Mapping Neurocognitive Complications of Pediatric Type 1 Diabetes (T1D) and Potential Risk and Protective Factors

PROJECT SUMMARY The pathophysiology of cognitive dysfunction in prepubertal children with Type 1 Diabetes Mellitus (T1DM) is not understood. It is likely that hyperglycemia, hypoglycemia, vascular disease, insulin resistance, and diabetic ketoacidosis (DKA) play important roles. However, the absence of longitudinal studies in T1DM children and our lack of understanding of the

pathogenesis of neuronal defects limit our ability to prevent cognitive disability and identify and treat those at highest risk. Despite preliminary evidence that T1DM is associated with alterations in brain structure and function, major gaps remain in our knowledge about how T1DM impacts the developing brain.

The overall premise of this project is that T1DM in children is associated with significant neurocognitive and brain alterations and the risk of developing neurocognitive deficits increases with both biological and psychosocial stress that ultimately delay/impede the normal maturation of associative brain systems supporting attention, learning and

memory, executive and social cognition. Our hypothesis is that children with greater net exposure to biological and psychosocial stress will have greater deficits in trajectory of brain development underlying complex cognition. Our multidisciplinary team of neuroimaging experts and endocrinologists will examine brain and

cognitive alterations in children with T1DM across three aims: Aim 1 will measure the differential impact of age of T1DM diagnosis on brain structure, micro-organization, metabolism and function and mental health. Aim 2 will Identify biological and psychosocial moderators and Risk and Resilience factors. We will evaluate the impact of both biological stressors and social

determinants of health (e.g., SES, Education, Adversity exposure, rurality, access to healthcare services, race, etc.) on neurocognitive function and maturation in children with T1DM. In Aim 3 we will develop a recruitment, retention and dissemination strategy to prepare for future clinical trials that build a precision risk- and resilience-prediction model.

The findings from this observational study will bridge gaps in our understanding of the development of neurocognitive dysfunction in T1DM. It will further inform key clinical targets to address to ensure the optimal care of children with T1DM. The power of a larger network will further allow the exploration of complex 2-way or even 3-way interactions between biological

and social determinants of health and neurofunctional outcomes in children with T1DM.