Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular disease and Alzheimers disease

了解糖尿病、脑血管疾病和阿尔茨海默病之间相互作用的跨学科研究

• 批准号: 9228539
• 负责人: ADAM M BRICKMAN
• 金额: $ 49.83万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228539
• 关键词: 2 year old; Adult; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anterior; Blood Glucose; Blood Vessels; Brain; Brain imaging; Categories; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Clinical; Cognitive; Dementia; Diabetes Mellitus; Diabetic mouse; Dyslipidemias; Electrophysiology (science); Goals; Health; Hippocampus (Brain); Human; Hyperglycemia; Hypertension; Image; Infarction; Inflammation; Insulin Resistance; Interdisciplinary Study; Joints; Magnetic Resonance Imaging; Mediating; Memory impairment; Middle Cerebral Artery Occlusion; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathologic; Persons; Physiological; Plasma; Populations at Risk; Positron-Emission Tomography; Prediabetes syndrome; Property; Proteomics; Research Project Grants; Risk Factors; Slice; Techniques; Testing; United States; Vascular Cognitive Impairment; White Matter Hyperintensity; aged; blood oxygen level dependent; cognitive performance; cohort; diabetic; entorhinal cortex; glucose tolerance; high risk; mild cognitive impairment; neuropathology; prevent; response; tau-1; vascular contributions

 DESCRIPTION (provided by applicant): The main goal of this proposal is to study the interplay of diabetes, cerebrovascular disease (CVD), and Alzheimer's disease (AD) in response to RFA-AG-15-010 "Interdisciplinary Research to Understand the Vascular Contributions to Alzheimer's Disease (R01)". Type 2 diabetes and pre-diabetes affect one third of United States adults, and the majority of persons aged 60 years and older, who are most susceptible to AD. Diabetes is a strong risk factor for CVD and for vascular cognitive impairment. Diabetes is also associated with a higher risk of the clinical manifestations of AD including dementia and amnestic mild cognitive impairment, but it is unclear whether AD, CVD, or both, mediate this association, and whether this association is causal. We hypothesize that diabetes causes AD in addition to CVD, and that the coexistence of AD and CVD mediate the association of diabetes with memory impairment, the earliest manifestation of AD. We will test these hypotheses in human and mouse studies. Our primary aim is to examine the association of diabetes with the interplay of AD and CVD in humans and mice. We will conduct a brain imaging study with 2 waves in a cohort of 200 persons with a mean age of 62 years followed at 2-year intervals in order to examine the cross-sectional and longitudinal association of diabetes with AD. We will categorize diabetes as pre-diabetes, diabetes, and normal glucose tolerance (NGT), and examine glycemia continuously using HbA1C. We will ascertain AD with amyloid β (Aβ) imaging using Positron Emission Tomography with 18F-Florbetaben. We will characterize CVD with brain magnetic resonance imaging (MRI) as white matter hyperintensities (WMH) and infarcts. We will also explore the coexistence of aggregate and regional CVD, AD, and cerebral amyloid angiopathy (CAA, ascertained as microbleeds on MRI) in relation to diabetes. We will explore if AD mediates the association of diabetes with memory impairment, and whether CVD modifies this association. We will compare among diabetic, AD (J20), AD/diabetic mice, and appropriate controls the distribution and load of AD neuropathology (phosphorylated tau, soluble Aβ peptides, and plaques) in three ages (2, 5 and 14 months) with and without transient occlusion of the middle cerebral artery (MCA). We will also compare cognitive performance in these groups. Our secondary aim is to examine if diabetes is related with AD-like brain functional correlates in humans and mice. Our exploratory aims are to explore in humans whether AD predicts incident pre-diabetes and diabetes and increasing glycemia among persons with NGT, whether AD mice are more likely to develop hyperglycemia, explore the plasma lipidomic and proteomic profile predictive of clinical, pathologic, and physiologic outcomes, and explore the association of correlates of diabetes, such as adiposity, dyslipidemia, inflammation, hypertension, insulin resistance, with AD.

 描述（由适用提供）：该提案的主要目标是研究糖尿病，脑血管疾病（CVD）和阿尔茨海默氏病的相互作用，以应对RFA-AG-15-010“跨学科研究”，以了解跨学科研究，以了解对阿尔茨海默氏病的血管贡献（一位diase and Unterains and Untials and Untials and Unter and diabiac and Unter and diabiabe and r01 and diabite and r01 exeblets and r01 exeblets。大多数60岁以上的人最容易受到AD的影响，这是CVD的强大风险因素，并且具有较高的痴呆症和Amnestic损害的临床表现，这是否与AD的关联，这是否与CAMITY相关糖尿病除了CVD外，AD和CVD的共存介导了糖尿病与记忆障碍的关联，我们将在人类和小鼠中测试这些假设。为了检查糖尿病与AD的横截面和纵向关联的年龄，我们将使用HBA1C（AMYPORRON）（A PROSITION a PROPRON）来检查糖尿病的横截面和纵向关联。 18F氯贝氏将以脑磁性成像（MRI）为白质超强度（WMH）和INFACTS的CVD。糖尿病与记忆障碍的关联，CVD是否会改变这种关联。 （MCA）我们还将比较这些群体中的认知性能。脂肪组和蛋白质组学特征可以预测临床，病理和生理结果，并探索糖尿病相关性的关联，例如脂肪，血脂异常，炎症，高血压，胰岛素抵抗，胰岛素抵抗，与AD。