Correlating symptoms and skin α-synuclein seeding parameters in olfactory dysfunction and Lewy body dementia

Abstract Objective We investigated profiles of clinical symptoms and kinetic α-synuclein seed amplification assay (αSyn-SAA) parameters in skin across the spectrum of Lewy body disease by comparing normosmic healthy controls (HC), individuals with idiopathic olfactory dysfunction (iOD), and dementia with Lewy bodies (DLB) patients. Methods In this cross-sectional, case–control study, we included 49 αSyn-SAA-negative HC, 18 αSyn-SAA-positive iOD, and 25 αSyn-SAA-positive DLB patients. αSyn-SAA was performed on olfactory mucosa swabs and skin biopsies. Only the skin-derived kinetic parameters were explored for comparative kinetic analysis (13 iOD and 24 DLB). Clinical assessments included the Sniffin’ Sticks 16 for olfaction, Montreal Cognitive Assessment (MoCA), REM Sleep Behavior Disorder Single-Question (RBD1Q), and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) I–III. Results We observed a stepwise increase in symptoms across groups from HC to iOD to DLB, measured by MoCA ( p < 0.05) and MDS-UPDRS I, II, III ( p < 0.001). Participants with iOD and DLB did not differ in olfactory function (mean [SD]: 6.5 [2.4] vs. 6.0 [2.5], p = 0.51). Accelerated αSyn seeding kinetics, particularly shorter time to 50% of maximal fluorescence, were detected in DLB vs iOD (median hours [interquartile range] 17 [15–20] vs 14 [13–16], p = 0.017), achieving a classification accuracy of 74% (95% CI 57–91), and correlated with number of symptoms related to DLB without and with adjusting for age and sex ( p = 0.002, R 2 = 0.605). Conclusions These findings delineate the Lewy body symptom profile in iOD positioning iOD as a prodromal stage in which peripheral αSyn aggregation kinetics can be detected.