Eight-year longitudinal changes in functional connectivity of the fatigue network in Parkinson's disease: evidence from four timepoints.

Fatigue is a prevalent non-motor symptom in Parkinson's disease (PD), yet its long-term neural substrates remain poorly understood. The aim of this study was to characterize eight-year, four-timepoint longitudinal changes in the fatigue-related brain functional connectivity (FC) in PD and examine their associations with fatigue severity. Fifty-one PD patients and 37 healthy controls (HC) were recruited. All variables were assessed at four timepoints: baseline (year-1), year-3, year-5, and year-8. Region of interest (ROI)-to-ROI analyses targeted a predefined fatigue-related network. A visual network served as a control system. Longitudinal FC effects were assessed using a 2 × 4 ANCOVA (group×time), adjusting for age, sex, and Levodopa Equivalent Daily dose. Fatigue severity was measured with the Fatigue Severity Scale. PD patients exhibited a significant progressive reduction in FC between the right dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior cingulate cortex (dACC) compared with HC. Results remained significant also including depression and global cognition as covariates. Within PD, lower right DLPFC-left dACC FC was associated with higher fatigue, whereas no associations were observed in HC. The fatigue network was specifically associated with fatigue scores, but not with depression or cognition; no longitudinal or fatigue-related effects were found in the visual control network. Across eight years and four assessments, PD is characterized by a gradual disruption of prefrontal-cingulate connectivity within a key fatigue-related hub. This evolving DLPFC-dACC decoupling is linked to worsening fatigue and is specific to the fatigue network, providing preliminary evidence for a neural marker and therapeutic target for fatigue progression in PD.