Brain blood flow, oxygenation, and cognition in adult onset iron deficiency anemia - Moderate anemia (hemoglobin < 11 g/dl) occurs 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 and minority populations. 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 overarching 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 from four donor centers in the Los Angeles area as well as women recruited from social media. Most of these subjects will be otherwise entirely healthy but we will exclude individuals with other mechanisms for their anemia as well as risk factors for small vessel disease including hypertension, sleep disordered breathing, and diabetes. All anemic and control subjects 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. Exploratory markers include brain iron deposition, white matter damage, and brain morphometry. 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 posit that all subjects who successfully replace their iron stores will normalize their MRI and cognitive function. However, we anticipate that iron restoration and durability in the standard-of- care arm will not be as robust as for intravenous iron because of poor compliance, insufficient therapy duration, and/or lack of adequate medical follow-up. Taken together, this study will determine the urgency of identifying and correcting IDA in adults, the mechanisms of brain toxicity, and potential targets to improve care practices.
