Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease

Objective: Autonomic nervous system is involved at the onset of Parkinson disease (PD), and alpha-synuclein (α-Syn) and its phosphorylated form (p-αSyn) have been detected in dermal autonomic nerve fibers of PD. We assessed disease specific conformation variant of α-Syn immunoreactivity in cutaneous nerves and characterized skin denervation patterns in PD and atypical parkinsonism (AP). Methods: We enrolled 49 subjects, 19 with PD, 17 age-matched healthy controls, and 13 with AP. The manifestations of disease were rated on clinical scales. Skin biopsies from ankle, thigh, and neck were analyzed by immunofluorescence for p-αSyn, 5G4 as a conformation specific antibody to pathogenic α-Syn and PGP9.5 as axonal marker. Intraepidermal nerve fiber density was measured in all anatomical sites as marker of neurodegeneration. Thirteen of the 19 PD underwent a 1 year follow-up visit plus skin biopsies. Results: PD subjects displayed more severe cervical skin denervation (P < 0.03), which correlated to disease duration and worsened between initial and follow-up examination (P < 0.001). p-αSyn and 5G4 were equally sensitive and specific for the diagnosis of PD (area under the ROC was 0.839 for p-αSyn and 0.886 for 5G4). PD and AP with possible alpha-synucleinopathies share the features of marked cervical denervation and the presence of 5G4. In contrast AP with possible tauopathies were normal. Interpretation: Conformational specific forms of α-Syn are detectable in skin biopsy by immunofluorescence in PD, with a promising diagnostic efficiency similar to p-αSyn. Cervical cutaneous denervation correlates with disease duration and increases over time standing out as a potential biomarker of PD progression.