Iron accumulation in the substantia nigra is linked to functional network connectivity alterations in early-stage...

Parkinson's disease (PD) involves dopaminergic nigrostriatal pathways degeneration and early structural brain abnormalities, including iron accumulation in the substantia nigra (SN). Understanding how these neurodegenerative changes relate to functional network adaptations may clarify disease progression and symptom variability. We used a cross-sectional design to evaluate resting-state functional MRI, quantitative susceptibility mapping (QSM) and structural MRI measures in 38 early-stage PD patients (Hoehn&Yahr ≤2; disease duration 4.4 ± 2.3 years) and 30 age- and sex-matched healthy controls. The SN showed the earliest increase in magnetic susceptibility in PD, indicating elevated iron levels, without detectable volumetric changes. Within the PD group, higher QSM SN susceptibility was associated with increased resting-state connectivity in motor, visual, dorsal-attention, and executive-control networks. Notably, connectivity within the SN-related executive-control network cluster correlated with better executive function and visuospatial memory. These findings highlight the sensitivity of QSM in early PD and the value of multimodal imaging for characterising early functional and cognitive consequences of PD.