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

项目2--项目摘要/摘要 胰岛素抵抗(IR)和中年中心性肥胖与认知能力下降和患糖尿病的风险增加有关 发展为阿尔茨海默病(AD)。越来越多的证据表明淀粉样蛋白和神经损伤参与了这一过程。 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，尤其是 在疾病的临床前阶段。项目2的目标是确定IR和CER的效果 阿尔茨海默病高危人群的纵向脑肥胖和认知改变。我们的总体假设是 中心性肥胖和胰岛素抵抗影响多条通路，最终导致神经负担加重。 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(在此提供) 显示中心性肥胖和胰岛素抵抗影响淀粉样蛋白沉积、灰质萎缩、葡萄糖代谢和 记忆功能。为了实现我们的目标并检验我们的假设，我们提出了三个具体目标：1)确定 胰岛素抵抗和中心性肥胖与中年β淀粉样蛋白联系的程度，2)决定胰岛素抵抗和 中心性肥胖对中后期神经健康的影响，以及3)决定淀粉样蛋白和神经的中介作用 记忆功能受损。我们将通过招募100名来自威斯康星州ADRC的参与者来实现这些目标 Impact队列进入项目2。Impact队列是一组无症状的中年成年人 关于AD的风险。我们将利用现有的数据和样本，除了预期收集的MRI(T1- 加权)、脑脊液(测定P-Tau、A？42、Sapp-？和胰岛素)认知、实验室和临床数据； 在至少三个时间点达到顶峰。项目2的一半参与者将被登记参加PET分部 研究将在两个时间点进行[F18]FDG-PET和[F18]Florbetapir成像。竣工后 在这项研究中，我们将a)确定胰岛素抵抗和中心性肥胖对分泌酶的影响程度 APP的裂解途径和淀粉样蛋白的纵向沉积，b)决定了IR和中枢 肥胖对纵向脑淀粉样变性的影响由[F18]Florbetapir，c)决定IR和 中心性肥胖对结构神经损伤和葡萄糖摄取的影响，d)决定了是否存在葡萄糖低代谢 是由于神经损伤或中枢性低胰岛素血症，以及e)决定了淀粉样蛋白和神经 损伤在IR、中心性肥胖和基于海马区的记忆衰退之间的关系中起中介作用。这个 拟议的研究与威斯康星州ADRC的资源和专业知识完全整合在一起。这个项目 取决于临床核心(影响队列)和神经病理学核心(液体样本管理)，以及 将利用其他资源，包括由神经成像核心和数据管理提供的服务 和统计核心。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。 将在项目2中研究的代谢异常影响到超过一半的老年人，同时也是 已确定的有可能被修改的AD风险因素。了解产生影响的机制 大脑和认知老化的轨迹有望导致延缓和预防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.