Abstract 16541: Abnormal Brain Connectivity and Poor Neurodevelopmental Outcome in Congenital Heart Disease Patients With Subtle Brain Dysplasia

Abstract

Introduction: Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments. Methods: The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained. Results: The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p<0.05), but not to specific heart lesions or white matter injury. Neurodevelopmental assessment of 20 patients at 18 months showed higher BDI score correlated with reduction in Total Developmental Quotient (p <0.05) and Adaptive Developmental Quotient (p<0.009). Conclusion: A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.

Cerebral Spinal Fluid Volumetrics and Paralimbic Predictors of Executive Dysfunction in Congenital Heart Disease: A Machine Learning Approach Informing Mechanistic Insights

“…Conjointly, we found that these study participants with CHD also exhibited increased extra-axial CSF volume (qualitatively assessed) 3 . In a follow-up, albeit limited study, we showed that brain dysmaturation was associated with poor neurodevelopmental outcomes 52 , which has been supported by other studies as well 10,53…”

Clinical Factors Associated with Microstructural Connectome Related Brain Dysmaturation in Term Neonates with Congenital Heart Disease

“…The BDS was based on previous correlative analysis of brain phenotype from CHD mouse mutant and human infant MRI including a spectrum of subtle brain dysplasia (hypoplasia or aplasia) including increased extra-axial CSF and abnormalities of the olfactory bulbs, cerebellum, hippocampus and corpus callosum and a composite brain dysplasia score, as previously described. 10, [30][31][32][33][34][35] Basic pediatric neuroradiological definitions and criteria were used from Barkovich et al for overall assessment of brain abnormalities. 55 For olfactory abnormalities, we assessed for aplasia/hypoplasia of the olfactory blub within the olfactory groove and aplasia/hypoplasia of the olfactory sulcus on high resolution coronal T2 images.…”

“…10, [30][31][32][33][34][35] This pattern of subcortical dysmaturation was predominantly seen in the olfactory bulb (dysmorphometry of left and right olfactory bulbs and sulci) , the cerebellum ( hypoplasia and/or dysplasia in cerebellar hemispheres and vermis) and the hippocampus (hypoplasia or malrotation) are components of a larger spectrum of structural abnormalities including extraaxial CSF fluid increases, corpus callosum abnormalities, choroid plexus abnormalities and brainstem dysplasia that we have recently observed in both human CHD patients and preclinical CHD mouse models. 10, [30][31][32][33][34][35] As such, we have derived a composite Brain Dysplasia Score (BDS) which was previously created with one point given for each positive finding in any of thirteen parameters including: hypoplasia in cerebellar hemispheres and vermis; dysplasia in cerebellar hemispheres and vermis; supratentorial extra-axial fluid; dysmorphometry of left and right olfactory bulbs and sulci; abnormalities in hippocampus and choroid plexus; malformation of corpus callosum; and brainstem dysplasia. 10, [30][31][32][33][34][35] There is little known about the relationship of these milder structural dysplastic abnormalities (relative to more gross brain malformation) to white matter connectivity.…”

“…10, [30][31][32][33][34][35] As such, we have derived a composite Brain Dysplasia Score (BDS) which was previously created with one point given for each positive finding in any of thirteen parameters including: hypoplasia in cerebellar hemispheres and vermis; dysplasia in cerebellar hemispheres and vermis; supratentorial extra-axial fluid; dysmorphometry of left and right olfactory bulbs and sulci; abnormalities in hippocampus and choroid plexus; malformation of corpus callosum; and brainstem dysplasia. 10, [30][31][32][33][34][35] There is little known about the relationship of these milder structural dysplastic abnormalities (relative to more gross brain malformation) to white matter connectivity.…”

Quantitative Magnetic Resonance Cerebral Spinal Fluid Flow Properties and Executive Function Cognitive Outcomes in Congenital Heart Disease

“…[6–9] Increased CSF volume has been shown to be correlated with brain dysmaturation (i.e., dysplastic cortical and subcortical structures, decreased cortical and subcortical volumes, and decreased cortical thickness), as well as poor neurodevelopmental outcomes in preoperative neonates[10] and young children with CHD. [2,3,11]…”