Cutaneous Alpha-Synuclein Deposition Informs Autonomic Function in Individuals with Early-Stage Multiple System Atrophy

Abstract

Purpose: Multiple system atrophy is a progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Phosphorylated alpha-synuclein in skin nerves has emerged as a promising biomarker, but longitudinal studies remain limited. This study evaluated changes in cutaneous alpha-synuclein deposition over time, its association with autonomic dysfunction, and its concordance with seed amplification assay findings. Methods: Seventeen participants with probable multiple system atrophy were followed for twelve months with clinical assessments, skin biopsies from posterior cervical and distal thigh regions, standardized orthostatic vital signs, and cerebrospinal fluid biomarker collection. Phosphorylated alpha-synuclein deposition was quantified using immunofluorescence microscopy and correlated with autonomic measures and seed amplification assay results. Results: Cutaneous alpha-synuclein deposition increased from baseline to twelve months. Total deposition was associated with orthostatic systolic blood pressure drop (ρ = 0.80, p = 0.0001) and with higher scores on the Orthostatic Hypotension Questionnaire and Composite Autonomic Symptom Score. Posterior cervical deposition showed stronger autonomic associations than distal thigh. No associations were found with global disease severity or neurofilament light chain levels. Two participants with negative seed amplification assay results showed phosphorylated alpha-synuclein on skin biopsy. Conclusion: In this cohort, cutaneous phosphorylated alpha-synuclein increased over time and correlated with objective orthostatic hypotension and autonomic symptom burden in early synucleinopathy. Skin biopsy may serve as a minimally invasive tool to support diagnosis, monitor progression, and stratify clinical trial participants.