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

项目摘要 有一个关键的需要，以确定是否过早的血管疾病观察到的青年2型 糖尿病（T2 D）扩展到大脑。该提案基于我们团队生成的令人兴奋的数据， 青少年大脑结构的差异和神经认知功能的临床意义下降 与肥胖和消瘦的同龄人相比，我们最突出的发现包括 灰质体积和较低的工作记忆分数。重要的是，我们还证明了 青年T2 D患者脑血管损害的一些初步证据，表现为灰质减少 脑血流量最后，我们有初步的证据表明，脑血流量与减少， 灰质体积和工作记忆测量。这些发现表明神经血管的破坏 NVU是一种生理结构，描述了脑血管系统、神经元和支持神经元之间的相互作用。 神经胶质和脑容量减少和认知障碍的机制。我们的首要假设是 在青年发病的T2 D中观察到的过早血管疾病延伸到大脑，并与结构性 大脑异常和神经认知障碍。重要的是，我们的目标是区分T2 D对 大脑免受肥胖的影响。因此，我们将比较T2 D青少年的NVU与年龄，性别和种族相似 肥胖的非糖尿病青少年（肥胖对照）和不肥胖的非糖尿病青少年（瘦对照）。目标1将 全面评估NVU结构和功能的各个方面，并识别影响NVU的风险因素; 2） 目标2将确定脑血管、神经解剖和认知结果之间的关系 3）目标3将评估NVU、大脑结构和认知随时间的变化。我们 我们的团队已经做好了进行这项研究的准备，因为我们已经在实验室中获得了令人信服的初步数据 (m-PI Shah & DiFrancesco），我们拥有在T2 D青年中进行研究的专业知识， 记录招募和留住参与者的能力（m-PI Shah），我们开发了最先进的MRI方法 在我们的实验室研究血管系统，并将其应用于其他血管后遗症疾病， 作为系统性红斑狼疮（m-PI DiFrancesco），我们在神经认知和 脑行为研究（co-I Beebe & m-PI DiFrancesco）。最后，我们记录了 在过去的五年里，研究小组的成员（沙阿，迪弗朗西斯科，毕比和阿尔泰）。的结果 一项提案将把T2 D的影响与肥胖分开，确定大脑健康的非侵入性成像生物标志物， 和可治疗的风险因素，并探索随着时间的推移，使我们能够测试青少年的干预措施， T2 D和肥胖症作为下一步。

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.