# The Impact of Cerebral Metabolic Stress on the Development of the Structural and Functional Connectome in Pediatric Sickle Cell Anemia

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $649,665

## Abstract

PROJECT SUMMARY
 Children with sickle cell anemia (SCA) suffer from cognitive decline, even when unaffected by stroke.
The pathophysiology of cognitive dysfunction in SCA is poorly understood. Understanding the mechanism and
trajectory of injury and degree of reversibility is necessary to prevent lifelong disability in this vulnerable
population. Furthermore, current screening tools are inadequate as transcranial Doppler ultrasound and
structural brain MRI only screen for risk of stroke and evaluate for presence of irreversible infarction. The long-
term goal of this proposal is to determine the mechanism of brain injury with MR measures of oxygen
metabolism, structural connectivity, and functional connectivity, and develop neuroimaging biomarkers for
cognitive dysfunction in SCA.
 Children with SCA experience cerebral metabolic stress, as measured by increased oxygen extraction
fraction (OEF). OEF peaks within the deep white matter, co-localizing with the brain region at greatest risk for
stroke in SCA. Increased metabolic stress is associated with disrupted connectivity within specific functional
brain networks, and the nodes of networks with diminished functional connectivity in SCA are anatomically-
contiguous, clustered and aligned with the region of elevated OEF in the white matter. However, OEF
decreases and executive function abilities improve with a single red blood cell transfusion in children with SCA,
suggesting some aspects of cognitive dysfunction, potentially driven by alterations in FC, are acutely reversible
as metabolic stress is attenuated in SCA. The central hypothesis of this proposal is that isolated disruption of
functional connectivity caused by increased metabolic stress will be acutely reversible; however, disruption of
functional connectivity mediated by structural connectivity will be irreversible. Treatment of the former may
improve cognitive function, while treatment of the latter may mitigate progressive cognitive decline. In order to
test her hypothesis, Dr. Fields will obtain longitudinal measures, separated by three years, of cognitive testing
and brain MRIs to measure OEF, structural connectivity and functional connectivity in control, non-transfused
SCA, and transfused SCA participants. The transfused participants will undergo cognitive testing and brain
MRI before and after red blood cell transfusion at study entrance. Using this data, she will test her central
hypothesis by completing the following specific aims: 1) Determine if disruption of the structural and functional
connectome is reversible with transfusion of RBCs in SCA, 2) Determine the impact of increased OEF on the
development of the structural and functional connectome, and 3) Determine if MR metrics of metabolic stress,
SC and FC predict aberrant cognitive trajectories. Completion of these aims will provide insight into the
pathophysiology of cognitive dysfunction in SCA, and allow the definition and development of biomarkers for
reversible neuro...

## Key facts

- **NIH application ID:** 10179749
- **Project number:** 1R01HL157188-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Melanie Erin Fields
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $649,665
- **Award type:** 1
- **Project period:** 2021-04-05 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179749

## Citation

> US National Institutes of Health, RePORTER application 10179749, The Impact of Cerebral Metabolic Stress on the Development of the Structural and Functional Connectome in Pediatric Sickle Cell Anemia (1R01HL157188-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179749. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*