoko; Akamatsu, Naoki; Tsuji, Sadatoshi; Nishizawa, Shigeru

    2014-06-01

    Recently, some reports have indicated that limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies (VGKC-Ab) is a cause of adult-onset mesial temporal lobe epilepsy (MTLE). We report a 53-year-old woman who had her first epileptic seizure at the age of 50 years old. Examination by 3-Tesla brain MRI revealed left hippocampal high signal intensity and swelling on fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging at 2 months after her first seizure. The patient received intravenous methylprednisolone and carbamazepine 300 mg/day. One month later, MRI revealed improvement of her left hippocampal abnormalities. Thereafter, she had no seizures, however, three years after her first seizure, EEG revealed a seizure pattern in the left temporal region. Brain MRI revealed left hippocampal high signal intensity and brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism. Her serum VGKC-Ab levels were 118 pM(normal < 100 pM). Intravenous methylprednisolone therapy was reinitiated. Two months later, her hippocampal abnormalities had improved and 3 months later her VGKC-Ab levels decreased to 4.4 pM. Remission of the epileptic seizures was also observed. This MTLE in the middle age was considered as limbic encephalitis associated with anti- VGKC-Ab. In cases of unexplained adult-onset MTLE, limbic encephalitis associated with anti-VGKC-Ab, which responds well to immunotherapy, should be considered in the differential diagnosis.

  17. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases.

    PubMed

    Duarte-Neves, Joana; Pereira de Almeida, Luís; Cavadas, Cláudia

    2016-11-01

    Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases.

  18. Microtubule-Stabilizing Agents as Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Brunden, Kurt R.; Trojanowski, John Q.; Smith, Amos B.; Lee, Virginia M.-Y.; Ballatore, Carlo

    2014-01-01

    Microtubules (MTs)1, cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. PMID:24433963

  19. Glutathione transferases and neurodegenerative diseases.

    PubMed

    Mazzetti, Anna Paola; Fiorile, Maria Carmela; Primavera, Alessandra; Lo Bello, Mario

    2015-03-01

    There is substantial agreement that the unbalance between oxidant and antioxidant species may affect the onset and/or the course of a number of common diseases including Parkinson's and Alzheimer's diseases. Many studies suggest a crucial role for oxidative stress in the first phase of aging, or in the pathogenesis of various diseases including neurological ones. Particularly, the role exerted by glutathione and glutathione-related enzymes (Glutathione Transferases) in the nervous system appears more relevant, this latter tissue being much more vulnerable to toxins and oxidative stress than other tissues such as liver, kidney or muscle. The present review addresses the question by focusing on the results obtained by specimens from patients or by in vitro studies using cells or animal models related to Parkinson's and Alzheimer's diseases. In general, there is an association between glutathione depletion and Parkinson's or Alzheimer's disease. In addition, a significant decrease of glutathione transferase activity in selected areas of brain and in ventricular cerebrospinal fluid was found. For some glutathione transferase genes there is also a correlation between polymorphisms and onset/outcome of neurodegenerative diseases. Thus, there is a general agreement about the protective effect exerted by glutathione and glutathione transferases but no clear answer about the mechanisms underlying this crucial role in the insurgence of neurodegenerative diseases.

  20. Cerebral correlates of psychotic syndromes in neurodegenerative diseases

    PubMed Central

    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 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. PMID:21418522

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

    PubMed Central

    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), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA), is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed. PMID:27313396

  2. Brief Report: No Association between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

    ERIC Educational Resources Information Center

    Schirmbeck, Frederike; Georgi, Alexander; Strohmaier, Jana; Schmael, Christine; Boesshenz, Katja V.; Muhleisen, Thomas W.; Herms, Stefan; Hoffmann, Per; Jamra, Rami Abou; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Nothen, Markus M.; Cichon, Sven; Rietschel, Marcella; Schulze, Thomas G.

    2008-01-01

    Whereas "Dysbindin" is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. ("J Autism Dev Disord"…

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

    NASA Astrophysics Data System (ADS)

    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.

  4. Neuroinflamm-aging and neurodegenerative diseases: an overview.

    PubMed

    Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

    2011-08-01

    Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

  5. Aging, Neurodegenerative Disease, and Traumatic Brain Injury: The Role of Neuroimaging

    PubMed Central

    Levine, Brian

    2015-01-01

    Abstract Traumatic brain injury (TBI) is a highly prevalent condition with significant effects on cognition and behavior. While the acute and sub-acute effects of TBI recover over time, relatively little is known about the long-term effects of TBI in relation to neurodegenerative disease. This issue has recently garnered a great deal of attention due to publicity surrounding chronic traumatic encephalopathy (CTE) in professional athletes, although CTE is but one of several neurodegenerative disorders associated with a history of TBI. Here, we review the literative on neurodegenerative disorders linked to remote TBI. We also review the evidence for neuroimaging changes associated with unhealthy brain aging in the context of remote TBI. We conclude that neuroimaging biomarkers have significant potential to increase understanding of the mechanisms of unhealthy brain aging and neurodegeneration following TBI, with potential for identifying those at risk for unhealthy brain aging prior to the clinical manifestation of neurodegenerative disease. PMID:25192426

  6. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

    PubMed Central

    Guo, Jing L; Lee, Virginia M Y

    2014-01-01

    A common feature of many neurodegenerative diseases is the deposition of β-sheet-rich amyloid aggregates formed by proteins specific to these diseases. These protein aggregates are thought to cause neuronal dysfunction, directly or indirectly. Recent studies have strongly implicated cell-to-cell transmission of misfolded proteins as a common mechanism for the onset and progression of various neurodegenerative disorders. Emerging evidence also suggests the presence of conformationally diverse ‘strains’ of each type of disease protein, which may be another shared feature of amyloid aggregates, accounting for the tremendous heterogeneity within each type of neurodegenerative disease. Although there are many more questions to be answered, these studies have opened up new avenues for therapeutic interventions in neurodegenerative disorders. PMID:24504409

  7. Episodic cervical dystonia associated with gastro-oesophageal reflux. A case of adult-onset Sandifer syndrome.

    PubMed

    Shahnawaz, M; van der Westhuizen, L R; Gledhill, R F

    2001-12-01

    Sandifer syndrome is a dystonic movement disorder described in children with severe gastro-oesophageal reflux. We now report a patient who had the features of Sandifer syndrome first developing in adult life. Onset of dystonic episodes followed closely the occurrence of a Bell's palsy, while symptoms of peptic oesophagitis had been present for several months beforehand. Successful symptomatic treatment of gastro-oesophageal reflux was accompanied by cessation of the dystonic episodes. Possible pathophysiological mechanisms of the abnormal movements in Sandifer syndrome are discussed. PMID:11714563

  8. Neuroprotection: the emerging concept of restorative neural stem cell biology for the treatment of neurodegenerative diseases.

