Multiple System Atrophy: Recent Developments and Future Perspectives

Abstract

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

Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies

“…(α-Syn) aggregates [62,67]. In these pathologies, a conformational change (misfolding) of the α-Syn monomer produces an aggregation nucleus (seed), which can induce the conversion of other α-Syn molecules, forming Lewy bodies (LB), the primary histopathological lesion of PD and DLB, or other oligodendroglial and neuronal cytoplasmic inclusions in MSA [29,42]. The seeded conversion mechanism, resulting in the self-propagation of misfolded α-Syn, is named nowadays as prion-like, due to the analogy to that initially identified in prion diseases [27,53,65].…”

Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations

“…MSA is a degenerative disorder of the central and autonomic nervous systems characterized by parkinsonian, cerebellar, and autonomic symptoms. 64 The completion time is about 30 to 45 minutes. Part II (motor examination) should be done by a trained health care professional.…”

A Phase 1 Randomized Trial of Specific Active α‐Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy

“…Therefore, disease-modifying therapies remain an urgent unmet need. 2,3 The neuropathological hallmark is the accumulation of α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, [4][5][6] qualifying MSA as a synucleinopathy together with Parkinson's disease and Lewy body dementia. The origin of α-synuclein in glial cytoplasmic inclusions remains under debate, and the exact mechanisms underlying the pathogenesis are only incompletely understood.…”

“…Nevertheless, the accumulation of α-synuclein aggregates and their cell-to-cell propagation are believed to play a central role at molecular and cellular levels in the neurodegenerative process in MSA. 1,3,[7][8][9][10] As a consequence, α-synuclein-targeting therapies are currently considered a promising approach to prevent disease progression in MSA. 3,11 One suitable approach being investigated is specific active immunotherapy.…”

“…1,3,[7][8][9][10] As a consequence, α-synuclein-targeting therapies are currently considered a promising approach to prevent disease progression in MSA. 3,11 One suitable approach being investigated is specific active immunotherapy. This involves immunization with short peptides (AFFITOPEs) mimicking the amino acid sequence of a segment of the target protein.…”