Neurology. Genetics · 2025
Parkinson Disease SNCA Risk Variants Are Associated With Higher Asymmetric Putamen Dopaminergic Dysfunction.
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Alhusaini Saud, Dayanim Gabriel, Kandil Mohamed, Krohn Lynne, Molino Janine, Gan-Or Ziv, Dagher Alain
Аннотация
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 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.
RESULTS: 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.
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.
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 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.
RESULTS: 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.
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.