Midlife Insulin Resistance and Obesity: Risk Factors for AD-Related Brain Change

项目2 -项目概要/摘要 中年时的胰岛素抵抗（IR）和向心性肥胖与认知能力下降和更大的 阿尔茨海默病（AD）的发病机制。越来越多的证据表明淀粉样蛋白和神经损伤介导了这一过程 效果然而，IR和中心性肥胖对大脑的影响在人类中仍然知之甚少， 在疾病的临床前阶段。项目2的目的是确定IR和中央的影响， 肥胖对AD风险人群的纵向大脑和认知变化的影响。我们的总体假设是 中心性肥胖和IR影响多个通路，最终导致神经系统的严重负担， 病理表现为认知能力下降。我们的假设是基于我们自己的试点数据（本文提供） 显示向心性肥胖和IR影响淀粉样蛋白沉积、灰质萎缩、葡萄糖代谢， 记忆功能为了实现我们的目标并验证我们的假设，我们提出了3个具体目标：1）确定 IR和向心性肥胖与中年β淀粉样蛋白相关的程度，2）确定IR的影响， 中心性肥胖对中晚期神经健康的影响，以及3）确定淀粉样蛋白和神经 记忆功能损伤。我们将通过从威斯康星州ADRC招募100名参与者来实现这些目标 影响队列进入项目2。IMPACT队列是一组无症状的中年成人， AD的风险。我们将利用现有的数据和样本，除了前瞻性收集的MRI（T1- 加权），CSF（检测P-Tau，A42，sAPP-β和胰岛素）认知，实验室和临床数据; 在至少三个时间点达到高潮。项目2的一半参与者将被纳入PET分中心， 研究，并将在两个时间点进行[F18]FDG-PET和[F18]Florbetapir成像。完成后 在这项研究中，我们将a）确定IR和中心性肥胖对β-分泌酶的影响程度， APP裂解途径和纵向淀粉样蛋白沉积，B）确定了IR和中枢神经系统的作用。 肥胖对纵向脑淀粉样变性的影响，如[F18]Florbetapir所指示的，c）确定IR的作用， 向心性肥胖对结构性神经损伤和葡萄糖摄取的影响，d）确定葡萄糖代谢是否降低 是由于神经损伤或中枢性低胰岛素血症，以及e）确定淀粉样蛋白和神经系统低胰岛素血症的程度。 损伤介导了IR、向心性肥胖和基于大脑的记忆力下降之间的关系。的 拟议的研究与威斯康星州ADRC的资源和专业知识完全整合。这个项目 取决于临床核心（IMPACT队列）和神经病理学核心（液体样本管理），以及 将利用其他资源，包括神经影像核心和数据管理提供的服务 统计核心。与威斯康星州ADRC的协同作用确保了拟议研究的强大可行性。 在项目2中研究的代谢异常影响了一半以上的老年人，同时也影响了老年人。 已确定的AD风险因素有可能被修改。了解影响的机制 大脑和认知老化的轨迹预计将导致延迟和预防AD的策略。

PROJECT 2 - PROJECT SUMMARY/ABSTRACT Insulin resistance (IR) and central obesity at midlife are associated with cognitive decline and greater risk for developing Alzheimer's disease (AD). Converging evidence suggests amyloid and neural injury mediate this effect. Yet, the impact of IR and central obesity on the brain remains poorly understood in humans, especially at the preclinical stage of the disease. The objective of Project 2 is to determine the effect of IR and central obesity on longitudinal brain and cognitive change in people at risk for AD. Our overall hypothesis is that central obesity and IR affect multiple pathways which ultimately contribute to a critical burden of neural pathology manifesting as cognitive decline. Our hypothesis is based on our own pilot data (presented herein) showing that central obesity and IR affect amyloid deposition, gray matter atrophy, glucose metabolism, and memory function. To carry out our objective and test our hypothesis, we propose 3 Specific Aims: 1) Determine the extent to which IR and central obesity are linked with midlife beta amyloid, 2) determine the effect of IR and central obesity on neural health in late-midlife, and 3) determine the mediating effect of amyloid and neural injury on memory function. We will achieve these aims by enrolling 100 participants from the Wisconsin ADRC IMPACT cohort into Project 2. The IMPACT cohort is an asymptomatic group of middle-aged adults enriched on risk for AD. We will utilize existing data and samples, in addition to prospectively collected MRI (T1- weighted), CSF (to be assayed for P-Tau, A�42, sAPP-�, and insulin) cognitive, laboratory and clinical data; culminating in at least three time points. Half of the participants in Project 2 will be enrolled into a PET sub- study and will undergo [F18]FDG-PET, and [F18]Florbetapir imaging at two time points. Following completion of this study, we will have a) determined the extent to which IR and central obesity affect the �-secretase pathway of APP cleavage, and longitudinal amyloid deposition, b) determined the effect of IR and central obesity on longitudinal brain amyloidosis as indexed by [F18]Florbetapir, c) determined the effect of IR and central obesity on structural neural injury and glucose uptake, d) determined whether glucose hypometabolism is due to neural injury or central hypoinsulinemia, and e) determined the extent to which amyloid and neural injury mediate the relationship between IR, central obesity, and hippocampal-based memory decline. The proposed research is fully integrated with the resources and expertise at the Wisconsin ADRC. This project depends on the Clinical Core (IMPACT cohort) and the Neuropathology Core (fluid sample management), and will utilize other resources including services provided by the Neuroimaging Core and the Data Management and Statistics Core. Synergy with the Wisconsin ADRC ensures the strong feasibility of the proposed research. The metabolic abnormalities to be studied in Project 2 affect more than half of all older adults, while also being established AD risk factors that have the potential to be modified. Understanding the mechanisms that impact trajectories of brain and cognitive aging is expected to lead to strategies that delay and prevent AD.