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

项目摘要/摘要 五分之一的美国青少年患有肥胖症，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 这些在青春期大脑发育过程中的作用尚不清楚。这项提议的目标是 研究IR导致神经认知功能和大脑功能减退的程度和机制 大脑和脑血管健康不良风险增加的青少年的血流(CBF)。我们正在测试 总体假设，神经认知能力下降与IR的严重程度有关，脑血流灌注减少也是如此。 胰岛素信号失灵。我们建议研究健康青少年(12-18岁)的急性脑血流控制。 在一系列IR(不包括糖尿病)中，与儿童神经心理学家专家合作，他们领导了 全面的测试方案。接下来，两种互补的MRI方法(ASL和相位对比)以及 一种挑战CBF的生理性应激源将被用来测试IR对脑大血管的影响 CBF和微血管灌注是区域性的，在颞叶和顶叶有更多的负面影响。 这些脑叶是一些最初要改变的大脑区域，涉及注意力、记忆、学习和 认知力。最后，这项研究测试了认知衰退的程度是否与CBF应激反应有关 以及IR的严重程度，以及脑低灌流在多大程度上介导IR导致的认知功能低下。 这项研究将首次对青少年大脑中的IR进行全面研究，通过使用广泛的 神经心理测试和最先进的磁共振成像，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关系。这些 研究旨在揭示胰岛素抵抗、神经认知功能和脑血流之间的基本关系 这些蓬勃发展的青春期大脑。令人兴奋的初步数据支持这些目标--特别是一项 生理性胰岛素激增--这意味着这些发现将作为前瞻性、机械性的基础 旨在减轻IR负担并改善这一临床重要人群的大脑和认知健康的研究。

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.