    PubMed

    Carletti, Barbara; Piemonte, Fiorella; Rossi, Ferdinando

    2011-06-01

    During the past decades Neural Stem Cells have been considered as an alternative source of cells to replace lost neurons and NSC transplantation has been indicated as a promising treatment for neurodegenerative disorders. Nevertheless, the current understanding of NSC biology suggests that, far from being mere spare parts for cell replacement therapies, NSCs could play a key role in the pharmacology of neuroprotection and become protagonists of innovative treatments for neurodegenerative diseases. Here, we review this new emerging concept of NSC biology.

  9. Human-induced pluripotent stem cells: potential for neurodegenerative diseases.

    PubMed

    Ross, Christopher A; Akimov, Sergey S

    2014-09-15

    The cell biology of human neurodegenerative diseases has been difficult to study till recently. The development of human induced pluripotent stem cell (iPSC) models has greatly enhanced our ability to model disease in human cells. Methods have recently been improved, including increasing reprogramming efficiency, introducing non-viral and non-integrating methods of cell reprogramming, and using novel gene editing techniques for generating genetically corrected lines from patient-derived iPSCs, or for generating mutations in control cell lines. In this review, we highlight accomplishments made using iPSC models to study neurodegenerative disorders such as Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Fronto-Temporal Dementia, Alzheimer's disease, Spinomuscular Atrophy and other polyglutamine diseases. We review disease-related phenotypes shown in patient-derived iPSCs differentiated to relevant neural subtypes, often with stressors or cell "aging", to enhance disease-specific phenotypes. We also discuss prospects for the future of using of iPSC models of neurodegenerative disorders, including screening and testing of therapeutic compounds, and possibly of cell transplantation in regenerative medicine. The new iPSC models have the potential to greatly enhance our understanding of pathogenesis and to facilitate the development of novel therapeutics.

  10. [Progress in induced pluripotent stem cell research for age-related neurodegenerative diseases].

    PubMed

    Ito, Daisuke; Yagi, Takuya; Suzuki, Norihiro

    2013-03-01

    In 2006, Takahashi et al. established a method for reprogramming somatic cells by introducing definite transcription factors, which enabled the generation of induced pluripotent stem cells (iPSCs) with pluripotency comparable to that of embryonic stem cells. In turn, it has become possible to use these iPSCs for producing various tissues needed for the treatment of neurodegenerative disorders, which have been difficult to obtain from living bodies. This advancement is expected to bring forth rapid progress in the clarification of mechanisms underlying the diseases and discovery of new innovative drugs and lead to rapid progress in regenerative medicine. In recent years, recapitulation and analysis of disease conditions using iPSCs derived from the patients themselves have been reported, and remarkable advances have been made, even for late-onset neurodegenerative disorders. These findings show that the phenotypes of late-onset neurodegenerative disorders can be recapitulated in iPSC-derived neuronal cells, which are reflected the early developmental stages, indicating cellular abnormalities exist from the prenatal period, despite the late onset diseases. In this review, we summarize the state of iPSCs research in the context of neurodegenerative disorders, discuss the possible ways for understanding the mechanisms underlying neurodegenerative disorders and discovering new drugs, and describe some other aspects of regenerative medicine.

  11. Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols.

    PubMed

    Rigacci, Stefania; Stefani, Massimo

    2015-01-01

    A common molecular feature of amyloid neurodegenerative diseases is the unfolding/misfolding of specific proteins/peptides which consequently become prone to aggregate into toxic assemblies and deposits that are the key histopathological trait of these pathologies. Apart from the rare early-onset familiar forms, these neurodegenerative diseases are age-associated disorders whose symptoms appear in aged people after long incubation periods. This makes the therapeutic approach particularly compelling and boosts the search for both early diagnostic tools and preventive approaches. In this last respect, natural compounds commonly present in foods and beverages are considered promising molecules, at least on the bench side. The so-called 'nutraceutical approach' suggests life-long healthy diets, particularly focusing on food molecules that are candidates to enter clinical trials as such or following a targeted molecular engineering. Natural phenols abundant in 'healthy' foods such as extra virgin olive oil, red wine, green tea, red berries and spices, appear particularly promising. PMID:25418871

  12. Advances in epigenetics and epigenomics for neurodegenerative diseases.

    PubMed

    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.

  13. Stem cell technology for neurodegenerative diseases.

    PubMed

    Lunn, J Simon; Sakowski, Stacey A; Hur, Junguk; Feldman, Eva L

    2011-09-01

    Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases.

  14. Summary of cerebrospinal fluid routine parameters in neurodegenerative diseases.

    PubMed

    Jesse, Sarah; Brettschneider, Johannes; Süssmuth, Sigurd D; Landwehrmeyer, Bernhard G; von Arnim, Christine A F; Ludolph, Albert C; Tumani, Hayrettin; Otto, Markus

