Characterizing Cutaneous α‐Synuclein Deposition and Seeding Activity in Parkinson's Disease Subtypes

OBJECTIVE: Cutaneous phosphorylated α-synuclein (p-syn) and α-synuclein seeding activity are promising biomarkers for Parkinson's disease (PD), but their clinical value remains uncertain due to disease heterogeneity. This study evaluates these two biomarkers in PD patients to inform phenotype-specific diagnosis and disease severity assessment. METHODS: We compared the diagnostic performance of cutaneous p-syn immunostaining and α-synuclein seed amplification assay (syn-SAA) in 108 PD patients and 60 controls. Additional analyses assessed the influence of clinical subtypes on p-syn distribution (positive rates and diffusion coefficients across regions), and syn-SAA characteristics, along with their correlations with clinical scales. RESULTS: Cutaneous p-syn immunostaining showed 100% specificity and 75% sensitivity, whereas syn-SAA showed 93.3% specificity and 86.1% sensitivity. Among the clinical subtypes, a significant regional difference in the diffusion coefficient was observed only in the suspected REM sleep behavior disorder subgroup, with higher values in the distal leg than in the posterior cervical region (p = 0.001). The diffusion coefficient correlated with the severity of both motor and non-motor symptoms (all p < 0.05). No significant differences in syn-SAA positivity rates or parameters were found across clinical subtypes. Syn-SAA parameters were consistent across biopsy sites and associated with disease duration and non-motor symptom severity, but not with motor symptom severity. INTERPRETATION: These findings highlight complementary roles for skin biomarkers in PD. P-syn deposition shows regional α-synuclein aggregation, reflecting clinical heterogeneity and supporting phenotype-specific diagnosis and severity assessment, whereas α-synuclein seeding activity enables early diagnosis and may serve as a potential biomarker for monitoring disease progression.