Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Small, Dana

Abstract

The association between type 2 diabetes (T2D) and cognitive impairment has been well established. This is critical because T2D is a key risk factor for Alzheimer’s disease. However, these studies often fail to account for adiposity and other co-morbid conditions that accompany T2D in older adults. As a result, the mechanisms linking connecting T2D and cognitive impairment consequently remain unclear. The overall aim of this dissertation is to understand the precise effects of dysfunctional glucose metabolism on neurocognition. To do this I capitalized on a unique opportunity to study dysregulated glucose in youth from the Pathogenesis of Youth Onset Diabetes (PYOD) cohort. The cohort includes adolescents with overweight/obesity and varying levels of glucose tolerance, with some classified as having prediabetes. This allowed me to control for adiposity and minimize impact of co-morbid conditions. Furthermore, by using a longitudinal design, I could investigate the impact of changes in glucose control on cognition. First, I investigated the cross-sectional effects of peripheral glucose control and central insulin resistance on cognitive performance and resting-state functional activity, while controlling for adiposity (Chapter 2). Youth with, versus without, prediabetes, had a lower IQ and poorer spatial working memory, psychomotor speed, and visuospatial processing. The deficit in spatial working memory persisted after controlling for i differences in IQ. I also found that peripheral insulin resistance was correlated with central insulin sensitivity in the intraparietal sulcus. This same area exhibited insulin- sensitive connectivity with the caudate, correlating with prior performance on the spatial working memory task. This study provides strong evidence that impaired glucose metabolism is correlated with poorer cognition, irrespective of adiposity and without the presence of co-morbid conditions. In Chapter 3, I examined the effect of change in glucose control over two years on cognition and brain structure. I found no evidence that change in glucose control contributed to change in cognition. Instead, the differences in IQ and visuospatial processing identified at baseline persisted based on original diagnoses. I also found that cortical surface area trended to be smaller at baseline for those with prediabetes. Individuals without, compared to with, prediabetes at baseline exhibited a significantly greater rate of cortical surface area reduction. This study shows that poorer cognition observed in prediabetes is largely stable, raising the possibility that it predates diagnoses. Collectively, the results from this dissertation demonstrate the presence of cognitive impairment, as well as altered cortical development and resting brain activity, in youth with prediabetes. However, they also raise the possibility that these deficits predispose adolescents to prediabetes, rather than result from metabolic dysfunction. Future studies will be important to test this critical question. Regardless, my findings establish the existence of cognitive impairment in prediabetes that cannot be attributed to adiposity or the existence of chronic co-morbid conditions.

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