Nigral Iron Deposition Influences Disease Severity by Modulating the Effect of Parkinson's Disease on Brain Networks

Background: In Parkinson's disease (PD), excessive iron deposition in the substantia nigra may exacerbate alpha-synuclein aggregation, facilitating the degeneration of dopaminergic neurons and their neural projection. Objective: To investigate the interaction effect between nigral iron deposition and PD status on brain networks. Methods: Eighty-five PD patients and 140 normal controls (NC) were included. Network function and nigral iron were measured using multi-modality magnetic resonance imaging. According to the median of nigral magnetic susceptibility of NC (0.095 ppm), PD and NC were respectively divided into high and low nigral iron group. The main and interaction effects were investigated by mixed effect analysis. Results: The main effect of disease was observed in basal ganglia network (BGN) and visual network (VN). The interaction effect between nigral iron and PD status was observed in left inferior frontal gyrus and left insular lobe in BGN, as well as right middle occipital gyrus, right superior temporal gyrus, and bilateral cuneus in VN. Furthermore, multiple mediation analysis revealed that the functional connectivity of interaction effect clusters in BGN and medial VN partially mediated the relationship between nigral iron and Unified Parkinson's Disease Rating Scale II score. Conclusion: Our study demonstrates an interaction of nigral iron deposition and PD status on brain networks, that is, nigral iron deposition is associated with the change of brain network configuration exclusively when in PD. We identified a potential causal mediation pathway for iron to affect disease severity thatwas mediated by bothBGNdysfunction andVNhyperfunction in PD.