R01HL152358

Exploring the Relationship Between Advanced Multimodal Brain MRI Phenotypes, Genes, and Cognitive Outcome in Adults with CHD

Congenital Heart Disease (CHD) affects approximately 1% of all live births in the United States. Over 85% of individuals with CHD now live well into adulthood, exposing a burden of non-cardiac disabilities, such as neurodevelopmental disabilities. In fact, over half of all children with moderate or complex CHD suffer from neuropsychological deficits, with impaired executive functions (EF) being the most common. EF are critical higher-order neurocognitive functions important for independent living and mental health. However, predicting who will be more impaired and in need of intervention is challenging, as routinely measured patient and medical factors explain only one-third of the variance in outcomes. Because impaired EF is particularly amenable to treatment, better predictors of EF are needed to appropriately allocate services and improve outcomes.

To develop such methods, we first focus on Dextro-Transposition of the Great Arteries (D-TGA). Among the severe forms of CHD, D-TGA is the more common, occurring in 3/10,000 live births. D-TGA leads to severe in utero hypoxia that is corrected soon after birth with an arterial switch operation. Additional surgery and cardiovascular sequelae are rare. Thus, D-TGA patients have the most uniform postnatal course of all CHDs but, like other CHDs, are associated with hypoxia and have significant yet variable impairment in EF. This project leverages adult D-TGA subjects being studied under R01HL135061 and D-TGA patients involved in prior Boston trials to create the largest, best-characterized D-TGA cohort to date.

We propose to perform sophisticated image analysis on brain MRI data and add genetic testing focused on neuroresilience and hypoxia response genes. First, we will employ our sulcal pattern analysis to determine the extent of in utero alterations in brain development, as sulcal patterns are determined prenatally and remain stable into adult life. Second, we will explore the rich club structural and functional networks to separate highly connected central hubs (rich club) that form early in life from less connected peripheral regions, which are thought to be adaptive.

The overarching goal of this study is to use novel MRI analyses to determine the brain organizational changes associated with altered EF and the modulating role of neuroresilience and hypoxia response genes in adults with D-TGA. Toward these ends, we propose the following specific aims:

Aim 1: Determine the relationship between sulcal patterns and executive function in adults with D-TGA and if this relationship is modified by (a) presence of neuro-resilience gene APOE E2 or E4 alleles or (b) variants in hypoxia response genes.

Aim 2/3: Determine the relationship between structural/functional connectivity using rich club and executive function in adults with D-TGA and if this relationship is modified by (a) presence of neuro-resilience gene APOE E2 or E4 alleles or (b) variants in hypoxia response genes.

Successful completion would help determine brain changes associated with altered EF and the potential modulating role of neuroresilience and hypoxia response genes, as well as inform the balance of in utero versus adaptive changes. This knowledge is relevant to the larger CHD group and will inform the need for prenatal versus postnatal interventions.

Children's Hospital Corporation

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. 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]

Boston, Massachusetts 021155724 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 379% from $822,644 to $3,938,586.