Development and Validation of a Paralimbic Related Subcortical Brain Dysmaturation MRI Score in Infants with Congenital Heart Disease

Abstract

Background Brain magnetic resonance imaging (MRI) of infants with congenital heart disease (CHD) shows brain immaturity assessed via a cortical-based semi-quantitative score. Our primary aim was to develop an infant paralimbic-related subcortical-based semi-quantitative dysmaturation score, a brain dysplasia score (BDS), to detect abnormalities in CHD infants and predict clinical outcomes. Our secondary aim was to validate our BDS in a preclinical mouse model of hypoplastic left heart syndrome. Methods A paralimbic-related subcortical BDS, derived from structural MRIs of infants with CHD, was correlated with clinical risk factors, regional cerebral volumes, feeding and 18-month neurodevelopmental outcomes. The BDS was validated in a known CHD mouse model named Ohia with two disease-causing genes, Sap130 and Pchda9. To relate clinical findings, RNA-Seq was completed on Ohia animals. Findings BDS showed high incidence of paralimbic-related subcortical abnormalities (including olfactory, cerebellar, and hippocampal abnormalities) in CHD infants (n=215) compared to healthy controls (n=92). BDS correlated with reduced cortical maturation, developmental delay, poor language and feeding outcomes, and increased length of stay. Ohia animals (n=63) showed similar BDS findings, and RNA-Seq analysis showed altered neurodevelopmental and feeding pathways. Sap130 mutants correlated with a more severe BDS whereas Pcdha9 correlated with a milder phenotype. Interpretation Our BDS is sensitive to dysmaturational differences between CHD and healthy controls, and predictive of poor outcomes. A similar spectrum of paralimbic-related subcortical abnormalities exists between human and Ohia mutants suggesting a common genetic mechanistic etiology.