The overall goal of this work is to apply novel MRI-based measures of blood oxygenation to evaluate relationships between oxygen extraction fraction (OEF; oxygen consumed/oxygen delivered), cerebral blood flow (CBF; ml blood/100g tissue/min), and clinical impairment in adults with sickle cell anemia (SCA). More specifically, unlike in children, no screening procedures exist for evaluating stroke risk in adults with SCA. Reduced oxygen carrying capacity is present in SCA, which may initially be compensated for by an increase in CBF, after which an increasing gradient of OEF may result in the presence of preserved cerebral metabolic rate of oxygen (CMRO2). As such, we hypothesize that OEF and CBF can be measured noninvasively and reproducibly with MRI in adults with SCA and that elevated OEF provides added discriminatory capacity for clinical impairment relative to simple vasculopathy extent and CBF.Standard T1-weighted and T2-weighted FLAIR MRI, intracranial and extracranial time-of-flight MRA, and CBF-weighted (pCASL single-shot EPI; spatial resolution=3x3x7mm; post-labeling delay=1900 ms) MRI were applied in sequence with a noninvasive blood oxygenation-weighted T2-relaxation-under-spin-tagging (TRUST)-MRI method [1] (TILT labeling; TI=1022 ms; effective TEs=0, 40, 80, 160 ms) in SCA adults (n=34) and race-matched controls without sickle trait (n=11). Hematocrit and hemoglobin-S percent (HbS%) were determined by venipuncture on the day of the scan. CBF was quantified from pCASL data [2] in gray matter of major flow territories (Figure 1) and OEF from TRUST data [3] using established models that accounted for hematocrit differences between patients and controls. A Kruskal-Wallis test was applied to evaluate mean differences between SCA and control parameters and between study parameters for SCA patients grouped by less or more clinical impairment (defined by presence of infarct, vasculopathy, or use of routine blood transfusion for SCA pain management). Two-sided p-values were corrected for multiple-comparisons using the Holm method, and significance was defined as corrected-p<0.05.CBF and OEF were elevated (p<0.05) in SCA participants not receiving monthly blood transfusions (n=27; interquartile range CBF=46.2-56.8 ml/100g/min; OEF=0.39-0.50) relative to control participants (interquartile range CBF=40.8-46.3 ml/100g/min; OEF=0.33-0.38) (Figures 1 and 2). OEF (p<0.0001) but not CBF was increased in patients with higher levels of clinical impairment (Figure 3). Figure 4 shows examples of representative cases and images. OEF was weakly, inversely correlated with CBF across all patients (R=-0.31; p=0.04). Consistent with the primary hypothesis of this study, the correlation is strongest for patients that are less impaired (R=-0.54; p=0.019) relative to those that are more impaired (R=-0.23; p=0.17). Ongoing work is focused on improving quantitative pCASL and OEF data by incorporating refined blood calibration models that incorporate knowledge of the blood hemoglobin-S fraction.OEF measured using TRUST MRI shows promise as a screening tool for hemodynamic impairment and stroke risk in adults with SCA. A long-term goal for this sort of methodology is to assess whether metabolic neuroimaging predicts overt stroke in patients with sickle cell anemia, and if so to use this method as a screening test for stroke risk in adults with sickle cell anemia for whom no test is currently available.