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

Purpose Multiple system atrophy is a progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. While molecular assays have improved diagnostic accuracy, reliable peripheral biomarkers to monitor disease progression are still lacking. Phosphorylated alpha-synuclein in skin nerves has emerged as a promising biomarker for synucleinopathies, but longitudinal studies remain limited. This study aimed to evaluate the change in cutaneous alpha-synuclein deposition over time, its association with clinical progression, and its concordance with fluid-based molecular assays. Methods Seventeen participants initially diagnosed with probable multiple system atrophy were enrolled in a longitudinal cohort study and followed for twelve months with repeated clinical assessments, brain imaging, fluid biomarker collection, and skin biopsies from the posterior cervical and distal thigh regions. Phosphorylated alpha-synuclein deposition was quantified using immunofluorescence microscopy. Associations with autonomic symptom severity and functional outcomes were assessed. We also evaluated the concordance between skin biopsy findings and results from a cerebrospinal fluid-based alpha-synuclein seed amplification assay. Results Cutaneous alpha-synuclein deposition significantly increased from baseline to twelve months. Greater deposition at follow-up was associated with more severe autonomic symptoms, including higher scores on validated questionnaires, but not with global disease severity or neurofilament light chain levels. Two participants with negative seed amplification assay results showed phosphorylated alpha-synuclein in skin biopsies. Conclusion Cutaneous phosphorylated alpha-synuclein increases over time and correlates with autonomic symptom burden in early multiple system atrophy. Skin biopsy may serve as a minimally invasive tool to support diagnosis, monitor progression, and stratify participants in clinical trials.