Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson's disease

The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of alpha Syn oligomers (alpha Syn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of alpha Syn-PLA and small nerve fiber reduction in PD in a longitudinal study. alpha Syn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated alpha Syn (P-alpha Syn) and 5G4 (alpha Syn-5G4), a conformation-specific antibody to aggregated alpha Syn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. alpha Syn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. alpha Syn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-alpha Syn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological alpha Syn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of alpha Syn-PLA, P-alpha Syn, alpha Syn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological alpha Syn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of alpha Syn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological alpha Syn is a potential progression marker for PD.

Automated summary

The study evaluated the diagnostic and prognostic capacity of alpha Syn oligomers in PD through skin biopsies. The findings showed that alpha Syn-PLA had the highest diagnostic accuracy, while small fiber neuropathy was detected in PD and MSA. Additionally, skin denervation, not pathological alpha Syn, was identified as a potential progression marker for PD.