Linking polygenic risk scores to dopaminergic neuron loss using neuromelanin-sensitive imaging.

Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), and neuromelanin-sensitive MRI provides a biomarker to track this neuronal loss. Isolated REM sleep behaviour disorder (iRBD), associated with cognitive decline, may represent a distinct subtype of synucleinopathy. Polygenic risk scores for these conditions may be associated with neuronal degeneration. This study investigates whether genetic risk scores for Parkinson's disease (PGS000903) or iRBD (PGS003414) are associated with neuromelanin signal loss in the SNc in the ICEBERG cohort. The analysis included 123 individuals with Parkinson's disease, 37 with iRBD and 48 healthy individuals. Neuromelanin signal intensity was analysed through linear mixed models by status and genetic risk, adjusted for age and sex. Compared with healthy controls, patients with Parkinson's disease had higher genetic risk scores for both disorders, while patients with iRBD had higher genetic risk scores only for RBD. Both patient groups showed significant signal loss over time (P < 0.001). In Parkinson's disease, higher genetic risk for the condition was associated with greater neuromelanin signal decline (P = 0.008), particularly in sensorimotor (P = 0.04) and limbic (P = 0.02) regions. No significant association was found in iRBD. In Parkinson's disease, genetic susceptibility was linked to neuromelanin signal loss, indicating genetic susceptibility to neuronal degeneration. The absence of a significant effect in iRBD may be due to a lack of power. These results should be replicated in independent studies.