Alpha-synuclein seed amplification assay longitudinal outcomes in Lewy body disease spectrum

Evidence from neuropathological cohorts indicates that a CSF α-synuclein (α-syn) seed amplification assay (SAA) may provide quantitative kinetic parameters correlating with α-syn pathology burden in patients with Lewy body disease (LBD). Studies are needed to assess their longitudinal trend during the pre-symptomatic and clinical disease phases and their correlation with measures of disease progression. We aimed to assess the baseline α-syn CSF SAA kinetic parameters, their longitudinal variations and associations with clinical outcomes in a cohort of longitudinally repeatedly sampled Lewy Body disease patients, including clinically unimpaired (asymptomatic LBD) and neurologically impaired individuals. Participants from the prospective BioFINDER-1 study with longitudinal CSF collections (n=718) were screened by α-syn SAA. CSF samples were tested in four replicates blinded to clinical diagnoses. The number of positive replicates (Nrep), the time needed by the fluorescence signal to reach the threshold (Lag) and the highest intensity of the fluorescent signal (Imax). were analysed at baseline (time of first positive SAA) in all participants and longitudinally in those with at least two α-syn positive CSF samples available. One hundred ninety-six individuals (whole cohort) showing α-syn seeding activity were included. Of those, 170 participants tested positive by SAA in all available samples, while 26 converted from a negative to a positive test result during follow-up (LBD-converters), suggesting an early LBD stage. At baseline, LBD-converters showed lower Nrep (p=0.001) and a longer Lag (p=0.001) than subjects displaying α-syn seeding activity from the first available sample. Nrep increased longitudinally in the whole cohort (β=0.09, 95% confidence interval (95%CI) 0.06-0.12, p<0.001), in asymptomatic LBD (β=0.15, 95%CI 0.09-0.21, p<0.001) and Parkinson's disease individuals without dementia (β=0.07, 95%CI 0.02-0.12, p=0.01). The Lag decreased longitudinally in asymptomatic LBD (β=-0.24, 95%CI -0.42 - -0.06, p=0.008). Baseline Nrep predicted the subsequent appearance of dementia in the whole cohort (Hazard ratio (HR) 1.57, 95%CI 1.19-2.07, p=0.001) and the Parkinson's disease subgroup (HR 1.83, 95%CI 1.17-2.85, p=0.008). The difference between the Lag at each sampling and that at baseline was negatively associated with the appearance of dementia in the whole cohort (HR 0.76, 95%CI 0.59-0.99, p=0.04) and Parkinson's disease subgroup (HR 0.69, 95%CI 0.50-0.95, p=0.02). α-syn SAA parameters Nrep and Lag showed associations with the LBD stage and the development of dementia. Furthermore, their longitudinal variation is coherent with pathology progression over time. These data support the use of SAA kinetic parameters to monitor disease progression and therapeutic response.