Progressive iron deposition and widespread neural dysfunction in Parkinson's disease: a multimodal MRI study

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, yet its stage-dependent neurobiological mechanisms remain incompletely understood. Multimodal magnetic resonance imaging (MRI) offers a noninvasive approach to investigate both functional and structural alterations across disease stages. Therefore, this study aimed to characterize stage-dependent functional and iron-related brain alterations in PD using multimodal MRI and to explore their associations with motor severity.

We enrolled 104 PD patients, stratified into early-stage (n=49) and advanced-stage (n=55) based on Hoehn and Yahr (H&Y) score, along with 53 age- and sex- matched healthy controls. Quantitative susceptibility mapping (QSM) quantified iron deposition in the substantia nigra (SN) and globus pallidus (GP), while resting-state functional magnetic resonance imaging (rs-fMRI) was used to assess functional alterations using regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF). Group comparisons were conducted using one-way analysis of variance (ANOVA) with post-hoc tests, and voxel-wise analyses were corrected using cluster-level false discovery rate (FDR, P<0.05). Correlation analyses were performed to evaluate associations between imaging metrics and Unified Parkinson's Disease Rating Scale part III (UPDRS-III) motor scores.

Compared with healthy controls, both early and advanced-stage PD patients showed significantly increased iron deposition in the bilateral SN and GP (all P<0.05), with higher QSM values in advanced-stage PD than in early-stage PD (all P<0.01). Iron deposition in these regions was positively correlated with motor severity assessed by UPDRS-III scores (all P<0.001). Early-stage PD primarily exhibited abnormal fALFF and ReHo in visual-related regions, whereas advanced-stage PD showed more widespread involvement of the basal ganglia-thalamocortical motor circuit, frontoparietal regions, and limbic structures. Functional alterations in motor-related regions were significantly associated with UPDRS-III scores (all P<0.001), while ReHo changes in limbic regions were correlated with cognitive performance (Mini-Mental State Examination, MMSE; P<0.001).

Building on established evidence that PD involves progressive iron deposition in the SN and GP and widespread neural network dysfunction, our multimodal MRI findings demonstrate that integrating ReHo, fALFF, and QSM provides a framework for characterizing stage-specific pathophysiological changes and support their potential as biomarkers for early diagnosis, disease staging, and therapeutic development.