    2011-06-01

    In neurodegenerative diseases, cerebrospinal fluid analysis (CSF) is predominantly performed to exclude inflammatory diseases and to perform a risk assessment in dementive disorders by measurement of tau proteins and amyloid beta peptides. However, large scale data on basic findings of CSF routine parameters are generally lacking. The objective of the study was to define a normal reference spectrum of routine CSF parameters in neurodegenerative diseases. Routine CSF parameters (white cell count, lactate and albumin concentrations, CSF/serum quotients of albumin (Q (alb)), IgG, IgA, IgM, and oligoclonal IgG bands (OCB)) were retrospectively analyzed in an academic research setting. A total of 765 patients (Alzheimer's disease (AD), Parkinson's disease (PD), Parkinson's disease dementia (PDD), vascular dementia (VD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), multisystem atrophy (MSA), motor neuron diseases (MND), spinocerebellar ataxia (SCA), Huntington's disease (HD)) and non-demented control groups including a group of patients with muscular disorders (MD). The main outcome measures included statistical analyses of routine CSF parameters. Mildly elevated Q (alb) were found in a small percentage of nearly all subgroups and in a higher proportion of patients with PSP, MSA, VD, PDD, and MND. With the exception of 1 MND patient, no intrathecal Ig synthesis was observed. Isolated OCBs in CSF were sometimes found in patients with neurodegenerative diseases without elevated cell counts; lactate levels were always normal. A slightly elevated Q (alb) was observed in a subgroup of patients with neurodegenerative diseases and does not exclude the diagnosis. Extensive elevation of routine parameters is not characteristic and should encourage a re-evaluation of the clinical diagnosis.

  15. Amyloidosis in Retinal Neurodegenerative Diseases.

    PubMed

    Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica

    2016-01-01

    As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer's disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer's patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer's patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a "window" to the brain. PMID:27551275

  16. Systems biology of neurodegenerative diseases.

    PubMed

    Wood, Levi B; Winslow, Ashley R; Strasser, Samantha Dale

    2015-07-01

    Neurodegenerative diseases (NDs) collectively afflict more than 40 million people worldwide. The majority of these diseases lack therapies to slow or stop progression due in large part to the challenge of disentangling the simultaneous presentation of broad, multifaceted pathophysiologic changes. Present technologies and computational capabilities suggest an optimistic future for deconvolving these changes to identify novel mechanisms driving ND onset and progression. In particular, integration of highly multi-dimensional omic analytical techniques (e.g., microarray, mass spectrometry) with computational systems biology approaches provides a systematic methodology to elucidate new mechanisms driving NDs. In this review, we begin by summarizing the complex pathophysiology of NDs associated with protein aggregation, emphasizing the shared complex dysregulation found in all of these diseases, and discuss available experimental ND models. Next, we provide an overview of technological and computational techniques used in systems biology that are applicable to studying NDs. We conclude by reviewing prior studies that have applied these approaches to NDs and comment on the necessity of combining analysis from both human tissues and model systems to identify driving mechanisms. We envision that the integration of computational approaches with multiple omic analyses of human tissues, and mouse and in vitro models, will enable the discovery of new therapeutic strategies for these devastating diseases.

  17. Peptide aggregation in neurodegenerative disease.

    PubMed

    Murphy, Regina M

    2002-01-01

    In the not-so-distant past, insoluble aggregated protein was considered as uninteresting and bothersome as yesterday's trash. More recently, protein aggregates have enjoyed considerable scientific interest, as it has become clear that these aggregates play key roles in many diseases. In this review, we focus attention on three polypeptides: beta-amyloid, prion, and huntingtin, which are linked to three feared neurodegenerative diseases: Alzheimer's, "mad cow," and Huntington's disease, respectively. These proteins lack any significant primary sequence homology, yet their aggregates possess very similar features, specifically, high beta-sheet content, fibrillar morphology, relative insolubility, and protease resistance. Because the aggregates are noncrystalline, secrets of their structure at nanometer resolution are only slowly yielding to X-ray diffraction, solid-state NMR, and other techniques. Besides structure, the aggregates may possess similar pathways of assembly. Two alternative assembly pathways have been proposed: the nucleation-elongation and the template-assisted mode. These two modes may be complementary, not mutually exclusive. Strategies for interfering with aggregation, which may provide novel therapeutic approaches, are under development. The structural similarities between protein aggregates of dissimilar origin suggest that therapeutic strategies successful against one disease may have broad utility in others. PMID:12117755

  18. Amyloidosis in Retinal Neurodegenerative Diseases

    PubMed Central

    Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica

    2016-01-01

    As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer’s disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer’s patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer’s patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a “window” to the brain. PMID:27551275

  19. Annual Research Review: The Promise of Stem Cell Research for Neuropsychiatric Disorders

    ERIC Educational Resources Information Center

    Vaccarino, Flora M.; Urban, Alexander Eckehart; Stevens, Hanna E.; Szekely, Anna; Abyzov, Alexej; Grigorenko, Elena L.; Gerstein, Mark; Weissman, Sherman

    2011-01-01

    The study of the developing brain has begun to shed light on the underpinnings of both early and adult onset neuropsychiatric disorders. Neuroimaging of the human brain across developmental time points and the use of model animal systems have combined to reveal brain systems and gene products that may play a role in autism spectrum disorders,…

  20. Sound Naming in Neurodegenerative Disease

    PubMed Central

    Chow, Maggie L; Brambati, Simona M; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Johnson, Julene K

    2010-01-01

    Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 of objects that required manipulation when producing the sound, and 28 that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p<0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p<0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left premotor region, extending from area 6 to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the premotor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain. PMID:20089342

  1. Protein aggregate spreading in neurodegenerative diseases: Problems and perspectives

    PubMed Central

    Lee, Seung-Jae; Lim, Hee-Sun; Masliah, Eliezer; Lee, He-Jin

    2014-01-01

    Progressive accumulation of specific protein aggregates is a defining feature of many major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, fronto-temporal dementia, Huntington’s disease, and Creutzfeldt–Jakob disease (CJD). Findings from several recent studies have suggested that aggregation-prone proteins, such as tau, α-synuclein, polyglutamine-containing proteins, and amyloid-β, can spread to other cells and brain regions, a phenomenon considered unique to prion disorders, such as CJD and bovine spongiform encephalopathy. Cell-to-cell propagation of protein aggregates may be the general underlying principle for progressive deterioration of neurodegenerative diseases. This may also have significant implications in cell replacement therapies, as evidenced by the propagation of α-synuclein aggregates from host to grafted cells in long-term transplants in Parkinson’s patients. Here, we review recent progress in protein aggregate propagation in experimental model systems and discuss outstanding questions and future perspectives. Understanding the mechanisms of this pathological spreading may open the way to unique opportunities for development of diagnostic techniques and novel therapies for protein misfolding-associated neurodegenerative diseases. PMID:21624403

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

    PubMed

    Lazzara, Carol A; Kim, Yong-Hwan

    2015-01-01

    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. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side-effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases.

