Cognitive, structural and functional impact of new onset type 1 diabetes on the brain of young children: understanding risks and protective factors - an increasing body of data show the brain is a…

Cognitive, structural and functional impact of new onset type 1 diabetes on the brain of young children: understanding risks and protective factors - an increasing body of data show the brain is a target of diabetes complications. We and others have investigated the impact of type 1 diabetes (T1D) in the developing brain in children as young as 4-years old. Using structural and functional brain MRI, neurocognitive assessments, and continuous glucose monitoring (CGM) we observed quantifiable differences in gray and white matter volume (and microstructure) in children with T1D compared to age-matched nondiabetic controls, and meaningful differences in working memory, executive function scores, and performance IQ. These differences widened when children were followed at 4-time points over nearly 8- years, findings strongly correlated to hyperglycemia. This funding opportunity seeks to further investigate neurocognitive and psychosocial function now in children with new onset diabetes, including those of diverse racial and socioeconomic (SES) backgrounds. This is timely given our preliminary data raise important questions as to the impact of better normalization of blood glucose using advanced insulin delivery (aid)/closed-loop systems. We propose an observational, longitudinal study in a large cohort of 4-10-year old prepubertal children with new onset T1D (n=525) presenting with or without diabetic ketoacidosis (DKA), studied within 4-6 weeks of diagnosis, compared to age-matched nondiabetic controls (preferably siblings and classmates) (n=175). Primary aims: (1) to determine their neurocognitive function (principal); (2) to correlate neurocognitive function scores with metrics of dysglycemia, and severity of diabetes and DKA at presentation; (3) to assess patient/family reported perceptions of quality of life, including diabetes distress and psychosocial aspects, in children, and mood in parents; (4) to correlate above aims with use of aid closed-loop technologies; (5) to assess structural gray and white matter volume and white matter microstructure and functional (f)MRI during cognitive tasks (baseline & 24-months). Pertinent social determinants of health (sdoh) will be collected, and all outcomes adjusted by SEX and SES and level of glycemia. To accomplish this, we will perform standardized neurocognitive testing using NIH toolbox, psychosocial assessments, structural and functional MRI using multimodal imaging, CGM downloads and HBA1C, sdoh data collected using NIH toolbox phenx. Children will be recruited across 10 centers selected along a biostatistical research core, in a new network. Children with T1D will be followed quarterly, CGM and pump (if applicable) data downloaded, principal assessments done at baseline, 12 and 24-months. This principal investigator, and the experienced team assembled, would bring considerable expertise and strength to the new network, with an outstanding record of accomplishments studying T1D and the brain in children and well-established clinical and research infrastructure. This innovative proposal is a prototype of the observational study we can perform. Results will offer critical insight on developmental and cognitive trajectories in young children with new onset T1D, racially and socioeconomically diverse, and whether better glycemic control, including early use of aid technology can prevent or improve cognitive outcomes.