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

 描述（由申请人提供）：本提案的主要目标是研究糖尿病、脑血管疾病（CVD）和阿尔茨海默病（AD）的相互作用，以响应RFA-AG-15-010“了解血管对阿尔茨海默病的贡献的跨学科研究（R 01）"。2型糖尿病和糖尿病前期影响三分之一的美国成年人，以及大多数60岁及以上的人，他们最容易患AD。糖尿病是心血管疾病和血管性认知障碍的一个重要危险因素。糖尿病还与AD临床表现（包括痴呆和遗忘型轻度认知障碍）的风险较高相关，但尚不清楚AD、CVD或两者是否介导了这种关联，以及这种关联是否是因果关系。我们假设糖尿病除了引起心血管疾病外还引起AD，AD和心血管疾病的共存介导了糖尿病与记忆障碍（AD的最早表现）的关联。我们将在人类和小鼠研究中测试这些假设。我们的主要目的是研究人类和小鼠中糖尿病与AD和CVD相互作用的关系。我们将在200名平均年龄为62岁的患者队列中进行2波脑成像研究，以检查糖尿病与AD的横向和纵向关联。我们将糖尿病分为糖尿病前期、糖尿病和正常葡萄糖耐量（NGT），并使用HbA 1C连续检查血糖。我们将使用18F-Florbetaben的正电子发射断层扫描技术，通过β淀粉样蛋白（Aβ）成像确定AD。我们将用脑磁共振成像（MRI）将CVD表征为白色高信号（WMH）和梗死。我们还将探讨聚集性和局部CVD、AD和脑淀粉样血管病（CAA，在MRI上被确定为微出血）与糖尿病的共存。我们将探讨AD是否介导了糖尿病与记忆障碍的关联，以及CVD是否改变了这种关联。我们将比较糖尿病、AD（J20）、AD/糖尿病小鼠和适当对照小鼠在三个年龄（2、5和14个月）伴和不伴大脑中动脉（MCA）短暂闭塞的AD神经病理学（磷酸化tau蛋白、可溶性Aβ肽和斑块）的分布和负荷。我们还将比较这些群体的认知表现。我们的第二个目的是检查糖尿病是否与人类和小鼠的AD样脑功能相关。我们的探索性目的是在人类中探索AD是否预测发生糖尿病前期和糖尿病以及NGT患者中糖尿病的增加，AD小鼠是否更可能发展高血糖症，探索预测临床、病理和生理结果的血浆脂质组学和蛋白质组学谱，并探索糖尿病的相关性，如肥胖、血脂异常、炎症、高血压、胰岛素抵抗、与AD

 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.