The relationship between neuropsychiatric dimensions and markers of Parkinson’s disease risk in the UK Biobank

Neuropsychiatric symptoms are a significant yet often overlooked aspect of Parkinson's disease (PD). Using UK Biobank data, we examined associations between neuropsychiatric dimensions and PD risk markers. Factor analysis identified four dimensions-Depression, Anxiety, Adult Stress-Adversity, and Alcohol- and Substance-Related Behaviours (ASRB) -across three groups: PD, healthy controls, and cerebrovascular disease (CVD) as neurological controls. These dimensions showed distinct patterns in PD. Depression scores were significantly elevated, while ASRB scores were consistently lower. Neuroimaging linked ASRB to subcortical changes specific to PD, particularly quantitative susceptibility mapping in the substantia nigra, consistent with the dopaminergic system's role in goal-directed behaviour. GBA1 carrier status was linked to age-related changes in this dimension. Furthermore, PD patients with higher ASRB showed greater volatility in cognitive and motor function, with worsening before diagnosis and subsequent improvement. These findings highlight the complex interplay between psychiatric symptoms, neurobiological changes, and genetic factors in PD, suggesting that specific neuropsychiatric profiles may serve as early indicators of disease risk and progression.