Hemispheric Asymmetry of Neuromelanin‐Iron Dysfunction in the Substantia Nigra: MRI ‐Based Evidence for Lateralized Motor Onset in Early‐Stage Parkinson's Disease

ABSTRACT Background Parkinson's disease (PD) often presents with lateralized motor symptoms at onset, reflecting asymmetric degeneration of the substantia nigra (SN). Neuromelanin (NM) loss and iron accumulation are hallmarks of SN pathology in PD, but their spatial distribution and interrelationship in PD patients with right‐sided (PDR) or left‐sided (PDL) motor symptom onset remain unclear. Purpose To investigate the spatial vulnerability and interrelationship of NM and iron in the SN among PDR, PDL, and healthy controls (HCs) using MRI. Study Type Prospective. Population 56 early‐stage PD patients (28 PDR: 55.93 ± 7.41 years, 16 female/12 male; 28 PDL: 59.04 ± 10.44 years, 13 female/15 male) and 30 age‐ and gender‐matched HCs (57.47 ± 4.07 years, 17 female/13 male). Field Strength/Sequence 3‐T, T1‐weighted Fast Spoiled Gradient Recalled (FSPGR) and gradient recalled echo (GRE) for quantitative susceptibility mapping (QSM). Assessment Voxel‐wise group comparisons of NM and iron were performed, and overlapping clusters with co‐localized NM loss and iron deposition were identified. Mean cluster values were extracted for subsequent group comparison and NM–iron relationship modeling. Statistical Tests Welch's analysis of variance (ANOVA), Chi‐squared test, Mann‐Whitney U, voxel‐wise analysis of covariance (ANCOVA), bidirectional mediation, partial correlation. Results Cluster 1 ( PDR vs. HC ) in left nigrosome‐1 showed concurrent NM reduction (1.14 ± 0.09 vs. 1.30 ± 0.06) and iron increase (0.14 ± 0.06 vs. 0.08 ± 0.04 ppm); Cluster 2 ( PDL vs. HC ) in right nigrosome‐1 also showed concurrent NM reduction (1.15 ± 0.06 vs. 1.28 ± 0.07) and iron increase (0.16 ± 0.05 vs. 0.10 ± 0.04 ppm). Bidirectional mediation revealed significant NM ‐iron direct and indirect effects in PDR and PDL (vs. HCs ). Data Conclusion This QSM‐based study demonstrates contralateral nigrosome‐1 as the vulnerable region with concurrent NM loss and iron accumulation and exhibits reciprocal mediation effects between NM and iron in early‐stage PD. Level of Evidence 2. Technical Efficacy Stage 2.