Regulation of brain iron homeostasis and its influence on cognitive function

Objectives: Iron is essential for oxygen transport and neuronal integrity, underscoring the importance of maintaining iron homeostasis for optimal brain function. This study aimed to elucidate the interplay among systemic iron status, brain iron levels, and cerebral blood flow (CBF), with a particular focus on their influence on cognitive performance. Materials and methods: A total of 332 healthy women without a history of iron-related disorders were recruited and stratified into three groups based on serum iron concentrations: low-iron, reference, and high-iron groups. Brain iron content and CBF were assessed in the basal ganglia (BG) using quantitative susceptibility mapping and arterial spin labeling perfusion-weighted imaging, respectively. Cognitive performance was evaluated using attention-focused assessments. Results: Although the low-iron group exhibited systemic iron deficiency, BG susceptibility values did not significantly differ from those of the reference group (p = 0.13). Path analysis revealed that lower blood iron levels were significantly associated with reduced BG susceptibility (p < 0.001), and that both lower blood iron (p < 0.001) and reduced susceptibility (p = 0.01) were associated with increased BG CBF. Decreased blood iron was associated with impaired attention performance, and a curvilinear relationship was observed between BG susceptibility and attention performance. Conclusion: These findings indicate a dynamic interaction between systemic and brain iron homeostasis, which influences BG CBF and attention performance. Key Points: Question What are the associations among blood iron levels, brain iron content, cerebral blood flow (CBF), and attention performance in healthy women? Findings Reduced systemic and brain iron levels were significantly associated with elevated CBF. Variability in both iron levels was linked to alterations in attention performance. Clinical relevance The observed associations between systemic and brain iron status and cognitive performance highlight the importance of maintaining blood–brain iron homeostasis to prevent cognitive dysfunction, particularly in individuals with iron deficiency.