Vascular Moderators of the Impact of Alzheimer's Pathology in the Oldest-Old

项目-1概要/摘要： 我们小组一直在验证系统和大脑 血管疾病是阿尔茨海默病（AD）的危险因素，并且血管疾病调节阿尔茨海默病（AD）的发作。 认知综合症的症状也就是说，有一种与血管相关的脆弱状态会改变大脑结构， 局部血流，这会干扰大脑补偿AD发展的能力 病理学，并因此减少MCI发作和后来的临床AD的临床潜伏期。但在 在验证这一假说的过程中，我们发现Aβ沉积与 和血管疾病，导致临床痴呆的病理事件可能更为复杂， 比以前想象的要复杂。这些新的发现表明，血管疾病有双重作用， AD的病理生理学;作为改变脑结构的因素和作为Aβ沉积的贡献者。 我们认为，有必要比较和对比两种假说的相对优点：1）血管 Aβ沉积和神经退行性变是痴呆的独立预测因子， 血管疾病通过增加脆弱性而增加认知症状早期表现的风险 状态和干扰血管相关的代偿机制，和2）血管疾病加速 Aβ沉积，因此，这种相互作用加速了临床症状的发作。虽然有 它们之间的微妙差异，两者的含义是截然不同的，这可能会影响我们的 了解老年痴呆症的病理生理学，并推广其预防性治疗。 为了达到研究目的，我们将完成对191名AD高风险个体（年龄 自2000年以来，对85岁以上的患者进行了详细的年度临床评价，他们患有C11匹兹堡化合物B (PiB)PET和脑MRI研究，2009年炎症标志物测量，以及结构和灌注 2010-11年至2015年期间的MRI和PiB PET以及血管研究。 在本提案中，我们将对所有参与者进行年度神经心理学和神经学检查， 重复结构和动脉自旋标记MRI和PiB PET扫描，以确定CNS结构的异常， 功能和Aβ沉积，重复颈动脉多普勒，EKG和动脉硬度测量，以确定 系统性亚临床血管疾病的严重程度，确定炎症标志物的水平，并进行 使用[F-18]AV-1451 PET进行tau配体扫描，以确定tau蛋白沉积的严重程度。 在拟议的研究结束时，我们将有20年的数据，其中包括临床评估， 实验室检查、临床和亚临床心血管疾病的发病率和患病率。这让我们 这是一个独特的机会来检查导致认知异常的病理机制， 老人

Project-1 Summary/Abstract: Our group has been testing the hypothesis that systemic and cerebral vascular diseases are risk factors for Alzheimer's disease (AD), and that vascular disease modulates the onset of the cognitive syndrome. That is, there is a vascular-related vulnerability state that alters brain structure and regional blood flow, which interferes with the brain's ability to compensate for the development of the AD pathology, and thus reducing the clinical latency period for the onset of MCI and later clinical AD. However, in the process of testing this hypothesis, we have found that there is close relationship between Aβ deposition and vascular disease, and that the pathological events leading to clinical dementia may be more complex and heterogeneous than previously thought. These new findings indicate that vascular disease has a double role in the pathophysiology of AD; as a factor that alters brain structure and as a contributor to Aβ deposition. We believe that is essential to compare and contrast the relative merits of two hypotheses: 1) vascular disease, Aβ deposition and neurodegeneration are independent predictors of dementia, and increased vascular disease increases the risk of earlier manifestation of cognitive symptoms by increasing a vulnerability state and interfering with vascular-related compensatory mechanisms, and 2) vascular disease accelerates the Aβ deposition, and consequently, this interaction accelerates the onset of clinical symptoms. While there are subtle differences between them, the implications of the two are critically different, and this can affect our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. In order to achieve the study aims, we will complete the follow-up of 191 individuals at high risk for AD (age 85+) who were followed with detailed annual clinical evaluations since 2000, had C11 Pittsburgh compound B (PiB) PET and brain MRI studies, and measures of inflammatory markers in 2009, and structural and perfusion MRI and PiB PET, and vascular studies between 2010-11 and 2015. In this proposal, we will complete annual neuropsychological and neurological exams on all participants, repeat structural and arterial spin-labeled MRI, and PiB PET scans to identify abnormalities in CNS structure, function and Aβ deposition, repeat carotid Doppler, EKG, and measures of arterial stiffness to determine severity of systemic sub-clinical vascular disease, determine the levels of inflammatory markers, and perform tau ligand scans using [F-18]AV-1451 PET to determine severity of tau protein deposition. At the end of the proposed study, we will have two decades of data, which include clinical evaluations, laboratory tests, incidence and prevalence of clinical and subclinical cardiovascular disease. This provides us with a unique opportunity to examine the pathological mechanisms that lead to abnormal cognition in the elderly.