Excess iron in deep gray matter is associated with cognitive and functional decline: The mediating role of white matter myelin

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BACKGROUND: Cerebral iron accumulation is a hallmark of aging and age-related neurodegenerative conditions. This study explored whether higher iron levels in deep gray matter (DGM) structures contribute to motor and cognitive decline and whether this association is mediated by demyelination in white matter (WM) tracts connecting the DGM to the cortex. METHOD: We used quantitative susceptibility mapping (QSM) to quantify brain iron and multi-component relaxometry to estimate myelin content in 86 cognitively unimpaired adults (ages 22-94) who underwent longitudinal assessments of cognitive and motor function. We analyzed age-related differences in DGM iron levels, examined their association with cognitive and functional decline, and conducted mediation analyses to evaluate the role of WM myelination. RESULTS: Higher iron levels in the putamen and caudate nucleus were significantly correlated with older age. Higher putamen iron level was negatively associated with usual and rapid gait speed. In longitudinal analyses, higher iron levels in DGM were associated with a steeper decline in verbal fluency, processing speed, and motor function. Myelin content revealed a significant indirect mediated effect on the relationship between high iron content and motor function in the superior corona radiata, a WM tract connecting the putamen to the cortex. CONCLUSION: These findings suggest that excessive iron is linked to cognitive and functional decline in aging, with motor deterioration specifically mediated by demyelination of white matter pathways connecting the deep gray matter to the cortex. Together, iron and myelin metrics may serve as early biomarkers of age-related clinical decline and represent promising therapeutic targets for preserving motor function in older adults.

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