L. Chahine, K. Chatterjee, C. Gochanour, D.-E. Lafontant, R. Akhtar, N. Shetty, N. Dahodwala, S. Brooker, P. Gonzalez-Latapi, N. Prakash, S. Defendorf, J. Midyette, T. Foroud, K. Merchant, D. Coughlin, T. F. Tropea, M. Frasier, D. Larson, C. Coffey, K. Marek, T. Simuni
Background: Dermal Serine-129-phosphorylated -synuclein (dermal-pS129-syn) is a promising biomarker, but its accuracy for CNS aggregated -synuclein (-syn) is unknown. We examined sensitivity and specificity of dermal-pS129-syn for neuronal -syn determined with CSF -syn seed amplification assay (CSF -syn SAA). Methods: A sample of individuals enrolled in the Parkinson Precision Medicine Initiative (PPMI) with positive or negative CSF -syn SAA underwent three 3-mm skin biopsies. Blinded assessment of dermal-pS129-syn was conducted. Participants were considered dermal-pS129-syn+ if [≥]1 sections demonstrated evidence of [≥]1 ps129-syn+ neuronal elements in any region biopsied. Results: The sample consisted of 50 participants; PPMI enrollment cohort included PD (n=11), healthy control (n=5), and prodromal (RBD n=5, hyposmia n=27, non-manifesting carrier of pathogenic variant n=2). 30/38 CSF -syn SAA+ were dermal-pS129-syn+; 6/12 CSF -syn SAA- were dermal-pS129-syn-, yielding sensitivity and specificity of 79% and 50% respectively. 7/10 (70%) of participants with clinical diagnosis of PD who were CSF -syn SAA+ were dermal-pS129-syn+. Of the 6 CSF -syn SAA- cases who were dermal-pS129-syn+, 3 were enrolled in the HC cohort of PPMI, and 3 were prodromal (hyposmia) cases. Conclusion: Low specificity for CSF -syn SAA precludes use of dermal-pS129-syn as a marker of CNS neuronal -syn aggregates. Future studies are needed to determine optimal methods to assess -syn aggregates in central and peripheral compartments.