Iron Deficiency Without Anemia and Reduced Basal Ganglia Iron Content in Youths.

Importance: Although brain iron is necessary for neurogenesis, myelination, and neurotransmitter synthesis, iron deficiency (ID) is defined solely based on hematological outcomes. Objective: To examine the association of ID without anemia with basal ganglia (BG) iron content and its structural and functional sequelae in adolescents. Design, Setting, and Participants: This cross-sectional study enrolled participants using the electronic medical record system from a large network of pediatrics clinics between December 2020 and April 2024. Otherwise healthy, unmedicated participants aged 10 to 17 years with a depressive or anxiety disorder or with no psychopathology were consecutively enrolled. Anemia and acute inflammation led to exclusion, and ID without anemia status was identified after procedure completion. Data were analyzed from May to November 2024. Exposure: Following the World Health Organization's guidelines, ID without anemia was defined as a serum ferritin concentration less than 15 ng/mL. Main Outcomes and Measures: Participants underwent a brain magnetic resonance imaging scan to measure BG susceptibility and structures volume, a clinical interview to rate psychiatric symptoms severity, and neuropsychological testing. Multivariable regression and correlational partial least-squares analyses examined the association of ID without anemia status and BG susceptibility with each other and with BG structures volume, psychiatric symptom severity, and neuropsychological performance. Results: Among a total of 209 participants (122 [58%] female; mean [SD] age, 13.5 [2.2] years; 62 participants [30%] with ID without anemia), ID without anemia was associated with a significantly lower susceptibility in the caudate (Cohen d = -0.41; 95% CI, -0.72 to -0.10; P = .01) and putamen (d = -0.38; 95% CI, -0.69 to -0.07; P = .02), after accounting for age and sex. Notably, in females, the age by ID without anemia status had a significant 2-way interaction, indicating larger difference in caudate (β = 1.11; 95% CI, 0.08 to 2.15; P = .04) and putamen susceptibility (β = 0.95; 95% CI, 0.18 to 1.71; P = .02) with increasing age, favoring those without ID without anemia. None of the 2-way interactions were significant in males. Moreover, BG susceptibility was inversely associated with BG structures volume and psychiatric symptom severity and positively associated with neuropsychological performance, particularly in female adolescents. Conclusions and Relevance: In this cross-sectional study, ID without anemia was associated with lower striatal iron content and disrupted structure and function during adolescence, a critical period when the brain develops and accrues iron, particularly in females.