P088 IMMUNE GENE EXPRESSION DURING ACTIVE DISEASE IS ASSOCIATED WITH BRAIN, COGNITIVE AND BEHAVIORAL CHANGES IN PEDIATRIC CROHN’S DISEASE

Abstract

Structural brain changes in gray and white matter have been found in adults with Crohn’s disease (CD). In adults, increased disease activity has also been associated with decreased cognitive performance. We have shown similar effects for pediatric CD, particularly for gray matter and associated cognitive and emotional functions. Underlying inflammation and steroid therapy have emerged as contributors, however, associations between brain structure and immune pathways have not been studied. We here aim to replicate earlier findings of brain involvement in pediatric CD, including study of white matter structures, and to elucidate the impact of immune response on the central nervous system. Sixty-one children age 10-15 years (20 CDActive, 23 CDRemission, 18 healthy controls) underwent structural and diffusion-weighted magnetic resonance imaging (MRI/DWI), neuropsychological assessment (IQ, memory, mood), disease severity ratings (PCDAI), and phlebotomy for immune gene expression. Gray matter data (cortical thickness, volume) was analyzed via Freesurfer, white matter [i.e. axial diffusivity (AD), isotropic free water (isoF)] with a diffusion compartment model (DIAMOND). Immune gene expression was assayed via multiplex array (NanoString® nCounter). Analyses were adjusted for age, sex, and steroid, and included correlation, regression, group comparison, and KEEG pathway analyses. Compared to healthy and CD controls, CDActive showed reduced cortical thickness in posterior brain regions [inferior, superior parietal, lateral occipital (ps<.05)], subcortical volume [thalamus, hippocampus (ps<.05)], widespread reduced AD (axonal integrity) and increased isoF (neuroinflammation) across white matter fiber tracts [corpus callosum, cingulum (ps<.01-.05)], poorer cognitive performance and mood [ps<.05]. Findings remained after controlling for steroids. We found 337/594 differentially expressed (240 upregulated) immune genes in CDActive compared to controls, with overlap with cytokine-cytokine receptor (IL-1r, IL-18r, TNF), TLR and Jak-STAT signaling, and complement (C1,2, CR1, ITGAM) gene pathways. Upregulated immune genes were associated with reduced gray and white matter structures, increased neuroinflammation, and poorer memory and mood. Both gray and white matter are reduced in children with active CD, with widespread changes in white matter tracts critical for brain connectivity and information processing, as well as in posterior cortical and limbic regions important for cognition, emotional and pain processing. We provide first indication for potential axonal injury and neuroinflammation. Further, the differentially expressed immune genes found in active CD play a role in synaptic pruning, recruitment of microglia, and apoptosis, and have been implicated in brain development and injury. Findings provide further insights in the molecular basis of brain involvement in CD, and warrant longitudinal study.