R01HL157188

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 functional connectivity, 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.
3) Determine if MR metrics of metabolic stress, structural connectivity, and functional connectivity 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.

Washington University

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Saint Louis, Missouri 631101010 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 428% from $584,700 to $3,089,102.