Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

2017 ◽  
Vol 89 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Shunsuke Koga ◽  
Dennis W Dickson
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Cytoplasmic Inclusion ◽  
Olivopontocerebellar Atrophy ◽  
Cytoplasmic Inclusions ◽  
Cellular Origin ◽  
Recent Advances ◽  
Neuronal Cytoplasmic Inclusions ◽  
Variable Combination

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a ‘prion hypothesis’ are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

scholarly journals A historical review of multiple system atrophy with a critical appraisal of cellular and animal models

2021 ◽  
Author(s):  
David J. Marmion ◽  
Wouter Peelaerts ◽  
Jeffrey H. Kordower
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Rem Sleep Behavior Disorder ◽  
Alpha Synuclein ◽  
Motor Symptom ◽  
Olivopontocerebellar Atrophy ◽  
Prodromal Phase ◽  
Sleep Behavior ◽  
Cytoplasmic Inclusions

AbstractMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.

scholarly journals Comparison of Neuropathological Characteristics between Multiple System Atrophy Cerebellar Type and Parkinsonian Type

2020 ◽  
Vol 38 (3) ◽  
pp. 194-203
Author(s):  
Eun-Joo Kim ◽  
Sukmin Lee ◽  
Sung-Hwan Jang ◽  
Myung Jun Lee ◽  
Jae-Hyeok Lee ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
University Hospital ◽  
Cytoplasmic Inclusions ◽  
Age Related ◽  
National University ◽  
Neuronal Cytoplasmic Inclusions ◽  
Cerebellar Type

Background: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized by various combinations of parkinsonism, cerebellar ataxia, autonomic dysfunction and pyramidal signs. Two clinical subtypes are recognized: MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). The aim of this study was to compare pathological features between MSA-C and MSA-P.Methods: Two autopsy confirmed cases with MSA were included from the Pusan National University Hospital Brain Bank. Case 1 had been clinically diagnosed as MSA-C and case 2 as MSA-P. The severity of neuronal loss and gliosis as well as the glial and neuronal cytoplasmic inclusions were semiquantitatively assessed in both striatonigral and olivopontocerebellar regions. Based on the grading system, pathological phenotypes of MSA were classified as striatonigral degeneration (SND) predominant (SND type), olivopontocerebellar degeneration (OPC) predominant (OPC type), or equivalent SND and OPC pathology (SND=OPC type).Results: Both cases showed widespread and abundant α-synuclein positive glial cytoplasmic inclusions in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures, leading to the primary pathological diagnosis of MSA. Primary age-related tauopathy was incidentally found but Lewy bodies were not in both cases. The pathological phenotypes of MSA were MSA-OPC type in case 1 and MSA-SND=OPC type in case 2.Conclusions: Our data suggest that clinical phenotypes of MSA reflect the pathological characteristics.

scholarly journals Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

2021 ◽  
Author(s):  
Nicole Campese ◽  
Alessandra Fanciulli ◽  
Nadia Stefanova ◽  
Johannes Haybaeck ◽  
Stefan Kiechl ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Substantial Contribution ◽  
Olivopontocerebellar Atrophy ◽  
Striatonigral Degeneration ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Neurodegenerative Process ◽  
Disease Modifying Therapy ◽  
Current State

AbstractMultiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger’s substantial contribution.

scholarly journals Multiple-System Atrophy in Long-Term Professional Painter: A Case Report

2012 ◽  
Vol 2012 ◽  
pp. 1-5
Author(s):  
Yusa Nagai ◽  
Riko Kitazawa ◽  
Miku Nakagawa ◽  
Munenori Komoda ◽  
Takeshi Kondo ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Medulla Oblongata ◽  
Neurodegenerative Disorder ◽  
Histopathological Examination ◽  
Neuronal Loss ◽  
Cytoplasmic Inclusion ◽  
Multiple Organ ◽  
Old Japanese ◽  
History Of