  3. Heavy metals and neurodegenerative diseases: an observational study.

    PubMed

    Giacoppo, Sabrina; Galuppo, Maria; Calabrò, Rocco Salvatore; D'Aleo, Giangaetano; Marra, Angela; Sessa, Edoardo; Bua, Daniel Giuseppe; Potortì, Angela Giorgia; Dugo, Giacomo; Bramanti, Placido; Mazzon, Emanuela

    2014-11-01

    In this study, we evaluated the levels of some of the most investigated metals (Cu, Se, Zn, Pb, and Hg) in the blood of patients affected by the most common chronic neurodegenerative diseases like Alzheimer's disease (AD) and multiple sclerosis (MS), in order to better clarify their involvement. For the first time, we investigated a Sicilian population living in an area exposed to a potentially contaminated environment from dust and fumes of volcano Etna and consumer of a considerable quantity of fish in their diet, so that this represents a good cohort to demonstrate a possible link between metals levels and development of neurodegenerative disorders. More specifically, 15 patients affected by AD, 41 patients affected by MS, 23 healthy controls, and 10 healthy elderly controls were recruited and subjected to a venous blood sampling. Quantification of heavy metals was performed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). This technique has allowed us to establish that there is a concomitance of heavy metal unbalance associated with AD more than in other neurodegenerative pathologies, such as MS. Also, we can assess that the concentration of these elements is independent from the diet, especially from occasional or habitual consumption of fruits and vegetables, prevalence in the diet of meat or fish, possible exposure to contaminated environment due both to the occupation and place of residence.

  4. Implications of glial nitric oxide in neurodegenerative diseases

    PubMed Central

    Yuste, Jose Enrique; Tarragon, Ernesto; Campuzano, Carmen María; Ros-Bernal, Francisco

    2015-01-01

    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. PMID:26347610

  5. Implications of glial nitric oxide in neurodegenerative diseases.

    PubMed

    Yuste, Jose Enrique; Tarragon, Ernesto; Campuzano, Carmen María; Ros-Bernal, Francisco

    2015-01-01

    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. PMID:26347610

  6. Potential application of lithium in Parkinson's and other neurodegenerative diseases

    PubMed Central

    Lazzara, Carol A.; Kim, Yong-Hwan

    2015-01-01

    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. 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. PMID:26578864

  7. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases.

    PubMed

    Tanna, Tanmay; Sachan, Vatsal

    2014-01-01

    Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.

  8. Mesenchymal stem cells for the treatment of neurodegenerative disease

    PubMed Central

    Joyce, Nanette; Annett, Geralyn; Wirthlin, Louisa; Olson, Scott; Bauer, Gerhard; Nolta, Jan A

    2010-01-01

    Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed. PMID:21082892

  9. Mesenchymal stem cells for the treatment of neurodegenerative disease.

    PubMed

    Joyce, Nanette; Annett, Geralyn; Wirthlin, Louisa; Olson, Scott; Bauer, Gerhard; Nolta, Jan A

    2010-11-01

    Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.

  10. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors.

    PubMed

    Campos, Carlos; Rocha, Nuno Barbosa F; Lattari, Eduardo; Paes, Flávia; Nardi, António E; Machado, Sérgio

    2016-06-01

    Age-related neurodegenerative disorders, like Alzheimer's or Parkinson's disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials. PMID:27086703

  11. Mitochondrial quality control: decommissioning power plants in neurodegenerative diseases.

    PubMed

    Mukherjee, Rukmini; Chakrabarti, Oishee

    2013-01-01

    The cell has an intricate quality control system to protect its mitochondria from oxidative stress. This surveillance system is multi-tiered and comprises molecules that are present inside the mitochondria, in the cytosol, and in other organelles like the nucleus and endoplasmic reticulum. These molecules cross talk with each other and protect the mitochondria from oxidative stress. Oxidative stress is a fundamental part of early disease pathogenesis of neurodegenerative diseases. These disorders also damage the cellular quality control machinery that protects the cell against oxidative stress. This exacerbates the oxidative damage and causes extensive neuronal cell death that is characteristic of neurodegeneration. PMID:24288463

  12. Corruption and spread of pathogenic proteins in neurodegenerative diseases.

    PubMed

    Walker, Lary C; LeVine, Harry

    2012-09-28

    With advancing age, the brain becomes increasingly susceptible to neurodegenerative diseases, most of which are characterized by the misfolding and errant aggregation of certain proteins. The induction of aggregation involves a crystallization-like seeding mechanism by which a specific protein is structurally corrupted by its misfolded conformer. The latest research indicates that, once formed, proteopathic seeds can spread from one locale to another via cellular uptake, transport, and release. Impeding this process could represent a unified therapeutic strategy for slowing the progression of a wide range of currently intractable disorders.

  13. [Microglial Phagocytosis in the Neurodegenerative Diseases].

    PubMed

    Cao, Sheng-nan; Bao, Xiu-qi; Sun, Hua; Zhang, Dan

    2016-04-01

    Microglia are the resident innate immune cells in the brain. Under endogenous or exogenous stimulates, they become activated and play an important role in the neurodegenerative diseases. Microglial phagocytosis is a process of receptor-mediated engulfment and degradation of apoptotic cells. In addition, microglia can phagocyte brain-specific cargo, such as myelin debris and abnormal protein aggregation. However, recent studies have shown that microglia can also phagocyte stressed-but-viable neurons, causing loss of neurons in the brain. Thus, whether microglial phagocytosis is beneficial or not in neurodegenerative disease remains controversial. This article reviews microglial phagocytosis related mechanisms and its potential roles in neurodegenerative diseases, with an attempt to provide new insights in the treatment of neurodegenerative diseases. PMID:27181903

  14. [Microglial Phagocytosis in the Neurodegenerative Diseases].

