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

<b>Background:</b> 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, termed brain dysplasia score (BDS), to detect abnormalities in CHD infants compared to healthy controls and secondarily to predict clinical outcomes. We also validated our BDS in a preclinical mouse model of hypoplastic left heart syndrome. <b>Methods:</b> A paralimbic-related subcortical BDS, derived from structural MRIs of infants with CHD, was compared to healthy controls and 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 <i>Ohia</i> with two disease-causing genes, <i>Sap130</i> and <i>Pchda9</i>. To relate clinical findings, RNA-Seq was completed on <i>Ohia</i> animals. <b>Findings:</b> BDS showed high incidence of paralimbic-related subcortical abnormalities (including olfactory, cerebellar, and hippocampal abnormalities) in CHD infants (<i>n</i> = 215) compared to healthy controls (<i>n</i> = 92). BDS correlated with reduced cortical maturation, developmental delay, poor language and feeding outcomes, and increased length of stay. <i>Ohia</i> animals (<i>n</i> = 63) showed similar BDS findings, and RNA-Seq analysis showed altered neurodevelopmental and feeding pathways. <i>Sap130</i> mutants correlated with a more severe BDS, whereas <i>Pcdha9</i> correlated with a milder phenotype. <b>Conclusions:</b> Our BDS is sensitive to dysmaturational differences between CHD and healthy controls and predictive of poor outcomes. A similar spectrum of paralimbic and subcortical abnormalities exists between human and <i>Ohia</i> mutants, suggesting a common genetic mechanistic etiology.