Effects of iron repletion on brain iron content, myelination, neural network activation, and cognition
Eldad A. Hod, Christian Habeck, Hangwei Zhuang, Alexey Dimov, Pascal Spincemaille, Debra Kessler, Zachary C. Bitan, Yona Feit, Daysha Fliginger, Elizabeth F. Stone, David Roh, Lisa Eisler, Stephen Dashnaw, Elise Caccappolo, Donald J. McMahon, Yaakov Stern, Yi Wang, Steven L. Spitalnik, Gary M. Brittenham
Eldad A. Hod, Christian Habeck, Hangwei Zhuang, Alexey Dimov, Pascal Spincemaille, Debra Kessler, Zachary C. Bitan, Yona Feit, Daysha Fliginger, Elizabeth F. Stone, David Roh, Lisa Eisler, Stephen Dashnaw, Elise Caccappolo, Donald J. McMahon, Yaakov Stern, Yi Wang, Steven L. Spitalnik, Gary M. Brittenham
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Clinical Research and Public Health Hematology Neuroscience

Effects of iron repletion on brain iron content, myelination, neural network activation, and cognition

Abstract

BACKGROUND Blood donation increases the risk of iron deficiency, but its effect on brain iron, myelination, and neurocognition remains unclear.METHODS This ancillary study enrolled 67 iron-deficient blood donors, 19–73 years of age, participating in a double-blind, randomized trial. After donating blood, positive and negative susceptibility were measured using quantitative susceptibility mapping (QSM) MRI to estimate brain iron and myelin levels, respectively. Furthermore, neurocognitive function was evaluated using the NIH Toolbox, and neural network activation patterns were assessed during neurocognitive tasks using functional MRI (fMRI). Donors were randomized to i.v. iron repletion (1 g iron) or placebo, and outcome measures repeated approximately 4 months later.RESULTS Iron repletion corrected systemic iron deficiency and led to trends toward increased whole brain iron (P = 0.04) and myelination (P = 0.02), with no change in the placebo group. Although overall cognitive performance did not differ significantly between groups, iron-treated participants showed improved engagement of functional neural networks (e.g., memory pattern activation during speed tasks, P < 0.001). Brain region-specific changes in iron and myelin correlated with cognitive performance: iron in the putamen correlated with working memory scores (P < 0.01), and thalamic myelination correlated with attention and inhibitory control (P < 0.01).CONCLUSION Iron repletion in iron-deficient blood donors may influence brain iron, myelination, and function, with region-specific changes in iron and myelination linked to distinct cognitive domains.REGISTRATION ClinicalTrials.gov NCT02990559FUNDING This work was funded by the NIH.

Authors

Eldad A. Hod, Christian Habeck, Hangwei Zhuang, Alexey Dimov, Pascal Spincemaille, Debra Kessler, Zachary C. Bitan, Yona Feit, Daysha Fliginger, Elizabeth F. Stone, David Roh, Lisa Eisler, Stephen Dashnaw, Elise Caccappolo, Donald J. McMahon, Yaakov Stern, Yi Wang, Steven L. Spitalnik, Gary M. Brittenham

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Figure 4

Relationship between brain iron and myelin levels and cognitive performance scores.

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Relationship between brain iron and myelin levels and cognitive performa...
Positive and negative susceptibility, which correlate with iron and myelin levels, respectively, were measured in all subjects before and after randomization to iron repletion by QSM. In separate mixed effect models for iron and myelin levels in a specific region of interest as labeled, and accounting for the repeated measures and the time point, the parameter estimate (β) and 95% CI is presented in a forest plot for each cognitive test performed using the NIH Toolbox standardized scores. Additional fixed effects include sex, age, and the interaction between sex and age. The subject was included in the model as a random effect. A variance component covariance matrix was used to model the within-subject variance-covariance errors. Larger positive parameter estimates represent stronger correlations between iron or myelin concentration in a particular brain region of interest and cognitive test performance on a specific task, as labeled. **P < 0.01, ***P < 0.001.