Iron Deficiency and Brain Development in Youth with Internalizing Disorders

Project Summary
Depressive and anxiety (referred to internalizing) disorders are increasing in prevalence in adolescents; yet,
no specific etiology has been clearly demonstrated. This is quite concerning given that these disorders are
associated with substantial distress and impairment, jeopardize one's trajectory towards a productive adulthood,
and increase suicide risk; the latter being the 2nd leading cause of death in adolescents, with worsening recent
trends. Iron deficiency (ID) has been associated with neuropsychiatric impairment, including depressive and
anxiety symptoms. This is not surprising, given iron's role in dendritic mitochondrial motility during hippocampal
neuron development, monoaminergic signaling, and myelination. In fact, across two independent samples of
medically-healthy adolescents, we have found prevalent ID and an inverse association between iron stores and
the severity of internalizing symptoms. Moreover, our preliminary evidence suggests that body iron stores are
associated with brain morphometry and connectivity, as captured by magnetic resonance imaging (MRI).
Building on these novel findings, the current research application seeks to enroll unmedicated 10 to 17 year-
old participants with and without internalizing disorders to examine the association between peripheral iron
stores, as captured by serum ferritin, and brain iron content, as measured by quantitative susceptibility mapping
(QSM), a state-of-the-art MRI-based technique (Aim 1). Moreover, in order to establish the impact of ID on brain
development, we will examine the association between brain and body iron stores, on the one hand, and brain
structure, brain connectivity, and white matter integrity, on the other (Aim 2). Finally, in order to establish the
clinical significance of the findings, we will examine the association between brain and body iron stores and
psychiatric symptom severity (Aim 3).
The proposed work will be the first to investigate the effect of ID on brain development and clinical symptoms
in late childhood and adolescence, a developmental period characterized by increased risk for ID as well as
rapid brain structural and functional changes. The ultimate goal is to determine the clinical significance of ID, in
the absence of anemia, informing future therapeutic interventions.

Grant Number: 5R01MH124848-05
NIH Institute/Center: NIH
Principal Investigator: Chadi Calarge