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.
- multisystem atrophy
- clinical neurology
- movement disorders
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Contributors SK and DWD contributed to the conception of the manuscript. SK contributed to the literature review, initial drafts of the manuscript, and preparing tables and figures. DWD contributed to the final editing of the manuscript.
Funding This research is supported by NIH grant P50 NS072187 and a Jaye F and Betty F Dyer Foundation Fellowship in progressive supranuclear palsy research.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published Online First. Reference 69 has been corrected.