ABSTRACTBackgroundFunctional brain connectivity alterations may be detectable even before the occurrence of brain atrophy, indicating their potential as early markers of pathological processes.ObjectiveWe aimed to determine the whole‐brain network topologic organization of the functional connectome in a large cohort of drug‐naïve Parkinson's disease (PD) patients using resting‐state functional magnetic resonance imaging and to explore whether baseline connectivity changes may predict clinical progression.MethodsOne hundred and forty‐seven drug‐naïve, cognitively unimpaired PD patients were enrolled in the study at baseline and compared to 38 age‐ and gender‐matched controls. Non‐hierarchical cluster analysis using motor and non‐motor data was applied to stratify PD patients into two subtypes: 77 early/mild and 70 early/severe. Graph theory analysis and connectomics were used to assess global and local topological network properties and regional functional connectivity at baseline. Stepwise multivariate regression analysis investigated whether baseline functional imaging data were predictors of clinical progression over 2 years.ResultsAt baseline, widespread functional connectivity abnormalities were detected in the basal ganglia, sensorimotor, frontal, and occipital networks in PD patients compared to controls. Decreased regional functional connectivity involving mostly striato‐frontal, temporal, occipital, and limbic connections differentiated early/mild from early/severe PD patients. Connectivity changes were found to be independent predictors of cognitive progression at 2‐year follow‐up.ConclusionsOur findings revealed that functional reorganization of the brain connectome occurs early in PD and underlies crucial involvement of striatal projections. Connectomic measures may be helpful to identify a specific PD patient subtype, characterized by severe motor and non‐motor clinical burden as well as widespread functional connectivity abnormalities. © 2021 International Parkinson and Movement Disorder Society