    PubMed

    Cao, Sheng-nan; Bao, Xiu-qi; Sun, Hua; Zhang, Dan

    2016-04-01

    Microglia are the resident innate immune cells in the brain. Under endogenous or exogenous stimulates, they become activated and play an important role in the neurodegenerative diseases. Microglial phagocytosis is a process of receptor-mediated engulfment and degradation of apoptotic cells. In addition, microglia can phagocyte brain-specific cargo, such as myelin debris and abnormal protein aggregation. However, recent studies have shown that microglia can also phagocyte stressed-but-viable neurons, causing loss of neurons in the brain. Thus, whether microglial phagocytosis is beneficial or not in neurodegenerative disease remains controversial. This article reviews microglial phagocytosis related mechanisms and its potential roles in neurodegenerative diseases, with an attempt to provide new insights in the treatment of neurodegenerative diseases.

  15. Stem cell challenges in the treatment of neurodegenerative disease.

    PubMed

    Feng, Zhongling; Gao, Feng

    2012-02-01

    Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.

  16. A previously undiagnosed case of Gerstmann-Sträussler-Scheinker disease revealed by PRNP gene analysis in patients with adult-onset ataxia.

    PubMed

    Cagnoli, Claudia; Brussino, Alessandro; Sbaiz, Luca; Di Gregorio, Eleonora; Atzori, Cristiana; Caroppo, Paola; Orsi, Laura; Migone, Nicola; Buffa, Carlo; Imperiale, Daniele; Brusco, Alfredo

    2008-07-30

    Ataxia is a frequently reported symptom in prion diseases (PD) and it is characteristic of Gerstmann-Sträussler-Scheinker syndrome (GSS), a genetic PD mainly related to the P102L mutation in the PRNP gene. Our aim was to screen for the P102L and other six known PRNP gene mutations (P105L, A117V, Y145X, E200K, D202N, and V210I) a group of 206 consecutive patients diagnosed with adult-onset cerebellar ataxia of unknown origin. The patients, negative for the most common acquired and genetic forms, were analyzed using a combination of restriction endonuclease digestion and pyrosequencing; eight, affected by ataxia and cognitive dysfunction, were also sequenced for the PRNP gene. One patient resulted to be heterozygous for the P102L mutation. Retrospectively, the clinical picture was consistent with a "classical" GSS phenotype. In conclusion, the screening for the P102L mutation, or even the sequencing of the PRNP gene should be taken in consideration in patients with late-onset ataxia (>50 years).

  17. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.

    PubMed

    Arnold, Eveline S; Ling, Shuo-Chien; Huelga, Stephanie C; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A; Da Cruz, Sandrine; Clutario, Kevin M; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E; Yeo, Gene W; Cleveland, Don W

    2013-02-19

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

  18. Successful Use of Higher-Dose Etanercept for Multirefractory Systemic Flare of Adult-Onset Still's Disease with Liver Failure with No Response to Tocilizumab Therapy

    PubMed Central

    Tamechika, Shinya; Iwagaitsu, Shiho; Maeda, Shinji; Togawa, Hiroyuki

    2013-01-01

    A 21-year-old woman with refractory systemic flare of adult-onset Still's disease with liver failure despite high-dose corticosteroids, cyclosporine, tacrolimus, and tocilizumab, was successfully treated with additional use of etanercept. Etanercept at a dose of 50 mg weekly was partially effective but could not reduce the dose of concomitant betamethasone from 5 mg/day. Etanercept at a dose of 75 mg weekly could lead her to clinical remission and enabled successful tapering off the corticosteroids and discontinuation of etanercept. Normalization of serum C-reactive protein and interleukin 6 and persistent elevation of serum tumor necrosis factor α under the treatment with high-dose corticosteroids and immunosuppressants suggest that tumor necrosis factor α was more deeply involved than at least interleukin 6 in the pathogenesis of refractoriness of the disease in this patient, and these findings might be indicative of potential efficacy for adjunctive use of a tumor necrosis factor inhibitor rather than an interleukin 6 inhibitor. PMID:24455384

  19. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses.

    PubMed

    Wilkaniec, Anna; Czapski, Grzegorz A; Adamczyk, Agata

    2016-01-01

    Cyclin-dependent kinase 5 (Cdk5) is involved in proper neurodevelopment and brain function and serves as a switch between neuronal survival and death. Overactivation of Cdk5 is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important link between disease-initiating factors and cell death effectors. A common hallmark of neurodegenerative disorders is incorrect folding of specific proteins, thus leading to their intra- and extracellular accumulation in the nervous system. Abnormal Cdk5 signaling contributes to dysfunction of individual proteins and has a substantial role in either direct or indirect interactions of proteins common to, and critical in, different neurodegenerative diseases. While the roles of Cdk5 in α-synuclein (ASN) - tau or β-amyloid peptide (Aβ) - tau interactions are well documented, its contribution to many other pertinent interactions, such as that of ASN with Aβ, or interactions of the Aβ - ASN - tau triad with prion proteins, did not get beyond plausible hypotheses and remains to be proven. Understanding of the exact position of Cdk5 in the deleterious feed-forward loop critical for development and progression of neurodegenerative diseases may help designing successful therapeutic strategies of several fatal neurodegenerative diseases. Cyclin-dependent kinase 5 (Cdk5) is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important factor involved in protein misfolding, toxicity and interaction. We suggest that Cdk5 may contribute to the vicious circle of neurotoxic events involved in the pathogenesis of different neurodegenerative diseases. PMID:26376455

  20. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses.

    PubMed

    Wilkaniec, Anna; Czapski, Grzegorz A; Adamczyk, Agata

    2016-01-01

    Cyclin-dependent kinase 5 (Cdk5) is involved in proper neurodevelopment and brain function and serves as a switch between neuronal survival and death. Overactivation of Cdk5 is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important link between disease-initiating factors and cell death effectors. A common hallmark of neurodegenerative disorders is incorrect folding of specific proteins, thus leading to their intra- and extracellular accumulation in the nervous system. Abnormal Cdk5 signaling contributes to dysfunction of individual proteins and has a substantial role in either direct or indirect interactions of proteins common to, and critical in, different neurodegenerative diseases. While the roles of Cdk5 in α-synuclein (ASN) - tau or β-amyloid peptide (Aβ) - tau interactions are well documented, its contribution to many other pertinent interactions, such as that of ASN with Aβ, or interactions of the Aβ - ASN - tau triad with prion proteins, did not get beyond plausible hypotheses and remains to be proven. Understanding of the exact position of Cdk5 in the deleterious feed-forward loop critical for development and progression of neurodegenerative diseases may help designing successful therapeutic strategies of several fatal neurodegenerative diseases. Cyclin-dependent kinase 5 (Cdk5) is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important factor involved in protein misfolding, toxicity and interaction. We suggest that Cdk5 may contribute to the vicious circle of neurotoxic events involved in the pathogenesis of different neurodegenerative diseases.

