Insulin resistance, amyloid, and memory in normal aging and preclinical AD

正常衰老和临床前 AD 中的胰岛素抵抗、淀粉样蛋白和记忆

• 批准号: 8647911
• 负责人: Jill Kathleen Morris
• 金额: $ 5.62万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647911
• 关键词: Acute; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Attenuated; Brain; Caring; Cerebrum; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Deposition; Diabetes Mellitus; Disease; Effectiveness; Elderly; Euglycemic Clamping; Exhibits; Foundations; Funding Opportunities; Future; Glucose; Glucose Clamp; Glucose Plasma Concentration; Goals; Gold; Health Care Costs; Healthcare; Human; Impaired cognition; Impaired fasting glycaemia; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; International; Intervention; Intravenous; Lead; Literature; Long-Term Care; Measurement; Mediating; Membrane Protein Traffic; Memory; Metabolic; Molecular; National Health and Nutrition Examination Survey; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Patients; Performance; Peripheral; Phase; Population; Prevalence; Procedures; Radiopharmaceuticals; Recruitment Activity; Research; Research Training; Resources; Risk Factors; Role; Services; Solid; Staging; Synapses; Techniques; Testing; Training; United States; Work; aging population; amyloid imaging; base; brain tissue; cerebral atrophy; cognitive function; cohort; cost; economic impact; experience; glucose disposal; hospice environment; improved; insight; insulin sensitivity; insulin signaling; meetings; normal aging; novel; novel therapeutic intervention; payment; pre-clinical; public health relevance; receptor expression; standard measure

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and Type 2 Diabetes (T2D) are two of the most common diseases in older adults and their prevalence is increasing with an aging population. Numerous studies have demonstrated that T2D and insulin resistance are risk factors for AD, and reduced markers of insulin signaling are apparent in brain tissue from those affected by AD. Interestingly, in culture, insulin signaling is protective against A¿-mediated synapse degeneration, and insulin may promote A¿ membrane trafficking and release. This relationship is bidirectional, as A¿ itself can cause decreased insulin receptor expression. These and other molecular studies that demonstrate an interplay between insulin and amyloid provide the rationale for clinical studies to more directly investigate the relationship between amyloid and insulin resistance in humans. The goal of this project is to further understand the relationship between metabolic function, cognition, and cerebral amyloid beta deposition. Post-mortem studies have shown a relationship between insulin signaling and amyloid, and clinical literature supports a role for insulin in cognitive function and memory. We will investigate these relationships in cognitively normal older adults with and without cerebral amyloid. For this project, our cohort will consist of subjects known to be positive or negative for A¿ but without cognitive impairment. A¿ positive subjects are thought to comprise a cohort in the very earliest stages of AD, or "preclinical AD." We will use the gold standard for measuring insulin resistance, the hyperinsulinemic-euglycemic clamp, to assess metabolic function. We will also evaluate cognitive performance in the insulin-stimulated state and determine whether amyloid status and level of insulin resistance affect cognition. This project will build upon studies that show intravenous or intranasal insulin improve memory in various cohorts. By investigating insulin sensitivity in subjects with or without cerebral amyloidosis, we will determine whether these factors influence insulin- mediated cognitive improvement in the very earliest stages of AD.

描述（由申请人提供）：阿尔茨海默病（AD）和2型糖尿病（T2 D）是老年人中最常见的两种疾病，其患病率随着人口老龄化而增加。许多研究表明，T2 D和胰岛素抵抗是AD的危险因素，并且在受AD影响的脑组织中胰岛素信号传导的标记物减少是明显的。有趣的是，在培养中，胰岛素信号对A？介导的突触变性具有保护作用，胰岛素可能促进A？膜的运输和释放。这种关系是双向的，因为A？本身可以导致胰岛素受体表达减少。这些和其他分子研究表明胰岛素和淀粉样蛋白之间的相互作用，为临床研究更直接地研究人类淀粉样蛋白和胰岛素抵抗之间的关系提供了理论基础。该项目的目标是进一步了解代谢功能，认知和大脑淀粉样蛋白β沉积之间的关系。尸检研究表明胰岛素信号和淀粉样蛋白之间存在关系，临床文献支持胰岛素在认知功能和记忆中的作用。我们将在有和没有脑淀粉样蛋白的认知正常的老年人中调查这些关系。对于这个项目，我们的队列将由已知A？阳性或阴性但没有认知障碍的受试者组成。A？阳性受试者被认为构成了AD最早期或“临床前AD”的队列。“我们将使用测量胰岛素抵抗的金标准，高胰岛素-正常血糖钳夹，来评估代谢功能。我们还将评估胰岛素刺激状态下的认知表现，并确定淀粉样蛋白状态和胰岛素抵抗水平是否影响认知。该项目将建立在研究的基础上，这些研究表明静脉注射或鼻内注射胰岛素可以改善各个队列的记忆力。通过研究患有或不患有脑淀粉样变性的受试者的胰岛素敏感性，我们将确定这些因素是否影响AD最早期胰岛素介导的认知改善。