QSM Measurement of Iron Deposition in the Substantia Nigra and ItsRelationship to Brain Functional Connectivity in Patients with Early Stageand Advanced Stage Parkinson's Disease

Objective: Iron deposition is thought to be associated with the physiological mechanisms of Parkinson's disease (PD). However, the pathogenesis remains unclear, and the aim of this study was to investigate the relationship between the progression of iron deposition in the substantia nigra (SN) at different stages of PD and alterations in brain functional connectivity (FC). Methods: MRI was performed for 106 patients with PD, who were divided into groups with Early Stage (ES) (51 patients) and Advanced Stage (AS) (55 patients) PD according to the Hoehn and Yahr (H&Y) score of clinical severity, along with 45 age and sex matched healthy controls (HC). The iron content of the SN was measured using Quantitative Susceptibility Mapping (QSM), and whole-brain functional connectivity (FC) analysis of functional Magnetic Resonance Imaging (rsfMRI) data was performed using the SN as a seed point. Results: The groups of patients with ES and AS both had significantly increased iron concentration in SN compared to HC, and significantly greater iron in the AS group compared to the ES group. In addition, seed-based FC analysis showed significantly lower FC between the SN and major functional networks, including the sensorimotor network (SMN), the default mode network (DMN), the visual network (VN), the dorsal attentional network (DAN), and the frontal-parietal network (FPN) in the ES and AS compared with the HC group. Discussion: These findings suggest that abnormal iron accumulation in the SN contributes to progressive disruption of brain networks, reflecting the underlying neurodegenerative process of PD. The association between increased iron load and decreased FC highlights the potential role of iron metabolism in driving network-level dysfunction. This provides new insights into the mechanisms linking microstructural pathology to functional disintegration in PD. Conclusion: The novelty in this work stems from the changing FC relationships with iron content in the SN and clinical symptoms for the early versus late stage PD subjects. The progression of PD and increase in iron content of the SN, along with the decrease in whole brain FC and increase in clinical symptoms, could provide stage-specific imaging biomarkers for monitoring PD progression. Furthermore, the identified relationship between iron deposition and network dysfunction may inform the future development of network-targeted therapeutic strategies.