Novel Aggressive Subtype of Multiple System Atrophy Identified by Unsupervised Machine Learning

OBJECTIVES: Multiple system atrophy (MSA) is classified into parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes based on predominant motor features, with corresponding pathological classifications of striatonigral (SN) degeneration and olivopontocerebellar (OPC) atrophy; however, disease progression patterns remain poorly understood. We aimed to identify novel MSA subtypes based on neuronal loss patterns using unsupervised machine learning. METHODS: We applied the Subtype and Stage Inference (SuStaIn) algorithm to analyze neuronal loss patterns in 167 autopsy-confirmed MSA. Neuronal loss was semi-quantitatively assessed in 5 brain regions: putamen, substantia nigra, pontine nucleus, inferior olivary nucleus, and cerebellar Purkinje cells. Obtained subtypes were validated by clinicopathological information. RESULTS: Three distinct subtypes were identified: SN-early subtype (54% [86/160]) with initial SN neuronal loss, OPC-early subtype (28% [44/160]) with early OPC involvement, and SN-OPC-synchronous subtype (19% [30/160]) with concurrent early neuronal loss in both systems. These subtypes corresponded well with clinical phenotypes. The SN-OPC-synchronous subtype exhibited significantly shorter survival (median 6.2 years vs 6.9 and 7.4 years in SN-early and OPC-early subtypes; p = 0.0049), more frequent rapid progression (57% vs 24% and 41% in SN-early and OPC-early subtypes; p = 0.0048), and more frequent early falls (70% vs 36% and 50% in SN-early and OPC-early subtypes; p = 0.0039). Immunohistochemical validation confirmed extensive α-synuclein pathology in both SN and OPC systems in the SN-OPC-synchronous subtype. INTERPRETATION: The SN-OPC-synchronous subtype provides insights into α-synuclein propagation mechanisms, suggesting multiple initial seeding sites rather than unidirectional spread. This computational approach uncovered disease heterogeneity undetectable by conventional methods, potentially benefiting clinical trials through patient stratification. ANN NEUROL 2026;99:989-1000.