Caudate-Centric Triphasic Network Reconfiguration Characterizes the Early Progression of Cognitive Impairment in Parkinson’s Disease: A Simultaneous PET/fMRI Study

Background: The stage-specific dynamics of functional brain networks in early Parkinson’s disease cognitive impairment (PD-CI) remain unclear. This study investigated caudate-centric hierarchical functional network reconfiguration across early PD-CI stages using simultaneous [18F]fluoropropyl-(+)-dihydrotetrabenazine positron emission tomography (18F-FP-DTBZ PET) and resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-six Parkinson’s disease (PD) patients underwent simultaneous 18F-FP-DTBZ PET/MR with rs-fMRI sequences. Patients were categorized as normal cognition (PD-NC, n = 15), subjective cognitive decline (PD-SCD, n = 16), and mild cognitive impairment (PD-MCI, n = 15). PET-identified striatal regions with significant dopaminergic deficits were used as seeds for stepwise functional connectivity (SFC) analysis. Associations with cognitive factors and network coupling in early PD-CI were evaluated. Results: 18F-FP-DTBZ PET revealed that the caudate nucleus was a critical dopaminergic hub in early PD-CI. Caudate seed-based SFC analysis revealed a triphasic reconfiguration: stable integration in PD-NC, compensatory hyperconnectivity in PD-SCD, and global inefficiency with rigidity in PD-MCI. Key circuits showed reduced connectivity in PD-MCI including caudate linkages with the globus pallidus, thalamus, right superior frontal gyrus, left inferior temporal gyrus, right superior orbitofrontal cortex, supplementary motor area, and right hippocampus. Clinical analysis showed that both global cognitive efficiency and memory control were associated with specific short- and long-range caudate connectivity. Conclusions: The caudate nucleus is central to the interplay between dopaminergic metabolic deficits and functional network reconfiguration during early PD-CI progression, shifting from compensatory hyperconnectivity to network rigidity. These findings provide a mechanistic framework for targeted neuromodulation strategies in early PD-CI.