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.