Description (from grant):
Significance: Women with iron deficiency anemia have profound impairment of basic brain energetics and cognitive function. We will characterize the relative importance of iron deficiency versus the anemia in determining brain blood flow, metabolism, functional connectivity and performance. We will evaluate the magnitude and duration of treatment response to intravenous and oral iron therapy.
Moderate anemia (hemoglobin < 11 g/dl) occurs in 1.5% – 2.0% of the general population. In young and middle- aged adults, iron deficiency from blood loss represents the dominant mechanism and is heavily over- represented in women. Iron deficiency anemia’s (IDA) negative impact on pediatric brain function is well established, but its consequences on adult brains are underappreciated. Our preliminary data demonstrates significant (one standard deviation) deficits in visual and verbal memory, fluid and visuospatial reasoning, and verbal learning. We also demonstrate decreased cerebral metabolic rate of oxygen and abnormal blood brain barrier permeability to water that suggest impaired microvascular blood flow regulation in the brain. The overall goal for this study is to deeply phenotype the cognitive and cerebrovascular derangements caused by adult-onset IDA and to determine their reversibility with iron replacement therapies. We will recruit 96 women ages 14-60 years diagnosed with moderate IDA, and 40 healthy control subjects. All participants will undergo comprehensive cerebrovascular MRI, baseline bloodwork, patient reported outcomes, and neurocognitive testing. Aims 1 and 2 focus on careful characterization of the cognitive, metabolic, flow, oxygenation, and connectivity changes in response to IDA. These data will provide new insights into the neuroscientific basis for cognitive dysfunction in IDA. Aim 3 is interventional; we will restudy all the previously acquired biomarkers after normalizing hemoglobin level to prove reversibility/irreversibility of the MRI and cognitive deficits. All patients with confirmed moderate IDA will be randomized to intravenous ferric carboxymaltose versus standard-of-care therapy (referral to primary care physician for oral iron therapy). The primary endpoint will be the cerebral metabolic rate by MRI and neurocognition at 12 months. Secondary markers include regional brain blood flow, cerebrovascular reactivity, tissue oxygenation, blood-brain barrier function, and functional connectivity. An exploratory markers will be brain iron deposition. We will exploit the rapid correction of iron sufficiency in the IV iron treated subjects to uncouple the relative impacts of iron and anemia. We hypothesize that all subjects who successfully replace their iron stores will normalize their MRI and cognitive function.