Parkinson Disease SNCA Risk Variants Are Associated With Higher Asymmetric Putamen Dopaminergic Dysfunction

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.

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 ¹²³I-FP-CIT SPECT and assessed at baseline and 24-month follow-up. Mixed models were applied to explore the relationship between striatal ¹²³I-FP-CIT SPECT specific binding ratios (SBRs) and PD SNCA risk variants.

No significant associations were observed between SNCA risk variants and the mean putamen or caudate ¹²³I-FP-CIT SPECT SBRs. However, a higher SNCA GRS was significantly associated with increased baseline putamen ¹²³I-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.

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.