Abstract
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.
Highlights
Multiple system atrophy (MSA), an atypical parkinsonian disorder, is a sporadic and rare neurodegenerative disorder affecting 1.9–4.9 of 100,000 people with an average onset in the sixth decade of life and a mean survival of 6–9 years [1]
Reduced myelination is accompanied by pronounced neuronal loss in distinct brain regions, including the motor cortex, dorsolateral putamen, globus pallidus, cerebellum, and substantia nigra correlating with GCI density and disease progression [3,13,15,19]
As neuronal loss may occur as a consequence of oligodendroglial dysfunction at a more advanced stage in MSA, the question raises whether targeting neurodegeneration is a timely appropriate target to delay disease progression
Summary
Multiple system atrophy (MSA), an atypical parkinsonian disorder, is a sporadic and rare neurodegenerative disorder affecting 1.9–4.9 of 100,000 people with an average onset in the sixth decade of life and a mean survival of 6–9 years [1]. In case patients show a sporadic, progressive adult-onset disease with parkinsonism or cerebellar ataxia and at least one additional symptom indicative for dysautonomia combined with other clinical or neuroimaging features, “possible” MSA is diagnosed. For the category of “probable” MSA, the patients must present a sporadic, adult-onset, and progressive disease course including cerebellar or parkinsonian symptoms with poor l-Dopa responsiveness in combination with autonomic symptoms. Since there is currently no valid clinical, biochemical, or imaging biomarker established, a “definite” MSA diagnosis requires the neuropathological presence of oligodendroglial cytoplasmic inclusions (GCI) containing alpha-synuclein (α-syn) aggregates. This is the most prominent structural hallmark of MSA [2,3,4]. This review provides an overview of the neuropathology of MSA, summarizes current symptomatic treatment strategies, and more importantly reflects on potential disease-modifying approaches for MSA
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