Monoaminergic Networks of Cognitive and Behavioral Symptoms in Early Parkinson's Disease

Abstract Background Parkinson's disease (PD) is associated with several behavioral and cognitive symptoms, the neurobiological background of which is not yet fully understood. Objectives The aim was to investigate the association between monoamine function and four specific nonmotor symptoms in early PD using the Parkinson's Progression Markers Initiative data. Methods [ 123 I]FP‐CIT SPECT imaging data of healthy controls ( n = 166) and patients with PD at baseline ( n = 349), 2‐year ( n = 240), and 4‐year follow‐up ( n = 140) were included. Depression, anxiety, rapid eye movement (REM) sleep behavior disorder (RBD) and cognition were evaluated using validated questionnaires. The associations between symptoms and subcortical monoamine transporter binding were analyzed voxel by voxel. Whole brain networks of symptom‐specific monoaminergic abnormalities were characterized using a functional connectome ( n = 1000) and normative neurotransmitter receptor maps. Results Cross‐sectionally, depression was associated with reduced ventral striatum (VS) binding at 2‐ and 4‐year and dorsal raphe (DRN) at 4‐year follow‐up ( P FWE < 0.05); trait anxiety was associated with reduced DRN binding at 4‐year follow‐up ( P FWE < 0.05). Longitudinally, lower baseline binding in these regions at baseline predicted more severe future depression and anxiety ( P FWE < 0.05). RBD was most strongly linked to reduced VS binding at 2‐ and 4‐year follow‐up (nonsignificant after correction, P FWE < 0.1). Each of the symptom‐specific clusters was connected to distinct brain networks, corresponding to specific monoamine receptors: serotonin (5HT 1F , 5HT 2A , 5HT 5A ) and histamine (H 3 ) for depression; histamine (H 1 ), serotonin (5HT 1E , 5HT 1F , 5HT 2A , 5HT 3B ), and adrenergic (α 1D ) for anxiety; and adrenergic (β 2 ) and serotonin (5HT 1F , 5HT 2C , 5HT 5A ) receptors for RBD. Conclusions The findings provide novel information about the monoaminergic networks underlying depression, anxiety, and RBD in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.