α-Synuclein in cutaneous autonomic nerves

Objective: To develop a cutaneous biomarker for Parkinson disease (PD). Methods: Twenty patients with PD and 14 age- and sex-matched control subjects underwent examinations, autonomic testing, and skin biopsies at the distal leg, distal thigh, and proximal thigh. alpha-Synuclein deposition and the density of intraepidermal, sudomotor, and pilomotor nerve fibers were measured. alpha-Synuclein deposition was normalized to nerve fiber density (the alpha-synuclein ratio). Results were compared with examination scores and autonomic function testing. Results: Patients with PD had a distal sensory and autonomic neuropathy characterized by loss of intraepidermal and pilomotor fibers (p, 0.05 vs controls, all sites) and morphologic changes to sudomotor nerve fibers. Patients with PD had greater alpha-synuclein deposition and higher alpha-synuclein ratios compared with controls within pilomotor nerves and sudomotor nerves (p < 0.01, all sites) but not sensory nerves. Higher alpha-synuclein ratios correlated with Hoehn and Yahr scores (r = 0.58-0.71, p < 0.01), with sympathetic adrenergic function (r = -0.40 to -0.66, p < 0.01), and with parasympathetic function (r = -0.66 to -0.77, p > 0.01). Conclusions: We conclude that alpha-synuclein deposition is increased in cutaneous sympathetic adrenergic and sympathetic cholinergic fibers but not sensory fibers of patients with PD. Higher alpha-synuclein deposition is associated with greater autonomic dysfunction and more advanced PD. These data suggest that measures of alpha-synuclein deposition in cutaneous autonomic nerves may be a useful biomarker in patients with PD.