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Dermal Phospho-Alpha-Synuclein Among Individuals With and Without Cerebrospinal Fluid Aggregated Alpha-Synuclein

Chahine, L.; Chatterjee, K.; Gochanour, C.; Lafontant, D.-E.; Akhtar, R.; Shetty, N.; Dahodwala, N.; Brooker, S.; Gonzalez-Latapi, P.; Prakash, N.; Defendorf, S.; Midyette, J.; Foroud, T.; Merchant, K.; Coughlin, D.; Tropea, T. F.; Frasier, M.; Larson, D.; Coffey, C.; Marek, K.; Simuni, T.

2025-12-27 neurology
10.64898/2025.12.17.25342090 medRxiv
Show abstract

BackgroundBiomarkers of abnormal alpha-synuclein (asyn) that can be obtained with minimal invasiveness are needed. Promising data on dermal serine-129-phosphorylated alpha-synuclein (dermal-ps129-asyn) have emerged but accuracy for aggregated asyn in cerebrospinal fluid (CSF) has not been examined. ObjectiveDetermine sensitivity and specificity of dermal-ps129-asyn for neuronal asyn measured with cerebrospinal fluid asyn seed amplification assay (CSFasynSAA). MethodsCross-sectional observational study; 50 individuals with positive or negative CSFasynSAA underwent 3 skin biopsies for blinded assessment of phospho-serine-129 asyn in nerve terminals. Sensitivity and specificity versus CSFasynSAA were calculated. ResultsAmong 50 participants, 30/38 CSFasynSAA+ were dermal-ps129-asyn+; 6/12 CSFasynSAA-were dermal-ps129-asyn-, yielding sensitivity of 79% and specificity of 50%. ConclusionDermal-ps129-asyn has low specificity for CSF asyn SAA in this small sample. This precludes its use as a marker of CSF neuronal asyn aggregates. Future studies are needed to determine optimal methods to assess asyn aggregates in central and peripheral compartments.

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