Diagnostic and prognostic value of alpha-synuclein seed amplification assay in Parkinson disease

BackgroundAlpha-synuclein seed amplification assay (a-syn SAA) has been proposed to be a diagnostic biomarker for Parkinsons disease (PD). Here, we have explored the diagnostic and prognostic value of cerebrospinal fluid (CSF) a-syn SAA status and seeding kinetics in PD. MethodsBaseline CSF a-syn SAA data and longitudinal clinical data were collected and analysed between 1st January 2010 and 1st April 2022 for the Parkinsons Progression Markers Initiative (PPMI) and UK parkinsonism cohorts respectively. We calculated the sensitivity and specificity of a-syn SAA in PD and controls, used linear regression to analyse a-syn SAA positive vs. negative group comparisons, and used time-to-event analyses to assess the ability of a-syn SAA seeding kinetic measures to predict clinical decline in PD. FindingsWe studied 1,402 participants: publicly available data from the PPMI cohort, n=1275 (PD, n=1,036; controls, n=239); newly generated data from the UK parkinsonism cohort, n=127 (PD, n=66; progressive supranuclear palsy (PSP), n=52; controls n=9). Over 2-5 years of follow-up, the sensitivity of a-syn SAA in PD was 87.7% and the specificity in controls was 91.9%. A-syn SAA was positive in 8/52 (15.4%) PSP samples with distinct low and slow kinetics. A-syn SAA negative LRRK2-PD participants (n=57) had an older mean (SD) age at symptom onset (63.0 (7.6) vs. 55.4 (9.9) years) and higher mean (SD) baseline serum neurofilament light chain levels (20.4 (13.2) vs. 13.8 (8.6) pg/ml), p<0.05, vs. a-syn SAA positive LRRK2-PD participants (n=110). The baseline seeding kinetic measure, time to threshold, predicted cognitive decline in PD, defined as MoCA [&le;]21 (HR 2.51, 95% CI 1.50-4.20, p=0.001). InterpretationIn PD, a-syn SAA may have value as a diagnostic and prognostic biomarker in clinical practice and as a stratification tool in clinical trials. Furthermore, we have highlighted the presence of pathological heterogeneity in LRRK2-PD. FundingMedical Research Council, PSP Association.