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.

The authors have declared no competing interest.

This work was supported in part by the National Natural Science Foundation of China [grant numbers 82401745, 82471271]. The Parkinson's Progression Markers Initiative (PPMI)-a public-private partnership-is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, Bial Portela, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, General Electric HealthCare, Genentech, GlaxoSmithKline (GSK), Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore Therapies, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, Union Chimique Belge (UCB), Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.

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