Iron-related nigral degeneration influences functional topology mediated by striatal dysfunction in Parkinson's disease

Abstract In Parkinson's disease (PD), iron accumulation in the substantia nigra (SN) exacerbates oxidative stress and α-synuclein aggregation, leading to neuronal death. However, the influence of iron-related nigral degeneration on the subcortical function and global network configuration in PD remains unknown. Ninety PD patients and 38 normal controls underwent clinical assessments and multimodality magnetic resonance imaging scans. Iron accumulation in the inferior SN and disrupted functional connectivity between the bilateral striatums were observed in PD, and negative correlation between them was found in the whole population. The binarized functional network exhibited enhanced global efficiency and reduced local efficiency while the weighted functional network exhibited reduction in both, and both changes were correlated with nigral iron accumulation in PD. Mediation analysis demonstrated that the functional connectivity between bilateral striatums was a mediator between the nigral iron accumulation and weighted functional network alterations. In conclusion, our findings reveal that iron-related nigral degeneration possibly influences the functional topology mediated by striatal dysfunction, which extends the scientific understanding of PD pathogenesis.