Longitudinal decline in striatal DAT binding in LRRK2 Parkinson's disease: connections with CSF α-synuclein seeding activity.

Objective: Parkinson's disease (PD) associated with mutations in the LRRK2 gene exhibits considerable pathological heterogeneity and may not present with Lewy body pathology. The α-Syn seed amplification assay (SAA) performed on cerebrospinal fluid (CSF) has emerged as a reliable in vivo biomarker of α-Syn aggregation. In this study, we aim to investigate the longitudinal trajectories of striatal dopaminergic imaging in LRRK2 PD patients stratified by CSF α-Syn SAA status.

Methods: Data were obtained from the Parkinson's Progression Markers Initiative. CSF α-Syn aggregation was assessed using SAA. Striatal DAT-specific binding ratios (SBR) were quantified using [¹²³I] FP-CIT SPECT at baseline, year 2, and year 4.

Results: At baseline, the α-Syn SAA-negative LRRK2 PD group exhibited higher DAT binding in the contralateral putamen and ipsilateral putamen compared to the SAA-positive group with comparable disease duration. Longitudinally, linear mixed-effects models demonstrated that the α-Syn SAA-negative LRRK2 PD maintained significantly higher DAT binding in both the contralateral and ipsilateral putamen over time. A significant group × time interaction was identified in the contralateral caudate, suggesting a slower rate of DAT loss in the α-Syn SAA-negative group. Sensitivity analyses restricted to participants with complete baseline and follow-up imaging data largely confirmed the main LMEM findings.

Conclusions: The observed differences in striatal dopaminergic degeneration between LRRK2 PD patients with and without detectable CSF α-synuclein aggregates may reflect region-specific vulnerability to underlying pathological processes. Our findings support the utility of CSF α-Syn SAA status as both a diagnostic and prognostic biomarker in LRRK2 PD.