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Multiple system atrophy (MSA) is a rare and fatal α-synucleinopathy characterized by a distinctive oligodendrogliopathy with glial cytoplasmic inclusions and associated neuronal multisystem degeneration. The majority of patients presents with a rapidly progressive parkinsonian disorder and atypical features such as early autonomic failure and cerebellar ataxia. We have previously reported that complete MSA pathology can be modeled in transgenic mice overexpressing oligodendroglial α-synuclein under conditions of oxidative stress induced by 3-nitropropionic acid (3-NP) including striatonigral degeneration, olivopontocerebellar atrophy, astrogliosis, and microglial activation. Here, we show that myeloperoxidase (MPO), a key enzyme involved in the production of reactive oxygen species by phagocytic cells, is expressed in both human and mouse MSA brains. We also demonstrate that in the MSA mouse model, MPO inhibition reduces motor impairment and rescues vulnerable neurons in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei, and inferior olives. MPO inhibition is associated with suppression of microglial activation but does not affect 3-NP induced astrogliosis in the same regions. Finally, MPO inhibition results in reduced intracellular aggregates of α-synuclein. This study suggests that MPO inhibition may represent a novel candidate treatment strategy against MSA-like neurodegeneration acting through its anti-inflammatory and anti-oxidative properties. 相似文献
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Micturitional Disturbance in Multiple System Atrophy 总被引:3,自引:0,他引:3
Ryuji Sakakibara M.D. Takamichi Hattori M.D. Masaki Tojo M.D. Tomonori Yamanishi M.D. Kosaku Yasuda M.D. Keizo Hirayama M.D. 《Psychiatry and clinical neurosciences》1993,47(3):591-598
Abstract: Detailed micturitional histories and urodynamic studies were conducted to investigate the micturitional disturbance in multiple system atrophy (MSA). Eighty-six patients with MSA comprised of 14 with striatonigral degeneration (SND), 42 with olivopontocerebellar atrophy (OPCA) and 30 with Shy-Drager syndrome (SDS). The results were as follows. Micturitional symptoms were noted in over 90% of patients with each type of MSA. Dominant symptoms were irritative ones in SND and OPCA, and a combination of irritative and obstructive ones in SDS. Micturitional symptoms in SDS appeared earlier than those in SND or OPCA. The degree of micturitional disturbance was severer in SDS than in SND or OPCA. Micturitional disturbance tended to become worse as the disease progressed. The responsible sites of lesions of micturitional disturbance seemed to be supra- as well as infranuclear lesions of the pelvic and pudendal nerves in MSA. Infranuclear lesions were more prominent in SDS than in SND or OPCA. Follow-up studies of some of the patients with SDS and OPCA suggested that the responsible sites of pelvic nerve lesions changed from supra- to infranuclear lesions during the course of disease. 相似文献
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Nilotinib Fails to Prevent Synucleinopathy and Cell Loss in a Mouse Model of Multiple System Atrophy
Miguel Lopez-Cuina MD PhD Paul A. Guerin PhD Marie-Hélène Canron BS Anna Delamarre MD Benjamin Dehay PhD Erwan Bezard PhD Wassilios G. Meissner MD PhD Pierre-Olivier Fernagut PhD 《Movement disorders》2020,35(7):1163-1172
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Brice Laurens Sylvain Vergnet Miguel Cuina Lopez Alexandra Foubert-Samier François Tison Wassilios G. Meissner 《Current neurology and neuroscience reports》2017,17(5):41
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder that is characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. Some symptomatic treatments are available while neuroprotection or disease-modification remain unmet treatment needs. The pathologic hallmark is the accumulation of aggregated alpha-synuclein (α-syn) in oligodendrocytes forming glial cytoplasmic inclusions, which qualifies MSA as synucleinopathy together with Parkinson’s disease and dementia with Lewy bodies. Despite progress in our understanding of the pathogenesis of MSA, the origin of α-syn aggregates in oligodendrocytes is still a matter of an ongoing debate. We critically review here studies published in the field over the past 5 years dealing with pathogenesis, genetics, clinical signs, biomarker for improving diagnostic accuracy, and treatment development. 相似文献
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Multiple system atrophy (MSA) is a progressive neurodegenerative disease variably associated with motor, nonmotor, and autonomic symptoms, resulting from putaminal and cerebellar degeneration and associated with glial cytoplasmic inclusions enriched with α-synuclein in oligodendrocytes and neurons. Although symptomatic treatment of MSA can provide significant improvements in quality of life, the benefit is often partial, limited by adverse effects, and fails to treat the underlying cause. Consistent with the multisystem nature of the disease and evidence that motor symptoms, autonomic failure, and depression drive patient assessments of quality of life, treatment is best achieved through a coordinated multidisciplinary approach driven by the patient’s priorities and goals of care. Research into disease-modifying therapies is ongoing with a particular focus on synuclein-targeted therapies among others. This review focuses on both current management and emerging therapies for this devastating disease.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00890-x) contains supplementary material, which is available to authorized users.Key Words: Multiple system atrophy, multidisciplinary care, α-synuclein, symptomatic therapy, disease-modifying 相似文献