  1. Neurodegenerative processes in Huntington's disease

    PubMed Central

    Bano, D; Zanetti, F; Mende, Y; Nicotera, P

    2011-01-01

    Huntington's disease (HD) is a complex and severe disorder characterized by the gradual and the progressive loss of neurons, predominantly in the striatum, which leads to the typical motor and cognitive impairments associated with this pathology. HD is caused by a highly polymorphic CAG trinucleotide repeat expansion in the exon-1 of the gene encoding for huntingtin protein. Since the first discovery of the huntingtin gene, investigations with a consistent number of in-vitro and in-vivo models have provided insights into the toxic events related to the expression of the mutant protein. In this review, we will summarize the progress made in characterizing the signaling pathways that contribute to neuronal degeneration in HD. We will highlight the age-dependent loss of proteostasis that is primarily responsible for the formation of aggregates observed in HD patients. The most promising molecular targets for the development of pharmacological interventions will also be discussed. PMID:22071633

  2. MicroRNAs in neurodegenerative diseases and their therapeutic potential.

    PubMed

    Junn, Eunsung; Mouradian, M Maral

    2012-02-01

    MicroRNAs (miRNAs) are abundant, endogenous, short, noncoding RNAs that act as important post-transcriptional regulators of gene expression by base-pairing with their target mRNA. During the last decade, substantial knowledge has accumulated regarding the biogenesis of miRNAs, their molecular mechanisms and functional roles in a variety of cellular contexts. Altered expression of certain miRNA molecules in the brains of patients with neurodegenerative diseases such as Alzheimer and Parkinson suggests that miRNAs could have a crucial regulatory role in these disorders. Polymorphisms in miRNA target sites may also constitute an important determinant of disease risk. Additionally, emerging evidence points to specific miRNAs targeting and regulating the expression of particular proteins that are key to disease pathogenesis. Considering that the amount of these proteins in susceptible neuronal populations appears to be critical to neurodegeneration, miRNA-mediated regulation represents a new target of significant therapeutic prospects. In this review, the implications of miRNAs in several neurodegenerative disorders and their potential as therapeutic interventions are discussed.

  3. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.

    PubMed

    Calabrese, Vittorio; Cornelius, Carolin; Mancuso, Cesare; Barone, Eugenio; Calafato, Stella; Bates, Timothy; Rizzarelli, Enrico; Kostova, Albena T Dinkova

    2009-01-01

    The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) heme oxygenase-1 and Hsp70, as well as the thioredoxin/thioredoxin reductase system. Heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Dietary antioxidants, such as curcumin, L-carnitine/acetyl-L-carnitine and carnosine have recently been demonstrated in vitro to be neuroprotective through the activation of hormetic pathways, including vitagenes. In the present review we discuss the importance of vitagenes in the cellular stress response and analyse, from a pharmacological point of view, the potential use of dietary antioxidants in the treatment of neurodegenerative disorders in humans.

  4. Human embryonic stem cell therapies for neurodegenerative diseases.

    PubMed

    Tomaskovic-Crook, Eva; Crook, Jeremy M

    2011-06-01

    There is a renewed enthusiasm for the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives. Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS cells.

  5. MicroRNAs: novel therapeutic targets in neurodegenerative diseases.

    PubMed

    Roshan, Reema; Ghosh, Tanay; Scaria, Vinod; Pillai, Beena

    2009-12-01

    The prevalence of neurodegenerative disorders is rising steadily as human life expectancy increases. However, limited knowledge of the molecular basis of disease pathogenesis is a major hurdle in the identification of drug targets and development of therapeutic strategies for these largely incurable disorders. Recently, differential expression of endogenous regulatory small RNAs, known as 'microRNAs' (miRNAs), in patients of Alzheimer's disease, Parkinson's disease and models of ataxia suggest that they might have key regulatory roles in neurodegeneration. miRNAs that can target known mediators of neurodegeneration offer potential therapeutic targets. Our bioinformatic analysis suggests novel miRNA-target interactions that could potentially influence neurodegeneration. The recent development of molecules that alter miRNA expression promises valuable tools that will enhance the therapeutic potential of miRNAs.

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

    PubMed Central

    Fan, Hueng-Chuen; Chi, Ching-Shiang; Cheng, Shin-Nan; Lee, Hsiu-Fen; Tsai, Jeng-Dau; Lin, Shinn-Zong; Harn, Horng-Jyh

    2015-01-01

    Neurodegenerative diseases (NDs) are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS) disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD) and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM), and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases. PMID:26712747

  7. FE65 and FE65L1 amyloid precursor protein–binding protein compound null mice display adult-onset cataract and muscle weakness

    PubMed Central

    Suh, Jaehong; Moncaster, Juliet A.; Wang, Lirong; Hafeez, Imran; Herz, Joachim; Tanzi, Rudolph E.; Goldstein, Lee E.; Guénette, Suzanne Y.

