Project Summary. Children with type 1 diabetes (T1D) suffer from subtle cognitive impairments and structural alterations in the brain. These impairments progress with age and may eventually lead to increased difficulty managing the disease, resulting in worsening glycemic control, potentially life-threatening complications, and reductions in quality of life. Causes of cognitive decline in T1D are not well understood. Episodes of hypoglycemia, chronic hyperglycemia, glycemic variability and diabetic ketoacidosis (DKA) have all been suggested to play roles. Increased understanding of factors linked to cognitive decline in T1D, and the mechanisms responsible for these associations, is essential such that interventions to preserve cognition could be proposed. Recent data suggest that neuroinflammation resulting from hyperglycemia and episodes of DKA may be play a prominent role in causing cognitive decline. There is also evidence that modifiable factors such as nutrition, exercise, and sleep quality might modulate effects of chronic neuroinflammation and influence cognitive outcomes. In this project, we will engage in efforts to plan a comprehensive study of factors associated with cognition in children with T1D. At the completion of the proposed planning project, we will be prepared to conduct a longitudinal cohort study of children with newly diagnosed T1D. This study will determine how glycemic control and DKA exposure predict altered brain structure and cognition and establish whether markers of neuronal injury and inflammatory processes explain these longitudinal relations. Proposed assessments will include T1D-related factors (glycemic control, glycemic variability, hypoglycemia, DKA), brain structure and cognitive function (attention, memory and IQ). In addition, we will plan measurements of inflammatory mediators and markers of neuroinflammation using blood assays (cytokine measurements, exosome analyses, RNA microarrays), and evaluate factors that might modify inflammation such as diet (nutrient content), sleep quality and exercise. To optimize the study design, we will utilize the expertise of a multidisciplinary team to develop the study protocol, including experts in pediatric diabetes, cognitive development, neural and systemic inflammation, MR imaging, nutrition, sleep medicine, and data science. The team will work together to finalizing the protocol, work-flow and outcome measures, and identify the necessary computational infrastructure and data analysis strategies. The team will also assess study feasibility (factors affecting enrollment success and tolerance of the protocol) and determine necessary sample size by evaluating variability in biochemical and imaging measures. Alternative approaches to increase participant retention, such as remote (online) versus in person cognitive testing, will be explored. At the conclusion of this planning project, we will have developed and optimized a protocol to explore factors associated with cognitive decline in children with T1D, laying a foundation for future studies aimed at preserving cognitive function.

Narrative. Individuals with type 1 diabetes often have declines in cognitive function over time, with a high risk of cognitive impairments and dementia as older adults. The physiological events responsible for cognitive damage in T1D are not understood, and it is unclear how cognitive decline might be prevented. In the proposed project, we will plan a comprehensive, multi-center study to investigate factors associated with declines in cognition in children with T1D at onset of the disease and over time.