Longitudinal analysis of 337 PPMI patients shows that depression and cognitive impairment independently and jointly mediate the effect of REM sleep behavior disorder on activities of daily living in PD, with mediating effects increasing over time.

Provides clinically actionable insight that early detection and treatment of depression and cognitive decline (and possibly RBD-targeted care) could preserve function in PD, though it offers limited mechanistic or molecular therapeutic targets for drug discovery.

INTRODUCTION: Rapid eye movement sleep behavior disorder (RBD) aggravates cognitive impairment and depression in patients with Parkinson's disease (PD) and significantly compromises their activities of daily living (ADL). This study aimed to explore the potential mediation roles of depression and cognitive impairment between RBD and ADL in PD patients. METHODS: Data from the Parkinson's Progression Markers Initiative (PPMI) database comprised 337 patients. RBD, ADL, depression, and cognitive function were assessed with validated rating scales. Bayesian dynamic mediation analysis was employed to evaluate the separate mediating effects of depression and cognition in mediating RBD and ADL with the time variable (9 times) standardized to the interval [0, 1] via min-max normalization. Multiple time-varying causal mediation analysis was used to assess the role of depression and cognition together in mediating RBD and ADL. RESULTS: At the second follow-up (0.25), the fourth follow-up (0.50), and the sixth follow-up (0.75), the Bayesian dynamic indirect mediating effect of depression between RBD and ADL were 0.058 (95%CI 0.039-0.077), 0.065 (95%CI 0.046-0.084), 0.082 (95%CI 0.061-0.103). The corresponding time-function curve revealed that the mediating effect of depression gradually increased with time. At the 0.25, 0.50, 0.75 standardized time points, the Bayesian dynamic indirect mediating effect of cognition between RBD and ADL were 0.062 (95%CI 0.038-0.086), 0.087 (95%CI 0.044-0.130), 0.136 (95%CI 0.096-0.176), and its time-function curve likewise indicated an increasing trend over time. The joint mediating analysis of the bidirectional decomposition method of the multiple time-varying causal mediation model confirmed that the joint mediating effect of depression and cognition between RBD and ADL was 7.42 (95%CI 4.48-10.36). DISCUSSION: This study demonstrates that depression and cognition can work independently and together, and that reducing depressive symptoms or improving cognition can mediate the reduction of RBD to improve the ADL of PD patients. Notably, this mediating effect gradually intensifies as the duration of the disease progresses. These findings highlight that for PD patients, preventing emotional depression and cognitive decline in the early stage of the disease may reduce the damage caused by RBD.