Abstract
OBJECTIVES: The aim of this study was to investigate the endophenotypic potential of striatal dopamine transporter (DAT) uptake in carriers of Parkinson disease (PD)-associated SNCA genetic risk variants. METHODS: We analyzed 381 patients with de novo PD from the Parkinson's Progression Markers Initiative (PPMI). The genotype of previously identified PD-related SNCA risk variants was extracted and used to compute an individual PD-specific SNCA genetic risk score (GRS). Striatal DAT uptake was quantified using (123)I-FP-CIT SPECT and assessed at baseline and 24-month follow-up. Mixed models were applied to explore the relationship between striatal (123)I-FP-CIT SPECT specific binding ratios (SBRs) and PD SNCA risk variants. RESULTS: No significant associations were observed between SNCA risk variants and the mean putamen or caudate (123)I-FP-CIT SPECT SBRs. However, a higher SNCA GRS was significantly associated with increased baseline putamen (123)I-FP-CIT SPECT SBR asymmetry index (p < 0.001). This relationship appeared primarily driven by the 3' variant rs356182 and the 5' region variant rs763443 (p < 0.001) and was not observed at 24-month follow-up. DISCUSSION: Our findings suggest that a more lateralized putaminal dopaminergic degeneration in early PD may represent a viable endophenotype in carriers of SNCA risk variants, emphasizing the relevant role of neuroimaging in PD subtyping and biomarker identification.