Molecular‐Informed Network Analysis Unveils Fatigue‐Related Functional Connectivity in Parkinson's Disease

Abstract Background Fatigue in Parkinson's disease (PD) is a prevalent and debilitating non‐motor symptom. Despite its significant impact on quality of life, the underlying neurochemical and network‐based mechanisms remain poorly understood. Objectives This observational study applied a multimodal imaging approach to explore potential links between the functional connectivity of neurotransmitter‐specific circuits and fatigue in a sample of patients with PD. Methods We acquired resting‐state functional magnetic resonance imaging data in 35 patients with PD including 18 with clinically significant fatigue and 17 without. We applied the receptor‐enriched analysis of functional connectivity by targets (REACT) pipeline to derive patients' specific molecularly enriched networks informed by the spatial distribution of the dopamine, noradrenaline, serotonin transporters, and metabotropic glutamate 5 receptors as assessed using molecular imaging data in independent samples of healthy controls. We then conducted whole‐brain analyses inspecting both categorical differences between groups of patients with and without clinically significant fatigue, and associations exploring the full within‐sample variation in symptom ratings. Results We found a significant decrease in noradrenaline‐enriched and glutamate‐enriched functional connectivity in key regions, belonging to the sensorimotor, salience, and default mode network, with increasing fatigue severity. Notably, noradrenaline‐enriched functional connectivity reductions were widespread, while glutamate‐enriched functional connectivity reductions were more restricted to the supplementary motor area. No significant relationships between fatigue and dopamine or serotonin‐enriched functional connectivity were found. Conclusions These findings offer supportive evidence for the putative involvement of the noradrenaline and glutamate systems in the genesis of fatigue in PD, opening new directions for treatment development exploring these neurochemical systems. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.