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

Area of Science:

• Neuroscience
• Genetics
• Radiology

Background:

• Parkinson disease (PD) is a neurodegenerative disorder with complex genetic underpinnings.
• The SNCA gene is a key genetic risk factor for PD.
• Understanding genetic influences on dopamine transporter (DAT) function is crucial for identifying PD endophenotypes.

Purpose of the Study:

• To investigate the relationship between SNCA genetic risk variants and striatal DAT uptake in de novo PD patients.
• To explore the potential of DAT uptake as an endophenotype for PD associated with SNCA variants.

Main Methods:

• Analysis of 381 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI) cohort.
• Genotyping of SNCA risk variants and calculation of a genetic risk score (GRS).
• Quantification of striatal DAT uptake using ¹²³I-FP-CIT SPECT at baseline and 24-month follow-up.

Main Results:

• No significant association between SNCA variants and mean putamen or caudate DAT uptake.
• A higher SNCA GRS was linked to increased baseline putamen DAT uptake asymmetry (p < 0.001).
• This asymmetry was primarily driven by specific SNCA variants (rs356182, rs763443) and not present at follow-up.

Conclusions:

• Lateralized putaminal dopaminergic degeneration may represent a valid endophenotype in early PD patients carrying SNCA risk variants.
• Neuroimaging plays a vital role in PD subtyping and the identification of novel biomarkers.
• SNCA genetic variants influence the pattern of dopaminergic degeneration in PD.