# MR-Derived Cerebral Oxygen Metabolism underlying Ischemic Vulnerability in Sickle Cell Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $683,879

## Abstract

Abstract: Sickle cell anemia (SCA) affects one in 1000 individuals worldwide, causing multi-organ ischemia,
long-term disability, and premature death, with a life expectancy of 42 years. Among its complications, cerebral
infarction and cognitive disability are prevalent and increase with age, with > 50% of young adults having silent
infarcts. Great headway has been made in pediatric SCA using neuroimaging screening tools to select high-risk
children, yet adults remain understudied. As the brain demands disproportionately more oxygen than other
organs at ~20% of total blood supply (but only 2% of body weight), low arterial oxygen content (CaO2) due to
anemia, places the sickle cell brain at lifelong risk of hypoxia. Thus, to try to meet cerebral oxygen demand
(CMRO2), the brain is continually under hemodynamic and metabolic “stress”, marked by elevated cerebral blood
flow and oxygen extraction fraction (OEF), respectively. Findings from our previous grant cycle have helped
shape a new understanding of ischemic brain injury mechanisms in SCA. Importantly, specificity of both global
and regional OEF for stratifying stroke risk, at patient and tissue levels, suggests great promise for the clinical
utility of this imaging biomarker. We are now completing follow-up MRIs to determine if OEF longitudinally
predicts infarction in pediatric SCA. Two unexpected findings emerged from our results which warrant further
investigation. First, we expected that compensatory increases in CBF and OEF in SCA would serve to maintain
a normal cerebral oxygen metabolic demand; however, we found that resting CMRO2 is globally elevated in SCA.
This increase in oxygen demand parallels an elevation in total body resting energy expenditure in SCA, which is
postulated to be due to chronic inflammation. The finding is intriguing as an elevated cerebral oxygen demand
may increase ischemic vulnerability. Indeed, sickling and high blood velocity injure the endothelium inducing a
variety of leukocyte-endothelial interactions. Therefore, we hypothesize that neuroinflammation may promote
ischemia by increasing cerebral oxygen demand. Second, while we find global OEF elevation in adults with
SCA compared to controls, regional OEF elevation in the deep white matter is less prominent in adults compared
to children, suggesting a decrease in regional OEF with disease duration. It is postulated that capillary flow
heterogeneity (CFH) due to change in capillary microarchitecture leads to a reduction in local OEF. This is of
great interest in SCA because capillary morphology is disrupted and transit times are short due to anemia. Thus,
we hypothesize that progressive microvascular disease in SCA will disrupt capillary flow patterns, decreasing
oxygen supply, as an additional ischemic mechanism. In this renewal, we shift focus to adults with SCA, as a
growing and understudied population. First, we will determine if cerebral metabolic stress predicts ischemic brain
injury and cognitive declin...

## Key facts

- **NIH application ID:** 9973340
- **Project number:** 2R01HL129241-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Hongyu An
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $683,879
- **Award type:** 2
- **Project period:** 2015-08-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973340

## Citation

> US National Institutes of Health, RePORTER application 9973340, MR-Derived Cerebral Oxygen Metabolism underlying Ischemic Vulnerability in Sickle Cell Disease (2R01HL129241-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973340. Licensed CC0.

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