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

IF 5.3 2区医学 Q1 NEUROIMAGING

NeuroImage Pub Date : 2026-02-15 Epub Date: 2026-01-15 DOI:10.1016/j.neuroimage.2026.121730

Jonghyun Bae , Angelique De Rouen , Zhaoyuan Gong , Nathan Zhang , Noam Y. Fox , Murat Bilgel , Christopher M. Bergeron , Luigi Ferrucci , Mustapha Bouhrara

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Abstract

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.

Abstract Image

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深灰质中过量的铁与功能衰退有关：白质髓磷脂的中介作用。

背景：脑铁积累是衰老和与年龄相关的神经退行性疾病的标志。本研究探讨了深部灰质（DGM）结构中的高铁水平是否会导致运动和认知能力下降，以及这种关联是否由连接DGM和皮层的白质束脱髓鞘介导。方法：我们使用定量易感性制图（QSM）来量化脑铁和多组分松弛法来估计86名认知功能未受损的成年人（22-94岁）的髓磷脂含量，他们接受了认知和运动功能的纵向评估。我们分析了DGM铁水平的年龄相关差异，研究了它们与功能衰退的关系，并进行了中介分析来评估WM髓鞘形成的作用。结果：壳核和尾状核铁水平与年龄显著相关。较高的壳核铁与正常和快速的步态速度负相关。在纵向分析中，DGM中较高的铁含量与语言流畅性、处理速度和运动功能的急剧下降有关。髓磷脂含量在高铁含量与上辐射冠（连接壳核和皮层的WM束）运动功能之间的关系中显示了显著的间接介导作用。结论：这些发现表明，过量的铁与衰老的功能下降有关，特别是由连接深灰质和皮层的白质通路脱髓鞘介导的运动退化。总之，铁和髓磷脂指标可以作为与年龄相关的运动衰退的早期生物标志物，代表了保留老年人运动功能的有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NeuroImage 医学-核医学

CiteScore

11.30

自引率

10.50%

发文量

809

审稿时长

63 days

期刊介绍： NeuroImage, a Journal of Brain Function provides a vehicle for communicating important advances in acquiring, analyzing, and modelling neuroimaging data and in applying these techniques to the study of structure-function and brain-behavior relationships. Though the emphasis is on the macroscopic level of human brain organization, meso-and microscopic neuroimaging across all species will be considered if informative for understanding the aforementioned relationships.