Wednesday, March 18, 2026 3/18/2026

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

Award Number: R01HL157188
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The Impact of Cerebral Metabolic Stress on the Development of the Structural and Functional Connectome in Pediatric Sickle Cell Anemia - 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 neurologic injury, which can potentially guide treatment effect, and improve outcomes in this vulnerable population.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	5	2/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $620,685 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	5	3/24/2025	NON-COMPETING CONTINUATION	$558,617
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	5	7/29/2025	NON-COMPETING CONTINUATION	$62,068
														Subtotal = $620,685

Issue Date FY: 2024 ( Subtotal = $609,774 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	4	4/17/2024	NON-COMPETING CONTINUATION	$559,997
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	4	6/22/2024	NON-COMPETING CONTINUATION	$49,777
														Subtotal = $609,774

Issue Date FY: 2023 ( Subtotal = $568,769 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	3	3/15/2023	NON-COMPETING CONTINUATION	$568,769
														Subtotal = $568,769

Issue Date FY: 2022 ( Subtotal = $640,209 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	2	6/17/2022	NON-COMPETING CONTINUATION	$64,023
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	2	3/18/2022	NON-COMPETING CONTINUATION	$576,186
														Subtotal = $640,209

Issue Date FY: 2021 ( Subtotal = $649,665 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	1	6/10/2021	NEW	$64,965
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	1	4/2/2021	NEW	$584,700
														Subtotal = $649,665

Grand Total All Awards = $3,089,102

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

Award Number: R01HL157188

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/05/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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