    2015-01-01

    FE65 and FE65L1 are cytoplasmic adaptor proteins that bind a variety of proteins, including the amyloid precursor protein, and that mediate the assembly of multimolecular complexes. We previously reported that FE65/FE65L1 double knockout (DKO) mice display disorganized laminin in meningeal fibroblasts and a cobblestone lissencephaly-like phenotype in the developing cortex. Here, we examined whether loss of FE65 and FE65L1 causes ocular and muscular deficits, 2 phenotypes that frequently accompany cobblestone lissencephaly. Eyes of FE65/FE65L1 DKO mice develop normally, but lens degeneration becomes apparent in young adult mice. Abnormal lens epithelial cell migration, widespread small vacuole formation, and increased laminin expression underneath lens capsules suggest impaired interaction between epithelial cells and capsular extracellular matrix in DKO lenses. Cortical cataracts develop in FE65L1 knockout (KO) mice aged 16 months or more but are absent in wild-type or FE65 KO mice. FE65 family KO mice show attenuated grip strength, and the nuclei of DKO muscle cells frequently locate in the middle of muscle fibers. These findings reveal that FE65 and FE65L1 are essential for the maintenance of lens transparency, and their loss produce phenotypes in brain, eye, and muscle that are comparable to the clinical features of congenital muscular dystrophies in humans.—Suh, J., Moncaster, J. A., Wang, L., Hafeez, I., Herz, J., Tanzi, R. E., Goldstein, L. E., Guénette, S. Y. FE65 and FE65L1 amyloid precursor protein–binding protein compound null mice display adult-onset cataract and muscle weakness. PMID:25757569

  8. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases.

    PubMed

    Banerjee, Antara; Chakraborty, Subhadip; Chakraborty, Abhijit; Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  9. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases

    PubMed Central

    Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  10. TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still’s Disease and Their Association with Disease Activity and Clinical Manifestations

    PubMed Central

    Kim, Hyoun-Ah; Han, Jae Ho; Kim, Woo-Jung; Noh, Hyun Jin; An, Jeong-Mi; Yim, Hyunee; Jung, Ju-Yang; Kim, You-Sun; Suh, Chang-Hee

    2016-01-01

    S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still’s disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD. PMID:27537874

  11. Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region.

    PubMed

    Sarfarazi, M; Child, A; Stoilova, D; Brice, G; Desai, T; Trifan, O C; Poinoosawmy, D; Crick, R P

    1998-03-01

    One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein.

  12. Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases

    PubMed Central

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

    2015-01-01

    Abstract 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

  13. Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases.

    PubMed

    Tan, Lin; Yu, Jin-Tai; Tan, Lan

    2015-01-01

    Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), originate from a loss of neurons in the central nervous system (CNS) and are severely debilitating. The incidence of neurodegenerative diseases increases with age, and they are expected to become more common due to extended life expectancy. Because of no clear mechanisms, these diseases have become a major challenge in neurobiology. It is well recognized that these disorders become the culmination of many different genetic and environmental influences. Prior studies have shown that microRNAs (miRNAs) are pathologically altered during the inexorable course of some neurodegenerative diseases, suggesting that miRNAs may be the contributing factor in neurodegeneration. Here, we review what is known about the involvement of miRNAs in the pathogenesis of neurodegenerative diseases. The biogenesis of miRNAs and various functions of miRNAs that act as the chief regulators will be discussed. We focus in particular on dysregulation of miRNAs which leads to several neurodegenerative diseases from three aspects: miRNA-generating disorders, miRNA-targeting genes and epigenetic alterations. Furthermore, recent evidences have shown that circulating miRNA expression levels are changed in patients with neurodegenerative diseases. Circulating miRNA expression levels are reported in patients in order to evaluate their application as biomarkers of these diseases. A discussion is included with a potential diagnostic biomarker and the possible future direction in exploring the nexus between miRNAs and various neurodegenerative diseases.

  14. HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

    PubMed Central

    2013-01-01

    Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity. PMID:23356410

  15. Oligonucleotide-based therapy for neurodegenerative diseases.

    PubMed

    Magen, Iddo; Hornstein, Eran

    2014-10-10

    Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer׳s disease, Parkinson׳s disease, Huntington׳s disease and amyotrophic lateral sclerosis, encourages direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity.

  16. Mitochondrial drug targets in neurodegenerative diseases.

    PubMed

    Lee, Jiyoun

    2016-02-01

    Growing evidence suggests that mitochondrial dysfunction is the main culprit in neurodegenerative diseases. Given the fact that mitochondria participate in diverse cellular processes, including energetics, metabolism, and death, the consequences of mitochondrial dysfunction in neuronal cells are inevitable. In fact, new strategies targeting mitochondrial dysfunction are emerging as potential alternatives to current treatment options for neurodegenerative diseases. In this review, we focus on mitochondrial proteins that are directly associated with mitochondrial dysfunction. We also examine recently identified small molecule modulators of these mitochondrial targets and assess their potential in research and therapeutic applications.

  17. Role of neuroinflammation in neurodegenerative diseases (Review)

    PubMed Central

    CHEN, WEI-WEI; ZHANG, XIA; HUANG, WEN-JUAN

    2016-01-01

    Neurodegeneration is a phenomenon that occurs in the central nervous system through the hallmarks associating the loss of neuronal structure and function. Neurodegeneration is observed after viral insult and mostly in various so-called 'neurodegenerative diseases', generally observed in the elderly, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis that negatively affect mental and physical functioning. Causative agents of neurodegeneration have yet to be identified. However, recent data have identified the inflammatory process as being closely linked with multiple neurodegenerative pathways, which are associated with depression, a consequence of neurodegenerative disease. Accordingly, pro-inflammatory cytokines are important in the pathophysiology of depression and dementia. These data suggest that the role of neuroinflammation in neurodegeneration must be fully elucidated, since pro-inflammatory agents, which are the causative effects of neuroinflammation, occur widely, particularly in the elderly in whom inflammatory mechanisms are linked to the pathogenesis of functional and mental impairments. In this review, we investigated the role played by the inflammatory process in neurodegenerative diseases. PMID:26935478

  18. Prism Management in Patients with Neurodegenerative Disease.

    PubMed

    Gilligan, Rikki

    2015-01-01

    Patients with motility problems due to neurodegenerative disease such as Parkinson's and its variations often present challenging cases for the orthoptist. A few "tricks of the trade" will be presented on how to make a Parkinson's patient's daily life a little easier.

  19. Induced pluripotent stem cells and neurodegenerative diseases.

    PubMed

    Chen, Chao; Xiao, Shi-Fu

    2011-04-01

    Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis, are characterized by idiopathic neuron loss in different regions of the central nervous system, which contributes to the relevant dysfunctions in the patients. The application of cell replacement therapy using human embryonic stem (hES) cells, though having attracted much attention, has been hampered by the intrinsic ethical problems. It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state, called induced pluripotent stem (iPS) cells. It is soon realized that iPS cells may be an alternative source for cell replacement therapy, because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection. What's more, certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes. Thus, patient-specific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient, and to study the vulnerability of neural cells to pathogenic factors in vitro, which may help reveal the pathogenesis of many neurodegenerative diseases. In this review, the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized, and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.