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Gilman S May SJ Shults CW Tanner CM Kukull W Lee VM Masliah E Low P Sandroni P Trojanowski JQ Ozelius L Foroud T;North American Multiple System Atrophy Study Group 《Journal of neural transmission (Vienna, Austria : 1996)》2005,112(12):1687-1694
Summary. The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from
the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate
pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group
enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian
features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed
levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence
occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress
upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate
several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson’s
disease and dementia with Lewy bodies. 相似文献
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IntroductionMultiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis.MethodsWe used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform.ResultsWe estimate the heritability among common variants of MSA in pooled cases at 2.09–6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis.DiscussionMSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants. 相似文献
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Stuart J. McCarter MD Elizabeth A. Coon MD Eduardo E. Benarroch MD Michael H. Silber MB ChB Erik K. St. Louis MD MS 《Annals of neurology》2023,93(1):205-212
Risk of sudden death in multiple system atrophy (MSA) is greatest during sleep with unknown mechanisms. We compared nocturnal pulse event frequency in 46 MSA patients and age-/sex-matched controls undergoing overnight pulse oximetry. Nocturnal oxyhemoglobin desaturation indices and pulse event indices (PEIs) were recorded, and relationships between pulse oximetry variables and survival were analyzed. MSA patients had lower PEI (3.1 ± 5.3 vs. 12.8 ± 10.8, p < 0.001) despite greater hypoxic burden and similar frequency of respiratory events. Nocturnal pulse events were not associated with severity of daytime autonomic failure. Two MSA patients had suspected sudden death, both with severely reduced PEI. MSA patients have fewer nocturnal pulse events compared with controls, despite similar respiratory event frequency, suggesting abnormal cardiac responses to sleep-disordered breathing. Whether this contributes to sudden death in MSA requires further study. ANN NEUROL 2023;93:205–212 相似文献
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Objectives: Evaluate the benefit of intrathecal baclofen (ITB) therapy on function, quality of life, and progression in patients with multiple system atrophy (MSA). Methods: We report on three MSA patients at different stages treated with ITB therapy. MSA patients were staged using Watanabe et al. ADL milestones for disease progression and by scales for tone (modified Ashworth scale) ambulation (Hauser ambulation index) and disability (expanded disability status scale) Results: All three patients had an improvement in the modified Ashworth scale and none had progression in their disability or ambulatory outcomes and did not progress as predicted by Watanabe et al. Conclusions: Our results suggest that ITB can maintain (or improve function) and maintain quality of life in patients with MSA. ITB is currently not indicated for patients with MSA but should be studied further for the quality of life benefits and delay in disease progression it potentially provides. 相似文献
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Jennifer Faber MD Ilaria Giordano MD Xueyan Jiang MS Christine Kindler MD Annika Spottke MD Julio Acosta-Cabronero PhD Peter J. Nestor MD PhD Judith Machts PhD Emrah Düzel MD PhD Stefan Vielhaber MD Oliver Speck PhD Ales Dudesek MD Christoph Kamm MD Lukas Scheef MD PhD Thomas Klockgether MD PhD 《Movement disorders》2020,35(5):816-824
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Wassilios G. Meissner Pierre‐Olivier Fernagut Benjamin Dehay Patrice Pran Anne Pavy‐Le Traon Alexandra Foubert‐Samier Miguel Lopez Cuina Erwan Bezard Franois Tison Olivier Rascol 《Movement disorders》2019,34(11):1629-1642
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α‐synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society 相似文献
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D. L. Pountney T. C. Dickson J. H. T. Power J. C. Vickers A. J. West W. P. Gai 《Neurotoxicity research》2011,19(1):115-122
Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9–10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson’s disease. Metallothioneins (MTs) are a class of low-molecular weight (6–7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments. 相似文献
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Alexey A. Shadrin PhD Sören Mucha PhD David Ellinghaus PhD Mary B. Makarious BSc Cornelis Blauwendraat PhD Ashwin A.K. Sreelatha MSc Antonio Heras-Garvin PhD Jinhui Ding PhD Monia Hammer PhD Alexandra Foubert-Samier MD Wassilios G. Meissner MD Olivier Rascol PhD Anne Pavy-Le Traon MD Oleksandr Frei PhD Kevin S. O'Connell PhD Shahram Bahrami PhD Stefan Schreiber MD Wolfgang Lieb MD Martina Müller-Nurasyid PhD Ulf Schminke MD Georg Homuth PhD Carsten O. Schmidt PhD Markus M. Nöthen MD Per Hoffmann PhD Christian Gieger PhD Gregor Wenning MD for the European Multiple System Atrophy Study Group J. Raphael Gibbs PhD Andre Franke PhD John Hardy PhD Nadia Stefanova PhD Thomas Gasser MD Andrew Singleton PhD Henry Houlden MD Sonja W. Scholz MD Ole A. Andreassen PhD Manu Sharma PhD 《Movement disorders》2021,36(2):449-459