PROJECT SUMMARY Sickle cell anemia (SCA) is a chronic hemolytic anemia that dramatically increases the risk of central nervous system complications including silent cerebral infarcts (SCI), overt strokes, and intracranial stenosis. Stroke risk screening procedures for adults with SCA are considerably underdeveloped compared to procedures for children with SCA and other populations of adults at risk for stroke. However, SCI and overt stroke risk persists across the lifespan, and SCIs occur in more than 50% of adults with SCA by age 30 years, representing a frequent cause of long-term disability. The absence of an approach to identify adults at risk for new or recurrent cerebral infarcts is a major limitation in adult SCA care, as treatments for SCA continue to improve and lifespan is increasing. The critical barrier to addressing stroke risk and prevention in adults rests with our inability to identify underlying brain tissue-level impairment as a part of routine medical care and our need to develop new screening tools to triage adults with SCA for appropriate stroke prevention therapies. The overall goal of this work is to utilize recently identified biomarkers of inadequate cerebral hemodynamic compensatory mechanisms to test fundamental hypotheses about stroke risk and treatment response in adults with SCA in a longitudinal study. Over the past seven years, we have established a multidisciplinary team to systematically evaluate adults with SCA, assessing known stroke risk factors in sequence with more novel pathophysiological indicators including: (i) oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), (ii) cerebral blood flow (CBF; rate of blood delivery to tissue), (iii) flow velocity, and (iv) cerebrovascular reactivity (CVR; ability of arterioles to respond to a vasoactive challenge). This work led to the findings that (i) OEF is elevated in adults with SCA and clinical impairment (prior stroke, intracranial stenosis, or monthly transfusions), (ii) OEF is elevated in adults with SCA and evidence of new or progressive infarcts (retrospective data), and (iii) CBF response to treatment with blood transfusion appears to be less robust in adults than children with SCA. We have developed methods to measure these hypothesized stroke risk biomarkers using MRI approaches that do not require exogenous contrast agents, making them a possible tool for SCI surveillance and for evaluating treatment response. Here, we propose to extend this work to (Aim 1) a longitudinal, prospective study, to evaluate how metabolic and hemodynamic stroke risk factors can be used to identify which adults with SCA will have new infarcts; (Aim 2) to quantify the impact of stem cell transplant, an emerging curative treatment, on brain tissue health; and (Aim 3) to compare OEF values obtained from the two most popular non-invasive MRI methods thereby informing their collective or individual use in future multi-site clinical trials. The long-term go...