Functional Magnetic Resonance Imaging (fMRI) Signatures of Progression and Phenoconversion in Prodromal Synucleinopathies

Abstract Background Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal manifestation of synucleinopathies and provides a critical window to identify early markers of progression to Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Time‐averaged (static) and time‐varying (dynamic) functional connectivity between large‐scale brain networks may sensitively capture early pathophysiological changes and offer prognostic value beyond structural imaging. Objectives To use functional magnetic resonance imaging (fMRI) on a longitudinal iRBD cohort to assess alterations in static and dynamic functional connectivity and explore their relationship with disease conversion and regional neurotransmitter density. Methods Static and dynamic resting state fMRI and clinical testing were acquired from 41 iRBD participants and 38 healthy controls, with 21 iRBD participants undergoing repeated scanning. Results Cross‐sectional analysis revealed reduced static connectivity within the visual network and a shift toward a more segregated functional architecture in iRBD. Longitudinally, a further increase in segregation was observed, characterized by heightened modularity and reduced intermodular connectivity. These changes were accompanied by static connectivity disruptions in somatomotor and attentional networks, particularly pronounced in patients who converted to DLB. Regions showing the greatest connectivity decline overlapped with areas rich in cholinergic and noradrenergic transporters, suggesting early neuromodulatory dysfunction as a potential driver. Conclusions Our findings reveal progressive functional segregation and widespread disrupted static connectivity of resting‐state networks in iRBD. These results identify imaging biomarkers of disease progression, describe likely neurotransmitter associations, and support the implementation of fMRI as a sensitive tool for detecting early neurobiological signatures of synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.