Polygenic Risk Score Combined with Transcranial Sonography Refines Parkinson's Disease Risk Prediction

Dopaminergic neuron depletion in the substantia nigra (SN) and the pathological aggregation of α-synuclein are the neuropathological hallmarks of Parkinson's disease (PD).

This study aimed to investigate the association between the polygenic risk score for PD (PD-PRS) and transcranial sonography (TCS)-measured SN hyperechogenicity to enhance the accuracy of PD susceptibility prediction.

PD-PRSs were calculated for over 41,000 Estonian Biobank participants age 55+ years without a PD diagnosis. Participants in the highest and lowest PD-PRS percentiles (n = 222) underwent TCS measurements and Sniffin' sticks olfactory testing. A multivariable logistic regression model was used to examine the associations between PD-PRS, risk and prodromal markers, and SN hyperechogenicity.

Data from 204 participants with TCS measurements were analyzed, including 107 individuals in the high-risk PD-PRS group and 97 in the low-risk PD-PRS group. Incorporating PD-PRS group assignment improved the explained variance in SN hyperechogenicity from 17.2% to 31.9%. Participants in the low-risk PD-PRS group had 0.16 times lower odds (95% confidence interval (CI) = 0.07-0.35, P < 0.001) of developing SN hyperechogenicity compared to high-risk PD-PRS individuals. Each unit increase in the Sniffin' sticks olfactory test score was significantly associated with reduced odds of SN hyperechogenicity (adjusted odds ratio = 0.60, 95% CI = 0.47-0.78, P = 0.002).

Our findings indicate that TCS-measured SN hyperechogenicity is associated with PD-PRS and olfactory impairment. This combined assessment may improve early diagnosis of prodromal PD by pinpointing individuals at increased risk.