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O-003 The Brain as Extraintestinal IBD Manifestation: Are Brain and Cognitive Differences in Pediatric Crohn's Disease Associated with Immune Gene Expression?

Background: Structural brain changes in gray and white matter have been previously found in adults with Crohn's disease (CD). We have recently shown similar effects for pediatric CD in 2 separate studies (Mrakotsky et al., 2012, 2013, 2015), particularly for cortical and subcortical brain regions important for cognition, memory and emotion. Our prior data also revealed serum markers of inflammation and steroid therapy to be negatively associated with cortical thickness, subcortical volume, cognitive and school function, however, associations between brain structure and more detailed inflammatory profiles have not been studied. This CCFA SRA aims to replicate prior studies on brain involvement in pediatric CD, and provide initial information on potential contributing immune pathways. Methods: Structural magnetic resonance imaging (MRI) was performed in 54 children age 10 to 14 years (CD patients: n = 37, age-and sex-matched healthy controls: n = 17) using a 3 Tesla Siemens Trio MRI system. Anatomical whole brain T1-weighted images were acquired at 1 mm3 voxel size. All subjects also underwent neuropsychological assessments (tests of attention, memory, IQ, emotional functions), disease severity ratings (PCDAI), and phlebotomy to obtain inflammatory markers. CD patients were scanned and tested during an active disease flare or in clinical remission. Cortical thickness and volume was analyzed using Freesurfer. Gene expression analysis of immunology-related genes was performed via multiplex array (Nanostring nCounter Human Immunology v2, nSolver v3 Advanced Analysis). Analyses were adjusted for age and sex, and included correlation, regression and group comparisons. Multiple comparisons were corrected with false discovery rate. Groups were comparable on demographics. Results: We confirmed our initial finding of reduced gray matter (cortical thickness in posterior brain regions (bilateral inferior parietal, superior parietal, supramarginal [all pFDR < 0.05]), subcortical volume (bilateral hippocampi and thalami [all pFDR < 0.05]), and poorer cognitive (P < 0.05) and memory function (P < 0.01) in CD patients compared to healthy children. We further found differences in mRNA gene expression in a range of immune-related genes in CD patients compared to controls (i.e., TIGIT, KLRG1, KLRK1 [downregulated], CD44, ITGA2B, NFKB [upregulated] [pFDR = 0.02–0.10]). Regression including both differentially expressed and a priori defined immune genes revealed some associations between cytokine (i.e., IL1R1, IL6R, IL18RAP), NK cells, NFKB1 gene expression with gray matter (supramarginal, inferoparietal thickness, thalamic volume), after controlling for steroids. Steroids remained a robust contributor to brain structural outcomes. Conclusions: Complete data from this CCFA SRA confirm our prior findings of reduced gray matter in pediatric CD, particularly in posterior cortical and subcortical limbic regions critical for higher cognition, emotional and pain processing. We found differentially expressed immune genes in CD patients that may play a role in inflammatory response, cell migration, and apoptosis and have also been implicated in brain development and injury. The preliminary association of immune gene expression with gray matter brain structures provides first insights in the molecular basis of brain involvement in IBD, and may further lend support for novel treatment targets.