Understanding the Impact of Youth Onset Obesity and Type 2 Diabetes on the Neurovascular Unit

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PROJECT SUMMARY There is a critical need to determine whether premature vascular disease observed in youth with type 2 diabetes (T2D) extends to the brain. This proposal builds on exciting data generated by our team showing differences in brain structure and clinically meaningful declines in neurocognitive function among adolescents with youth-onset T2D compared to their obese and lean peers. Our most prominent findings include lower brain gray matter volume and lower scores on measures of working memory. Importantly, we have also demonstrated some of the first evidence of cerebrovascular impairment in youth with T2D, manifested as reduced gray matter cerebral blood flow. Finally, we have preliminary evidence that cerebral blood flow correlates with reduction in gray matter volume and working memory measures. These findings suggest the breakdown of the neurovascular unit (NVU), a physiological construct describing the interplay between brain vasculature, neurons, and supporting glia and a mechanism for reduced brain volume and cognitive impairment. Our overarching hypothesis that premature vascular disease observed in youth-onset T2D extends to the brain and is associated with structural brain abnormalities and neurocognitive impairment. Importantly, we aim to differentiate the impact of T2D on the brain from the effect of obesity. Thus, we will compare NVU in adolescents with T2D to age, sex and race similar non-diabetic adolescents with obesity (obese controls) and without obesity (lean controls). Aim 1 will comprehensively assess aspects of NVU structure and function and identify risk factors impacting the NVU; 2) Aim 2 will determine the relationships between cerebrovascular, neuroanatomical, and cognitive outcomes cross-sectionally, and 3) Aim 3 will evaluate changes in the NVU, brain structure and cognition over time. Our team is well positioned to conduct this study as we have generated compelling preliminary data in our laboratory (m-PI Shah & DiFrancesco), we have expertise in conducting research studies in youth with T2D with documented ability to recruit and retain participants (m-PI Shah), we developed the state of the art MRI methods to study the vasculature in our laboratory and have applied these to other diseases with vascular sequelae such as systemic lupus erythematous (m-PI DiFrancesco), and we have extensive expertise in neurocognition and brain-behavior research (co-I Beebe & m-PI DiFrancesco). Finally, we have documented collaboration between the members of the study team over the last five years (Shah, DiFrancesco, Beebe & Altaye). The results of this proposal will separate the effects of T2D from obesity, identify noninvasive imaging biomarkers of brain health and treatable risk factors, and explore progression over time, positioning us to test interventions for youth with T2D and obesity as an immediate next step.