In this supplement (PA-18-658: Administrative Supplement for Research on Sex/Gender Influences), I will expand my cohort of children and young adults to examine sex influence on age-dependent cerebral oxygen metabolism as a mechanism for sex-differences of pediatric stroke incidence. Cerebral oxygen metabolism (CMRO2) is the product of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and arterial oxygen content (CaO2). Components of CMRO2, i.e. an elevated OEF, herald ischemic stroke in adults. My parent K23 ?Age-dependence of cerebral oxygen metabolism and stroke risk in pediatric sickle cell disease (1K23NS099472-01)? hypothesizes developmental changes of CBF and OEF underlie the age-dependent ischemic vulnerability in children with sickle cell disease (SCD). In addition to age, male sex is an understudied risk factor for pediatric stroke. In SCD, the overwhelmingly higher stroke incidence in males and disproportionately high number of females receiving transfusions for stroke prevention raise the concern that females with SCD may be over-exposed to blood transfusions. Understanding the mechanisms for of stroke incidence discrepancies is imperative to address Goal 3 of the NIH Strategic Plan for Women?s Health Research, ?to actualize personalized prevention, diagnostics, and therapeutics for girls and women?. Here, I propose to build upon my prior work to understand whether sex-dependent developmental changes of CBF and OEF provide potential mechanisms for sex differences in pediatric stroke incidence. I could not have included sex as a variable in my parent K23, as preliminary data for sex differences of CMRO2 in children did not exist. Due to positron-emission tomography (PET) historically being the primary modality to study CMRO2, and radiation inherent with PET, few studies are published about CMRO2 in children. Those published have too few subjects to examine sex-differences. CBF is known to be dynamic in childhood, and recent work shows developmental trajectories of CBF differ between males and females, but OEF values in childhood were unknown. In the course of my funded research, I found that OEF is age-dependent, with higher values observed in younger children, using novel magnetic resonance imaging sequences. My data suggests, but is underpowered to confirm, that OEF is also sex-dependent. These supplemental activities will model CMRO2 and its components to determine if sex significantly impacts age-dependent oxygen metabolism and achieve the stated objective of the NIH Strategic Plan to ?study sex differences in the aging process? in the first decades of life, as well as the stated interest of projects ?aimed at increasing mechanistic understanding of sex differences?. Success in this work will advance our knowledge of ischemic vulnerability in children, and provide mechanistic foundations for sex-differences of stroke in children with SCD, which may ultimately lead to fewer blood transfusions in girls and women with SCD and fewer strokes in all children.

Public Health Relevance

Pediatric stroke is a leading cause of morbidity and mortality in children, and for reasons not yet explained, boys have strokes more often than girls. The changing oxygen demands of the brain throughout childhood may render children more vulnerable to stroke when demands are highest, and the oxygen demands of the brain may be different in boys and girls during the first decades of life. This project uses novel, non-invasive MRI techniques to determine how age and sex 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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Hartman, Adam L
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Washington University
Schools of Medicine
Saint Louis
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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
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