The Relation of Regional Brain Structure to Long-term Development and Behavior in d-TGA Patients

Doctor's Name: 
Jane W. Newburger, M.D., M.P.H.
Hospital/Institution: 
Children’s Hospital Corporation

The proposed study represents a secondary analysis of recently-gathered brain MRI and neurodevelopmental data in adolescents with d-transposition of the great arteries (d-TGA). Striking improvement in the survival of patients with critical congenital heart disease (CHD) has revealed that this population harbors a high prevalence of neurologic and developmental abnormalities. Furthermore, most patients with CHD now survive to adulthood, when consequences of neurodevelopmental impairment have major societal and economic implications, including employability. Since 1988, we have studied a cohort of children with d-TGA, without known genetic abnormalities or phenotypic syndromes, who underwent corrective surgery in early infancy. Follow-up evaluations of the children were conducted in the early postoperative period, and at ages 1, 4, 8, and 16 years.

 

From the 16-year evaluation, we have collected complete datasets that comprise detailed neurodevelopmental evaluations and quantitative magnetic resonance imaging (MRI) data that consist of whole brain volumetric MRI and diffusion tensor imaging (DTI) on 101 d-TGA children and 48 controls. Herein, we propose to analyze the relationship of regional brain structure and microstructure with neurodevelopment. Using recently-gathered volumetric MRI and DTI data, regional brain structure will be determined through parcellation of the brain into discrete neuroanatomical regional volumes. White matter microstructure will be determined in the corresponding regions using fractional anisotropy (FA) and apparent diffusion coefficient (ADC).

 

Our specific aims are as follows: In Aim 1, we will evaluate regional brain structure. We hypothesize that adolescents with d-TGA, compared to controls, will have reduced volumes in parcellated regions within the parietal, temporal, and prefrontal regions on structural MRI. The primary outcome measures using quantitative volumetric MRI and parcellation will be the regional volumes of subcortical gray matter nuclei and hippocampus. Secondary outcome measures will comprise regional volumes and regional cortical thickness measures resulting from complete parcellation of the brain.

In Aim 2, we will evaluate regional white matter microstructure. We hypothesize that adolescents with d-TGA, compared to controls, will have reduced fractional anisotropy (FA), reflecting disruption of white matter organization, in parcellated regions within the parietal, temporal, and prefrontal regions. The primary outcome measures using diffusion tensor MRI will be regional white matter microstructure, as measured by FA within the parcellated regions. Secondary outcome measures will be regional ADC.

In Aim 3, we will evaluate the relationship of regional brain structure and white matter microstructure on MRI to neurodevelopmental domains. We hypothesize that regional MRI volumes and white matter microstructure (i.e., smaller parcellated volume, diminished FA, and increased ADC) will correlate with worse performance in important neuropsychological domains, including executive function, visual-spatial function, memory, and attention. We will use Pearson correlation and linear regression methods for scalar outcomes. When multiple outcomes are considered simultaneously, we will use multivariate analysis of variance and multivariate linear regression. We will also explore whether medical and sociodemographic factors modify these relationships.

 

Given the economic and societal implications of neurodevelopmental impairments in the burgeoning CHD population, it is critically important to define the underlying mechanisms for their neurodevelopmental deficits. The proposed study will advance our understanding of the relationships of regional brain structure and white matter organization to neurodevelopmental domains, including executive function, visual-spatial function, memory, and attention. Moreover, this study should stimulate development of MRI measures of late neurodevelopmental outcome that can serve as surrogate endpoints to shorten the duration of randomized clinical trials aimed at maximizing cognitive and behavioral function in the CHD population. Finally, this proposal offers a unique opportunity to address important questions of broad biologic significance regarding the relationships of brain structure and function to neurodevelopment, as well as to medical factors.

 

Award Date 1: 
2010
Award Amount 1: 
$89,750
Award Date 2: 
2011
Award Amount 2: 
$45,590