Biomarkers and Prognostic Factors in Multiple System Atrophy: A Protocol for a Three-Year, Multicenter, Prospective, Longitudinal Cohort Study in Japan and South Korea

Background: Multiple system atrophy (MSA) is a sporadic, adult-onset neurodegenerative disorder characterized by autonomic failure, Parkinsonism, and cerebellar ataxia. Early diagnosis remains a major unmet need because current clinical criteria often identify the disease only after considerable progression. The recently proposed Movement Disorder Society (MDS) prodromal MSA criteria provide a framework for earlier recognition; however, their specificity is limited. In particular, individuals who initially present isolated parkinsonism or cerebellar ataxia without overt autonomic dysfunction may be overlooked, although some of them eventually progress to MSA. To address this critical gap, this multinational, multicenter study aims to clarify the earliest detectable clinical and biological phases of MSA, identify predictors of disease conversion, and refine prodromal diagnostic criteria within a well-characterized East Asian cohort. Methods: This project will be conducted across multi-centers in Japan and South Korea in two phases. Phase 1 is a retrospective analysis of patients initially suspected but not diagnosed with MSA, who were later confirmed as probable or clinically established MSA, to delineate early clinical, imaging, and autonomic features. Phase 2 is a prospective longitudinal cohort enrolling patients aged 30–80 years classified as mono-system MSA (moMSA), possible prodromal MSA according to MDS criteria, or pure autonomic failure. Participants will undergo standardized clinical, neuroimaging, and biomarker assessments including serum and CSF every six months for up to 36 months to identify predictors of conversion to probable or clinically established MSA. Conslusion: This protocol represents the first multinational effort in East Asia to establish a longitudinal prodromal MSA cohort. By integrating clinical, neuroimaging (brain MRI), and biomarker data (α-synuclein strain and genetic analysis), the study aim to clarify the earliest detectable phase of MSA, refine prodromal diagnostic criteria, and provide a platform for future disease-modifying trials. Trial registration: Clinical research information service (CRIS) number: KCT0011830