Heterogeneous Deep Gray Matter Iron Deposition Patterns across Multiple Sclerosis Subgroups Defined by the Clinico-Radiological Paradox.

The clinico-radiological paradox in multiple sclerosis (MS) describes the disconnect between white matter lesion load and clinical disability. This study investigated the role of deep gray matter (DGM) iron deposition in this paradox, specifically regarding cognitive impairment. We classified 134 MS patients into subgroups based on T2-lesion volume (LV) and disability (EDSS): LL/LD, HL/LD, LL/HD, HL/HD, comparing them to 46 healthy controls (HCs). Using quantitative susceptibility mapping (QSM) and volumetric analysis, we assessed iron content and atrophy in DGM nuclei, alongside cognitive testing (MoCA, SDMT). Subgroups with high lesion burden (HL/LD, HL/HD) showed significantly increased iron and atrophy in the globus pallidus, putamen, and caudate versus HCs. A critical group-by-volume interaction on susceptibility was found in the putamen for HL/LD (β=-0.55) and HL/HD (β=-0.35) subgroups. Mediation analysis revealed that putamen volume mediates the effect of iron on cognition, with significant indirect effects on SDMT (β=-0.18) and MoCA (β=-0.14) across all patients. In the HL/HD subgroup, this pathway accounted for 45.8 % of iron's total effect on processing speed (SDMT). Our findings demonstrate heterogeneous DGM iron deposition and identify putaminal iron-induced atrophy as a key mechanistic pathway for cognitive deficits, offering a novel explanation for the paradox and a potential biomarker for cognitive risk stratification.