scholarly journals Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

2020 ◽  
Vol 21 (8) ◽  
pp. 2775 ◽  
Author(s):  
Lisa Mészáros ◽  
Alana Hoffmann ◽  
Jeanette Wihan ◽  
Jürgen Winkler
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Autonomic Failure ◽  
Neuronal Loss ◽  
Symptomatic Treatment ◽  
Alpha Synuclein ◽  
Rapid Progression ◽  
Cytoplasmic Inclusions ◽  
Atypical Parkinsonian Syndrome ◽  
Disease Modifying

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

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 Current experimental disease-modifying therapeutics for multiple system atrophy

2021 ◽  
Author(s):  
Miguel Lemos ◽  
Gregor K. Wenning ◽  
Nadia Stefanova
Keyword(s):  
Multiple System Atrophy ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Neurodegenerative Disorder ◽  
Rapid Progression ◽  
Cytoplasmic Inclusions ◽  
Disease Modifying ◽  
Aggressive Clinical Course ◽  
Preclinical And Clinical Studies ◽  
Variable Clinical Presentation

AbstractMultiple system atrophy (MSA) is a challenging neurodegenerative disorder with a difficult and often inaccurate early diagnosis, still lacking effective treatment. It is characterized by a highly variable clinical presentation with parkinsonism, cerebellar ataxia, autonomic dysfunction, and pyramidal signs, with a rapid progression and an aggressive clinical course. The definite MSA diagnosis is only possible post-mortem, when the presence of distinctive oligodendroglial cytoplasmic inclusions (GCIs), mainly composed of misfolded and aggregated α-Synuclein (α-Syn) is demonstrated. The process of α-Syn accumulation and aggregation within oligodendrocytes is accepted one of the main pathological events underlying MSA. However, MSA is considered a multifactorial disorder with multiple pathogenic events acting together including neuroinflammation, oxidative stress, and disrupted neurotrophic support, among others. The discussed here treatment approaches are based on our current understanding of the pathogenesis of MSA and the results of preclinical and clinical therapeutic studies conducted over the last 2 decades. We summarize leading disease-modifying approaches for MSA including targeting α-Syn pathology, modulation of neuroinflammation, and enhancement of neuroprotection. In conclusion, we outline some challenges related to the need to overcome the gap in translation between preclinical and clinical studies towards a successful disease modification in 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 Multiple system atrophy: genetic risks and alpha-synuclein mutations

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2072 ◽  
Author(s):  
Heather T Whittaker ◽  
Yichen Qui ◽  
Conceição Bettencourt ◽  
Henry Houlden
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Research Collaboration ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Common Mechanism ◽  
International Research Collaboration ◽  
Cytoplasmic Inclusions ◽  
Genetic Risks

Multiple system atrophy (MSA) is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings. Families with certain types of α-synuclein mutations develop diseases that mimic MSA, and the spectrum of clinical and pathological features in these families suggests a spectrum of severity, from late-onset Parkinson’s disease to MSA. Nonetheless, controversies persist, such as the role of common α-synuclein variants in MSA and whether this disorder shares a common mechanism of spreading pathology with other protein misfolding neurodegenerative diseases. Here, we review these issues, specifically focusing on α-synuclein mutations.

Medullary neuronal loss and alpha-synuclein burden in Multiple System Atrophy

2015 ◽  
Vol 192 ◽  
pp. 48
Author(s):  
E.A. Coon ◽  
A.M. Schmeichel ◽  
J.E. Parisi ◽  
P.A. Low ◽  
E.E. Benarroch
Keyword(s):  
Multiple System Atrophy ◽  
Neuronal Loss ◽  
Alpha Synuclein

Abstract P381: Understanding the Symptoms of Neurogenic Orthostatic Hypotension: Results From a Survey of Patients and Caregivers

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Lawrence A Hewitt ◽  
Charles H Adler ◽  
Daniel O Claassen ◽  
Christopher H Gibbons ◽  
Satish R Raj
Keyword(s):  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Orthostatic Hypotension ◽  
Autonomic Failure ◽  
Alpha Synuclein ◽  
Pure Autonomic Failure ◽  
Motor Symptoms ◽  
Neurogenic Orthostatic Hypotension ◽  
The Past ◽  
Increased Risk

Objective: To understand the burden and impact of symptoms of neurogenic orthostatic hypotension (nOH) on patients Background: nOH and its symptoms such as dizziness/lightheadedness are common in patients with Parkinson disease (PD) and other forms of autonomic dysfunction. Methods: An author-designed, US-based survey was conducted by Harris Poll. Eligible participants were aged ≥18 years with PD, multiple system atrophy (MSA), or pure autonomic failure and ≥1 of the following: orthostatic hypotension, nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Results: Most patients (90%) had a diagnosis of PD, and most caregivers (88%) cared for a patient with PD (Table 1) . Patients (34%) and caregivers (49%) reported experiencing nOH symptoms before PD or MSA motor symptoms and >40% indicated that nOH symptoms were more troublesome than motor manifestations of PD or MSA. Less than a quarter (22%) of respondents suggested symptoms were most severe in the morning; more (30%) reported a consistent severity throughout the day. Patients (40%) and caregivers (63%) reported trouble managing symptoms during the day. In the past 12 months, a fall due to nOH symptoms was reported by 57% of patients and 80% of caregivers. Conclusions: These findings suggest that nOH symptoms may predate the onset of motor symptoms in neurodegenerative conditions linked to alpha-synuclein pathology. Many respondents report nOH symptoms are the same severity through the day. Patients with nOH may have trouble managing symptoms and note an increased risk for falls.

scholarly journals Cognitive impairment in multiple system atrophy: Changing concepts

2011 ◽  
Vol 5 (4) ◽  
pp. 303-309 ◽  
Author(s):  
Agessandro Abrahão ◽  
Livia Almeida Dutra ◽  
Pedro Braga Neto ◽  
José Luiz Pedroso ◽  
Ricardo Araújo de Oliveira ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Multiple System Atrophy ◽  
Diagnostic Criteria ◽  
Cerebellar Ataxia ◽  
Neuropsychological Assessment ◽  
Autonomic Failure ◽  
Current Data ◽  
Clinical Feature ◽  
Neuropsychological Profile ◽  
Variable Combination

Abstract Multiple system atrophy (MSA) is characterized by a variable combination of cerebellar ataxia, parkinsonism and pyramidal signs associated with autonomic failure. Classically, cognitive impairment was not considered a clinical feature of MSA and dementia was pointed out as an exclusion diagnostic criteria. Based on comprehensive neuropsychological assessment, cognitive impairment was found to be a frequent feature in MSA, and clinically-defined dementia is now reported in 14-16% of cases. This article reviews the current data on cognitive impairment in MSA along with its neuropsychological profile and pathophysiology.

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 Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

2022 ◽  
Author(s):  
Berkiye Sonustun ◽  
Firat M Altay ◽  
Catherine Strand ◽  
Geshanthi Hondhamuni ◽  
Thomas T Warner ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Post Translational Modifications ◽  
Variable Extent ◽  
Neurologically Normal ◽  
Main Component ◽  
Initiating Factors

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

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.

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