Pediatric stroke may occur because of an inadequate oxygen supply to meet the high energy demands of a developing brain. The brain undergoes tremendous growth and development throughout childhood. Brain tissues consume oxygen delivered by the blood, providing energy for cellular processes. The brain?s demand for oxygen appears to peak between ages 5-9. If regions of the brain do not get enough oxygen, either because the blood does not carry enough oxygen, or because blood does not reach the tissue, a stroke can occur. The cerebral metabolic rate of oxygen utilization (CMRO2), reflecting the energy demands of the brain, is a product of amount of oxygen available in the blood, rate of blood delivery (cerebral blood flow, or CBF) and the percentage of oxygen delivered taken up by the brain tissue (oxygen extraction fraction, or OEF). CBF and OEF are dynamic processes, able to compensate for minor perturbations or increased demand as needed to maintain a steady energy consumption rate. In adults, an increased OEF demonstrates high metabolic compensation and signifies a high stroke risk. Because the oxygen demand is higher in children than adults and changes throughout childhood, it is unclear whether increased OEF and increased CBF also denote a high stroke risk. One reason this is unknown is because previously OEF has required radiation for tissue-level measurements; thus rendering OEF measurements unethical for pediatric research. Our team has developed novel MR sequences to measure tissue-level OEF. Children with sickle cell disease (SCD) have lower amounts of oxygen available in their blood due to anemia. Children with SCD also have a high incidence of stroke, with 1 of 3 children demonstrating stroke on MRI before reaching adulthood. This project seeks to understand whether or not age-dependent increases in OEF and CBF predict stroke in children with SCD. I hypothesize that age and oxygen metabolism predict stroke risk in children with SCD. The long- term goal of this project is to develop these methods to assess stroke risk and mechanism across pediatric stroke populations.
Aim 1 : To determine effects of age and SCD on oxygen metabolism. I will examine the contribution of age, blood counts, and SCD on CBF and OEF.
Aim 2 : To determine if age and oxygen metabolism predict individual stroke risk in subjects with SCD. I will follow subjects with SCD for 4 years to determine the predictive value of global and regional measures of age and oxygen metabolism, accounting blood counts, and disease severity.
Aim 3 : To determine if oxygen metabolism response to therapeutic intervention is age- dependent. I will examine how global and regional metabolism changes with transfusion.

Public Health Relevance

Pediatric stroke is a leading cause of morbidity and mortality in children. The changing oxygen demands of the brain throughout childhood may render children more vulnerable to stroke when demands are highest. This project uses novel, non-invasive MRI techniques to determine how age influences oxygen use and stroke risk in children with sickle cell disease, who are at a particularly high risk for pediatric strokes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Hartman, Adam L
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Washington University
Schools of Medicine
Saint Louis
United States
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Ford, Andria L; Ragan, Dustin K; Fellah, Slim et al. (2018) Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow. Blood 132:1714-1723
Fields, Melanie E; Guilliams, Kristin P; Ragan, Dustin K et al. (2018) Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease. Neurology 90:e1134-e1142
Guilliams, Kristin P; Fields, Melanie E; Ragan, Dustin K et al. (2018) Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood 131:1012-1021