  20. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    PubMed Central

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

    2012-01-01

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

  1. DNA methylation, a hand behind neurodegenerative diseases

    PubMed Central

    Lu, Haoyang; Liu, Xinzhou; Deng, Yulin; Qing, Hong

    2013-01-01

    Epigenetic alterations represent a sort of functional modifications related to the genome that are not responsible for changes in the nucleotide sequence. DNA methylation is one of such epigenetic modifications that have been studied intensively for the past several decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature of DNA methylation. A simple change as such can be caused by a variety of factors, which can be the cause of many serious diseases including several neurodegenerative diseases. In this review, we have reviewed and summarized recent progress regarding DNA methylation in four major neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The studies of these four major neurodegenerative diseases conclude the strong suggestion of the important role DNA methylation plays in these diseases. However, each of these diseases has not yet been understood completely as details in some areas remain unclear, and will be investigated in future studies. We hope this review can provide new insights into the understanding of neurodegenerative diseases from the epigenetic perspective. PMID:24367332

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

    PubMed Central

    Flanagan, Michael F.

    2015-01-01

    The craniocervical junction (CCJ) is a potential choke point for craniospinal hydrodynamics and may play a causative or contributory role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, MS, and ALS, as well as many other neurological conditions including hydrocephalus, idiopathic intracranial hypertension, migraines, seizures, silent-strokes, affective disorders, schizophrenia, and psychosis. The purpose of this paper is to provide an overview of the critical role of the CCJ in craniospinal hydrodynamics and to stimulate further research that may lead to new approaches for the prevention and treatment of the above neurodegenerative and neurological conditions. PMID:26770824

  3. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).

    PubMed

    Chitu, Violeta; Gokhan, Solen; Gulinello, Maria; Branch, Craig A; Patil, Madhuvati; Basu, Ranu; Stoddart, Corrina; Mehler, Mark F; Stanley, E Richard

    2015-02-01

    Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore

  4. Insights into the evolutionary features of human neurodegenerative diseases.

    PubMed

    Panda, Arup; Begum, Tina; Ghosh, Tapash Chandra

    2012-01-01

    Comparative analyses between human disease and non-disease genes are of great interest in understanding human disease gene evolution. However, the progression of neurodegenerative diseases (NDD) involving amyloid formation in specific brain regions is still unknown. Therefore, in this study, we mainly focused our analysis on the evolutionary features of human NDD genes with respect to non-disease genes. Here, we observed that human NDD genes are evolutionarily conserved relative to non-disease genes. To elucidate the conserved nature of NDD genes, we incorporated the evolutionary attributes like gene expression level, number of regulatory miRNAs, protein connectivity, intrinsic disorder content and relative aggregation propensity in our analysis. Our studies demonstrate that NDD genes have higher gene expression levels in favor of their lower evolutionary rates. Additionally, we observed that NDD genes have higher number of different regulatory miRNAs target sites and also have higher interaction partners than the non-disease genes. Moreover, miRNA targeted genes are known to have higher disorder content. In contrast, our analysis exclusively established that NDD genes have lower disorder content. In favor of our analysis, we found that NDD gene encoded proteins are enriched with multi interface hubs (party hubs) with lower disorder contents. Since, proteins with higher disorder content need to adapt special structure to reduce their aggregation propensity, NDD proteins found to have elevated relative aggregation propensity (RAP) in support of their lower disorder content. Finally, our categorical regression analysis confirmed the underlined relative dominance of protein connectivity, 3'UTR length, RAP, nature of hubs (singlish/multi interface) and disorder content for such evolutionary rates variation between human NDD genes and non-disease genes.

  5. Role of the Retromer Complex in Neurodegenerative Diseases.

    PubMed

    Li, Chaosi; Shah, Syed Zahid Ali; Zhao, Deming; Yang, Lifeng

    2016-01-01

    The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. In most cases, the retromer acts as a core that interacts with associated proteins, including sorting nexin family member 27 (SNX27), members of the vacuolar protein sorting 10 (VPS10) receptor family, the major endosomal actin polymerization-promoting complex known as Wiskott-Aldrich syndrome protein and scar homolog (WASH), and other proteins. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. Here, we summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases.

  6. The Importance of Tau Phosphorylation for Neurodegenerative Diseases

    PubMed Central

    Noble, Wendy; Hanger, Diane P.; Miller, Christopher C. J.; Lovestone, Simon

    2013-01-01

    Fibrillar deposits of highly phosphorylated tau are a key pathological feature of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and some frontotemporal dementias. Increasing evidence suggests that the presence of these end-stage neurofibrillary lesions do not cause neuronal loss, but rather that alterations to soluble tau proteins induce neurodegeneration. In particular, aberrant tau phosphorylation is acknowledged to be a key disease process, influencing tau structure, distribution, and function in neurons. Although typically described as a cytosolic protein that associates with microtubules and regulates axonal transport, several additional functions of tau have recently been demonstrated, including roles in DNA stabilization, and synaptic function. Most recently, studies examining the trans-synaptic spread of tau pathology in disease models have suggested a potential role for extracellular tau in cell signaling pathways intrinsic to neurodegeneration. Here we review the evidence showing that tau phosphorylation plays a key role in neurodegenerative tauopathies. We also comment on the tractability of altering phosphorylation-dependent tau functions for therapeutic intervention in AD and related disorders. PMID:23847585

  7. Endogenously Nitrated Proteins in Mouse Brain: Links To Neurodegenerative Disease

    SciTech Connect

    Sacksteder, Colette A.; Qian, Weijun; Knyushko, Tanya V.; Wang, Haixing H.; Chin, Mark H.; Lacan, Goran; Melega, William P.; Camp, David G.; Smith, Richard D.; Smith, Desmond J.; Squier, Thomas C.; Bigelow, Diana J.

    2006-07-04

    Increased nitrotyrosine modifica