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

BACKGROUNDBlood donation increases the risk of iron deficiency, but its effect on brain iron, myelination, and neurocognition remains unclear.METHODSThis 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.RESULTSIron 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).CONCLUSIONIron 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.REGISTRATIONClinicalTrials.gov NCT02990559FUNDINGThis work was funded by the NIH.