Importance: Alpha-synuclein seed amplification assay (a-syn SAA) has been proposed to enhance the diagnostic accuracy of Parkinson disease (PD). Objective: To explore the diagnostic and prognostic value of cerebrospinal fluid (CSF) a-syn SAA status and seeding kinetics in PD. Design: A longitudinal cohort study of: participants in the Parkinsons Progression Markers Initiative (PPMI) cohort, recruited from 2010-2022 and followed up over 2-5 years; participants in the UK parkinsonism cohort, recruited from 2015-2022 and followed up over 2 years. Setting: Cohort study. Participants: Sporadic and monogenic PD, progressive supranuclear palsy (PSP), and controls. Exposure: CSF a-syn SAA status (positive or negative) and seeding kinetics (maximum Thioflavin T fluorescence, time to threshold (TTT), and area under the curve). Main outcomes and measures: Sensitivity and specificity of a-syn SAA in clinically-defined PD and controls; comparison of a-syn SAA positive vs. negative PD; baseline a-syn SAA seeding kinetic predictors of clinical decline in PD. Results: We studied 1,402 participants: publicly available data from the PPMI cohort, n=1275 (sporadic PD n=764, monogenic PD n=272, controls n=239); newly generated data from the UK parkinsonism cohort, n=127 (sporadic PD n=66, PSP n=52, controls n=9). Over 2-5 years of follow-up, the sensitivity of a-syn SAA in clinically-defined PD was 87.7% and the specificity in controls was 91.9%. In the UK parkinsonism cohort, a-syn SAA was positive in 8/52 (15.4%) PSP samples with distinct low and slow kinetics. In the comparison of a-syn SAA positive (n=110) vs. negative (n=57) LRRK2-PD, we found that SAA negative participants had an older mean (standard deviation) age at symptom onset (63.0 (7.6) vs. 55.4 (9.9) years) and higher mean (standard deviation) baseline serum neurofilament light chain levels (20.4 (13.2) vs. 13.8 (8.6) pg/ml), p<0.05. In a combined analysis of sporadic and monogenic PD, fast vs. slow TTT at baseline predicted cognitive decline, defined as MoCA <22 (HR 2.51, 95% CI 1.50-4.20, p=0.001). Conclusions and relevance: This study has highlighted the diagnostic value of a-syn SAA status in clinically-defined PD, and suggests the presence of pathological heterogeneity in LRRK2-PD. Furthermore, time to threshold may have a potential role as a prognostic biomarker in PD.