Introduction. Multiple system atrophy (MSA) is a rare and severe adult-onset, sporadic, and progressive neurodegenerative disorder. Here, we describe an autopsy case of MSA in a long-term professional painter. Although typical glial cytoplasmic inclusion (GCI) was not observed in a routine histological examination, strong α-synuclein immunostaining in the nucleus confirmed the diagnosis of MSA.Case Presentation. A 48-year-old Japanese man with a long occupational history of professional painter was sent to the emergency room, where he died of multiple organ failure. The patient had suffered tremors and inarticulateness at age 28, developed diabetes at 42 and was diagnosed with spinocerebellar degeneration at 46. A histopathological examination showed severe neuronal loss, gliosis, and tissue rarefaction in the paleostriatum, striate body of the substantia nigra, the pons, and the olivary nucleus of the upper medulla oblongata, intermediolateral of the spinal gray matter (sacral region). α-synuclein-positive GCI in oligodendroglia was occurred in the cerebral cortex, the midbrain, the medulla oblongata, and the spinal cord. These findings confirmed the presence of multiple-system atrophy (OPCA+SDS).Conclusion. Although the pathogenesis of MSA is still unclear, prolonged, and extensive exposure to organic solvents, together with a hyperglycemic morbidity attributed to diabetes, may have contributed to the onset and clinical course of the present case.

scholarly journals Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lisa Mészáros ◽  
Markus J. Riemenschneider ◽  
Heiko Gassner ◽  
Franz Marxreiter ◽  
Stephan von Hörsten ◽  
...  
Keyword(s):  
Mouse Model ◽  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Purkinje Cells ◽  
Alpha Synuclein ◽  
Significant Loss ◽  
Disease Stage ◽  
Cytoplasmic Inclusions ◽  
Unsteady Gait ◽  
Advanced Disease Stage

AbstractMultiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

scholarly journals Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1798-1810 ◽  
Author(s):  
Yasuo Miki ◽  
Sandrine C Foti ◽  
Daniela Hansen ◽  
Kate M Strand ◽  
Yasmine T Asi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Multiple System Atrophy ◽  
Dentate Gyrus ◽  
Memory Impairment ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Cornu Ammonis ◽  
Neuronal Cytoplasmic Inclusions ◽  
With Memory ◽  
Normal Cognition

Abstract Recent post-mortem studies reported 22–37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1–4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal–subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.

XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy

2014 ◽  
Vol 33 (01) ◽  
pp. 76-83 ◽  
Author(s):  
Yasuhiro Kawamoto ◽  
Hidefumi Ito ◽  
Masafumi Ihara ◽  
Ryosuke Takahashi
Keyword(s):  
Multiple System Atrophy ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions

scholarly journals Bereitschaftspotential in Multiple System Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi-Chien Yang ◽  
Fang-Tzu Chang ◽  
Jui-Cheng Chen ◽  
Chon-Haw Tsai ◽  
Fu-Yu Lin ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Healthy Control Group ◽  
Control Group ◽  
Clinical Tool ◽  
Movement Onset ◽  
Parietal Area ◽  
Healthy Control ◽  
Motor Cortical

Objective: Multiple system atrophy (MSA) is a neurodegenerative disorder manifesting as parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is categorized into MSA with predominant parkinsonism (MSA-P) and into MSA with predominant cerebellar ataxia (MSA-C). The pathophysiology of motor control circuitry involvement in MSA subtype is unclear. Bereitschaftspotential (BP) is a feasible clinical tool to measure electroencephalographic activity prior to volitional motions. We recorded BP in patients with MSA-P and MSA-C to investigate their motor cortical preparation and activation for volitional movement.Methods: We included eight patients with MSA-P, eight patients with MSA-C, and eight age-matched healthy controls. BP was recorded during self-paced rapid wrist extension movements. The electroencephalographic epochs were time-locked to the electromyography onset of the voluntary wrist movements. The three groups were compared with respect to the mean amplitudes of early (1,500–500 ms before movement onset) and late (500–0 ms before movement onset) BP.Results: Mean early BP amplitude was non-significantly different between the three groups. Mean late BP amplitude in the two patient groups was significantly reduced in the parietal area contralateral to the movement side compared with that in the healthy control group. In addition, the late BP of the MSA-C group but not the MSA-P group was significantly reduced at the central parietal area compared with that of the healthy control group.Conclusions: Our findings suggest that patients with MSA exhibit motor cortical dysfunction in voluntary movement preparation and activation. The dysfunction can be practicably evaluated using late BP, which represents the cerebello-dentato-thalamo-cortical pathway.

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