Cerebral oxygen extraction efficiency in patients with sickle cell anemia

PROJECT SUMMARY This work proposes to refine novel non-invasive magnetic resonance imaging (MRI) methods to quantify cerebral oxygen extraction and to apply these methods in persons with sickle cell anemia (SCA) to elucidate potential mechanisms for cerebral infarct development. SCA, caused by homozygous inheritance of mutant hemoglobin S (HbS), is the most severe and yet common form of sickle cell disease affecting approximately 1 in every 500 African Americans in the United States. The disease is characterized by the sickling of erythrocytes following deoxygenation of mutant HbS, which manifests in patients as chronic hemolytic anemia and possible vascular occlusion. More than half of individuals with SCA will have a silent cerebral infarct (SCI) by age 30 years; while largely asymptomatic at the time of injury, these SCIs can lead to progressive infarctions and cognitive deficits. Despite the high risk of infarction in these patients, few patients exhibit traditional risk factors for stroke such as macrovascular steno-occlusion and as such it has been difficult to develop biomarkers that can be used to triage patients for conservative versus more aggressive disease-modifying or curative therapies. Cerebral infarctions in persons with SCA are likely due to alternative vascular and metabolic changes at the tissue level secondary to the disease. It is well-established that cerebral blood flow (CBF) is elevated in SCA to compensate for reduced hemoglobin, but CBF is an incomplete predictor of ischemic risk by itself. Prior work in our lab has shown reduced capillary transit times in the presence of elevated CBF in individuals with SCA may lead to inefficient cerebral oxygen extraction at the capillary level. It is critical to accurately characterize these and possibly related changes in tissue physiology to establish functional biomarkers that can be used to triage patients with SCA to risk- appropriate treatments, or rather, to use these biomarkers as end-points in clinical trials. To address these needs, non-invasive imaging methods such as the asymmetric spin echo (ASE) MRI sequence have been developed to characterize cerebral oxygen extraction in humans. However, current methodological variants underestimate cerebral oxygen extraction metrics due to technical shortcomings of isolating extravascular water signal in the sequence. The goals of this proposal are (1) to refine and evaluate MRI methods to accurately quantify regional cerebral oxygen extraction and (2) to understand relationships between regional changes in oxygen extraction and blood transit times in adults with SCA before and after blood transfusions that modulate hemoglobin and flow velocities. Successful completion should provide new methods to monitor tissue health in SCA and to improve our understanding of how tissue subserves oxygen in the setting of anemia and in response to treatments.