As the most common inherited blood disorder, sickle cell disease (SCD) affects one in 400 African-Americans. The disorder alters the shape of the red blood cell, leading to systemic, multi-organ effects, reducing the median life expectancy to 40 years. Among its complications, ischemic stroke is common and disabling, beginning in infancy - overt strokes cause acute neurological deficits and silent strokes manifest as intellectual decline. A screening method to prevent strokes, transcranial Doppler ultrasound (TCD), is helpful for selecting SCD children who will benefit from transfusion therapy as a means to reduce stroke occurrence. Unfortunately, however, the screening mechanism has several limitations including its insensitivity for predicting those at risk for silent strokes. Moreover, nearly half of children continue to have recurrent overt strokes, silent strokes, and/or progressive vasculopathy, despite screening and being placed on transfusions. Thus, an improved biomarker for stratifying stroke risk in SCD children is needed. In this proposal, we hypothesize that the brain's hemodynamic and metabolic compensatory responses to reduced blood oxygen content in SCD will reveal mechanisms leading to ischemic stroke. We will determine if MR-derived cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of this hemodynamic and metabolic stress, may provide novel tools to stratify stroke risk in SCD children so that treatment may be individualized, identifying those at highest risk for more aggressive therapies, while sparing those at lower risk any unnecessary adverse effects of treatment. We hypothesize that measurements of CBF and OEF at the brain- tissue level will be more sensitive and specific for stroke risk than blunt measures of blood velocity as measured by TCD. Over the past 15 years, we have developed a novel, noninvasive MR approach to measure brain OEF at the voxel-level. Until now, OEF could only be measured by PET imaging, and thus has never been studied in SCD children due to the risks of radiation.
Aim1. To determine if CBF and OEF are increased in SCD children compared to sibling controls indicating an elevated stroke risk.
Aim2. To determine if hemispheric CBF and OEF demonstrate greatest alteration in the subset of SCD children with vasculopathy indicating a very high risk of stroke in the territory of the affected vessel.
Aim3. To determine if transfusion therapy normalizes CBF and OEF, thereby reducing hemodynamic and metabolic stress as a means to reduce stroke risk.
Aim 4. To determine if elevated CBF and/or OEF predict future stroke on 3 year follow-up MRI better than TCD.

Public Health Relevance

Children with sickle cell disease carry a high risk for strokes (300 times that of healthy children) which cause sudden and lifelong disability as well as an even higher risk of silent strokes which cause progressive cognitive decline. In this grant application, we propose to perform non-invasive MRI scans to measure cerebral blood flow and oxygen metabolism in children with sickle cell disease in order to improve the understanding of the mechanisms that lead to stroke. We will also determine if these MRI measures are predictive of increased stroke risk and if they can be used to identify children who will benefit from more aggressive preventative therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL129241-03
Application #
9281883
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Klauzinska, Malgorzata
Project Start
2015-08-15
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$508,470
Indirect Cost
$141,844
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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
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