This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

Key Points Question Does the pathological α-synuclein (αSyn P ) detected by immunohistochemistry in the skin of individuals with Parkinson disease (PD) have aggregation seeding activity, and is skin αSyn P seeding activity a potential biomarker for diagnosis of PD and other synucleinopathies? Findings In this diagnostic study including skin samples from 160 autopsies and 41 biopsies, a statistically significant increase in αSyn P seeding activity was observed in individuals with PD and synucleinopathies compared with controls with tauopathies and nonneurodegenerative diseases. Meaning Skin αSyn P has aggregation seeding activity in patients with PD and non-PD synucleinopathies and may be a biomarker for antemortem diagnosis of PD and other synucleinopathies.

An age- and gender-adjusted normative dataset for IENF density at the lateral distal lower leg obtained with indirect immunofluorescence is presented for the first time by sharing data from four experienced laboratories worldwide. This dataset can be used as reference for laboratories processing skin biopsies with this technique.