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, and neuromelanin-sensitive MRI provides a biomarker to track this neuronal loss. Isolated rapid eye movement sleep behavior disorder, associated with cognitive decline, may represent a distinct subtype of synucleinopathy. Polygenic risk scores for these conditions may be associated with the neuronal degeneration. This study investigates whether genetic risk scores for Parkinson's disease (PGS000903) or isolated rapid eye movement sleep behavior disorder (PGS003414) are associated with neuromelanin signal loss in the substantia nigra in the ICEBERG cohort. The analysis included 123 individuals with Parkinson's disease, 37 with isolated rapid eye movement sleep behavior disorder, and 48 healthy individuals. Neuromelanin signal intensity was analyzed through linear mixed models by status and genetic risk adjusted for age and sex. Compared to healthy controls, patients with Parkinson's disease had higher genetic risk scores for both disorders, while patients with isolated rapid eye movement sleep behavior disorder had higher genetic risk scores only for rapid eye movement sleep behavior disorder. 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 neuromelanine signal decline (P=0.008), particularly in sensorimotor (P=0.04) and limbic (P=0.02) regions. No significant association was found in isolated rapid eye movement sleep behavior disorder. In Parkinson's disease, genetic susceptibility was linked to neuromelanin signal loss, indicating genetic susceptibility to neuronal degeneration. The absence of significant effect in isolated rapid eye movement sleep behavior disorder may be due to a lack of power. These results should be replicated in independent studies.