Objective: To assess α-synuclein seed amplification assay (αS-SAA) in cerebrospinal fluid (CSF) from a cohort of PD patients and non-manifesting carriers (NMCs) of pathogenic GBA and LRRK2 variants.

Background: The α-synuclein seed amplification assay (αS-SAA) represents a promising strategy for identifying individuals with defined α-synuclein pathology, empowering development of tailored Parkinson’s disease (PD) therapeutics and clinical trial design.

Method: 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 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 GBA-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-G2019S-PD carriers with and without positive αS-SAA status were similar in all phenotype characteristics, except for age at diagnosis (p=0.04).

Prodromal PD probability scores were higher in αS-SAA–positive versus –negative GBA-NMCs (p<0.001) and NMNCs (p<0.001).

Conclusion: GBA-PD but not LRRK2-PD is universally associated with αS-SAA positivity. 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 strongly associated with probability scores for prodromal PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-%ce%b1-synuclein-seed-amplification-assay-in-carriers-of-gba-and-lrrk2-pathogenic-variants/