Analysis of α-synuclein seed amplification assay in carriers of GBA1 and LRRK2 pathogenic variants

Background The α-synuclein seed amplification assay (αS-SAA) represents a promising strategy for identifying individuals with α-synuclein pathology, empowering development of tailored Parkinson's disease (PD) therapeutics and clinical trial design. Objective To assess the αS-SAA in cerebrospinal fluid (CSF) from PD patients, non-manifesting carriers (NMCs) and non-manifesting non-carriers (NMNCs) of pathogenic GBA1 and LRRK2 variants. Methods This study collected phenotype data from participants in the single-center, longitudinal, natural history BEAT-PD study (TLV-0204-16), which included PD patients and high-risk individuals for whom CSF samples were collected at baseline and 2 years post baseline. Clinical assessments in high-risk individuals enabled calculation of the International Parkinson and Movement Disorder Society probability scores for prodromal PD. Results CSF from 98 participants was evaluated, with no differences in age or sex distribution observed between PD and NMC subgroups. All iPD (14/14) and GBA1 -PD (14/14) participants were αS-SAA positive at baseline versus only 5/13 LRRK2 -PD participants (p < 0.001); 44/45 participants with longitudinal follow-up-maintained baseline αS-SAA status at year 2. LRRK2- PD carriers, all who carried the G2019S variant, with and without positive αS-SAA status were similar in all phenotype characteristics, except for younger age at diagnosis among αS-SAA positive individuals (p = 0.04). Prodromal PD probability scores were higher in αS-SAA positive versus negative GBA1 -NMCs (p < 0.001) and NMNCs (p < 0.001). Conclusions In LRRK2- PD, αS-SAA was associated with younger age of onset but not with motor or non-motor symptoms. In at-risk participants, αS-SAA–positive status was associated with probability scores for prodromal PD. Longitudinal follow up is required to test if αS-SAA-positivity predicts future conversion to clinical PD.