Insulin resistance, cognitive health, and perfusion of the adolescent brain

项目总结/摘要 五分之一的美国青少年肥胖，其中许多患者表现出一定程度的胰岛素抵抗 （IR）。IR与脑血管疾病、记忆力、注意力和认知能力下降有关，但IR如何影响脑血管疾病的发生？ 在青少年大脑发育过程中对这些的贡献尚不清楚。本提案的目的是 研究IR驱动神经认知功能和大脑功能下降的程度和机制。 脑血流量（CBF）在青少年中处于不良脑和脑血管健康的高风险中。我们正在测试 总体假设认为，神经认知功能下降与IR的严重程度有关，脑灌注减少也是如此， 胰岛素信号传导功能障碍我们建议研究健康青少年（12-18岁）的急性CBF控制 在一系列IR（糖尿病除外）与儿童神经心理学家专家合作，他们领导了一个 全面测试协议。接下来，两种互补的MRI方法（ASL和相位对比），沿着 一种生理性应激刺激，以挑战CBF，将被用来测试IR是否对脑大血管的影响 CBF和微血管灌注具有区域特异性，在颞叶和顶叶具有更多的负面影响。 这些脑叶是最初发生变化的大脑区域，与注意力、记忆力、学习和 认知.最后，本研究测试了认知能力下降的程度是否与CBF应激反应有关 以及脑灌注不足在多大程度上介导了IR驱动的认知功能降低。 这项研究将提供第一个全面了解IR在青少年的大脑，通过利用广泛的 神经心理学测试和最先进的MR成像，并利用跨学科合作 发展神经心理学家、血管生理学家和儿科内分泌学家之间的合作。这些 研究旨在揭示IR，神经认知功能和CBF之间的基本关系， 这些青春期的大脑令人兴奋的初步数据支持aims-特别是由一个 生理性胰岛素激增-这些发现将作为前瞻性，机制性 研究以减轻IR负担并改善这一临床重要人群的大脑和认知健康。

Project Summary/Abstract One in five American adolescents are obese, and many of these patients exhibit some level of insulin resistance (IR). IR is associated with cerebrovascular disease, reduced memory, attention, and cognition, but how IR contributes to these in the course of adolescent brain development is unclear. The goal of this proposal is to investigate the extent and mechanisms by which IR drives reductions in neurocognitive function and cerebral blood flow (CBF) in adolescents at elevated risk of poor brain and cerebrovascular health. We are testing the overall hypothesis that neurocognitive decline is linked to severity of IR, as are reductions in brain perfusion, due to dysfunctional insulin signaling. We propose to study acute CBF control in healthy adolescents (12-18 years) across a range of IR (diabetes excluded) in collaboration with expert childhood neuropsychologists who lead a comprehensive testing protocol. Next, two complementary MRI methods (ASL and Phase Contrast), along with a physiologic stressor to challenge CBF, will be used to test whether the impact of IR on brain macrovascular CBF and microvascular perfusion is regionally specific, with more negative effects in temporal and parietal lobes. These lobes are some of the initial brain areas to change, and are involved in attention, memory, learning, and cognition. Finally, this study tests whether the degree of cognitive decline is linked to the CBF stress response and to severity of IR, and to what extent brain hypoperfusion mediates the IR-driven lower cognitive function. This study will provide the first comprehensive look at IR in adolescent brains, by utilizing extensive neuropsychological testing and state-of-the-art MR imaging, and drawing on interdisciplinary collaborations between developmental neuropsychologists, vascular physiologists, and pediatric endocrinologists. These studies are designed to uncover fundamental relationships between IR, neurocognitive function, and CBF in these blossoming adolescent brains. Exciting preliminary data support the aims—particularly uncovered by a physiologic insulin surge—signifying these findings will serve as a foundation for prospective, mechanistic studies to reduce the burden of IR and improve brain and cognitive health in this clinically important population.