Resting state fMRI network topographies in preclinical and early Parkinson’s disease stages

Functional brain network disruptions, including PD-related (PDRP) and cognition-related (PDCP) patterns identified by [ 18 F]-FDG PET, occur in Parkinson’s disease (PD). This study assessed whether these patterns are detectable in preclinical and early PD using resting-state fMRI (rs-fMRI) in first-degree non-manifesting carriers (NMCs) of PD-associated mutations ( GBA1 , LRRK2 ). We analyzed 295 rs-fMRI datasets from 52 early PD patients, 92 NMCs (47 GBA1 , 45 LRRK2 ), and 58 healthy non-carriers (NMNCs). Using independent component analysis and support vector machine classification, distinguishing PD from NMNCs with 87% accuracy (78% average). Local interpretable model-agnostic explanations isolated fMRI-derived PD-related (fPDRP) and cognition-related (fPDCP) patterns. Expression scores were compared across groups relative to MDS likelihood risk (LR), genetic status, and CSF α-synuclein seed amplification assay (SAA) status and validated in an independent cohort of 33 NMCs followed for ten years. PD patients showed significantly higher fPDRP and fPDCP expression than preclinical groups. Among preclinical individuals, high LR ( ≥ 60) showed elevated fPDRP but unchanged fPDCP. Genetic and CSF SAA status did not significantly affect expression in clinical PD. Patterns were reproducible in the validation cohort. Eight converters showed numerically higher baseline fPDRP than non-converters (ns). These findings support functional network measures as markers of early PD risk and progression.