Distinct cutaneous α-synuclein signatures in body-first and brain-first Parkinson’s disease subtypes

Abstract Parkinson’s disease (PD) is characterized by pathological α-synuclein (α-syn) aggregation, yet the origin of α-syn pathology (central or peripheral) remains debated. The synuclein origin and connectome (SOC) model proposes two subtypes, including brain-first (pathology initiating in brain structures) and body-first (originating in peripheral autonomic nerves) subtypes. This study aimed to delineate cutaneous α-syn signatures between these subtypes to validate the SOC model. In this cross-sectional study, 126 brain-first PD patients, 79 body-first PD patients, and 60 healthy controls were enrolled. Subtype classification was based on the presence of REM sleep behavior disorder preceding motor symptoms. All participants underwent skin biopsies at two anatomical sites: the distal leg (DL) and the posterior cervical region (C7). Intraepidermal, sudomotor, and pilomotor nerve fiber densities were quantified. Phosphorylated α-syn (p-α-syn) deposition was assessed by immunostaining, and α-syn seeding activity was evaluated using real-time quaking-induced conversion (RT-QuIC). Clinical correlations and diagnostic performance were systematically analyzed. Body-first PD patients exhibited more prominent non-motor symptoms (e.g., REM sleep behavior disorder, autonomic dysfunction) and severe autonomic denervation (reduced sweat gland and pilomotor nerve densities; P < 0.01). Immunostaining revealed significantly higher p-α-syn positivity (92.4% vs. 61.9%) and a greater p-α-syn diffusion coefficient (0.2 vs. 0.0) in body-first versus brain-first PD patients. Body-first PD patients displayed a distal-to-proximal α-syn gradient (DL:86.1% vs. C7:55.7%), contrasting the proximal-dominant pattern in brain-first PD patients (DL:40.5% vs. C7:50.8%). Body-first PD patients also demonstrated accelerated α-syn seeding activity (higher maximum fluorescence intensity, shorter time to reach threshold; P < 0.001). Cutaneous α-syn parameters strongly correlated with non-motor symptom severity in body-first PD patients (P < 0.05). Receiver operating characteristic analysis showed that DL α-syn signatures have discriminative power for subtype differentiation (AUC = 0.774). Our findings provide direct pathological evidence for the body-first versus brain-first PD framework and highlight the value of skin biopsy as a minimally invasive biomarker for PD subtyping. This study contributes to precision medicine approaches targeting α-syn pathology-specific propagation pathways in PD.