PROJECT SUMMARY Many individuals living with Type 1 diabetes (T1D) experience significant cognitive impairments. These impairments are more common in people diagnosed in early childhood, particularly under 5-6 years of age, and are associated with measurable neuropathologic brain structure changes. Across the lifespan, these cognitive difficulties can impact adaptive functioning, academic performance, and disease management. Strategies to decrease the likelihood of cognitive deficit development are needed. The study we propose in this application is designed to address current gaps in our knowledge regarding the underpinnings of neurocognitive changes in persons living with diabetes. We anticipate that it would be implemented by a multicenter collaborative effort of pediatric endocrinologists, psychologist, and radiologists whose ultimate goals are to: 1) better understand the impact of T1D on the developing brain; 2) identify and evaluate potential risk and protective factors associated with T1D-related neurocognitive impact; and 3) assess potential associations between use of newer and emerging diabetes management technologies and neurocognitive functioning among children with T1D. With this application we propose two aims to achieve these goals: Firstly, we propose to characterize associations of cognitive function and brain structure with clinical and environmental parameters in children with T1D enrolled at 6-<8 years of age relative to healthy controls. Children will be assessed at baseline and 18 months, with every 3-month interval clinical assessments including measures of glycemia. Secondly, we propose to enroll a second younger cohort of children 3-5 years of age and follow them prospectively with regular glycemic data collection until they undergo cognitive assessments and neuroimaging at 6-8 years of age to characterize the relationship of early glycemic exposure (assessed primarily using time in optimal glycemic range) to subsequent cognitive function and neuroimaging metrics. With our application, the Indiana University Clinical Center pledges to work collaboratively with other consortium sites, a biostatistics research center, and patient partner stakeholders to develop and implement a uniform protocol. This protocol will entail recruiting diverse cohorts of prepubertal recently-diagnosed children with type 1 diabetes and healthy controls, following participants longitudinally, and performing neurocognitive assessments and imaging. Success will ultimately be measured by the consortium determining mechanisms underlying cognitive dysfunction in very young persons with T1D. Once modifiable determinants have been elucidated, strategies to optimize neurocognitive functioning for persons with T1D throughout the lifespan will be possible.