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

Abstract

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.

Phosphorylated Alpha-Synuclein in Red Blood Cells as a Potential Diagnostic Biomarker for Multiple System Atrophy: A Pilot Study

“…In the present study, by measuring the levels of pS-α-syn-RBC in a Chinese cohort consisting of 107 MSA patients and 220 healthy controls, we provide evidence that the pS-α-syn-RBC in MSA patients was also significantly increased in comparison to that in healthy controls. Using pS-α-syn-RBC as a biomarker, the MSA patients were separated well from the healthy controls, with a sensitivity of 80.37%, a specificity of 88.64%, and an AUC of 0.91. e diagnostic values for MSA obtained using pS-α-syn-RBC were better than those obtained by detecting any species of plasma-and CSF-derived α-syn [4][5][6][8][9][10][11][12][13] and by measuring the total and oligomeric α-syn in RBCs [16,18,19]. e high performance of pS-α-syn-RBC in MSA diagnosis can be explained not only by the lack of the interfering factors encountered in detecting plasma α-syn [5,14], but also by the close relevance of pS-α-syn to the neuropathology of MSA, since this type of α-syn is a dominant pathological modification of α-syn in familial and sporadic Lewy body disease including PD, DLB, and MSA [20].…”

“…Various molecules, including α-syn, DJ-1, tau, Aβ, neurofilament light chain, dopamine and its metabolites, and neuroinflammatory cytokines, have been investigated for their usefulness as biomarkers for the diagnosis of MSA [4][5][6], among which α-syn in body fluids is the most studied, owing to the critical role of this protein in the pathogenesis of MSA [7]. However, results obtained so far in the detection of the total, oligomeric, and phosphorylated α-syn in cerebrospinal fluid (CSF) and blood plasma have been inconsistent and variable, with the low diagnostic performance [4][5][6][8][9][10][11][12][13]. e lack of consistency and stability has been attributed to the interference by plasma proteins such as lipoproteins and heterophilic antibodies, contamination by hemolysis, and differences in detection methods [5,14].…”

Diagnosis of multiple system atrophy

“…Despite the availability of consensus criteria for clinical diagnosis and recent advances in diagnostic techniques, the diagnostic accuracy of MSA remains sub-optimal. Recent neuropathology studies raise the possibility of additional phenotypes, including a “minimal change” variant, and a frontotemporal lobar degeneration-synuclein variant (Koga et al, 2017a). As other factors emerge, including the possibility of specific genomic traits (Federoff et al, 2015), better recognition of all the phenotypic variants of MSA should be possible.…”

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

“…To investigate whether GCI-α-Syn and LB-α-Syn represent two distinct strains, sarkosyl-insoluble α-Syn was isolated from MSA, which contains two subtypes [the parkinsonian subtype (MSA-P) and the cerebellar subtype (MSA-C) 9,10 ], and LB disease brains (Extended Data Fig. 1a, Supplementary Table 1&2).…”