Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's Disease

 描述(由申请人提供)：引起痴呆症的年龄相关疾病是一种日益严重的全球、社会和经济灾难，需要进行广泛和积极的研究。阿尔茨海默病(AD)是老年人认知障碍的最常见原因，仅在美国就有500多万人受到影响。血管对痴呆症和阿尔茨海默病的作用日益被认识到。然而，脑血管系统在痴呆和阿尔茨海默病发病机制中的作用，以及潜在的神经血管机制，到目前为止仍然很不清楚和研究不足，这是该领域的一个关键障碍。该计划的总体目标是促进关于血管对痴呆和AD的贡献的现有知识，并确定神经血管系统是否在认知能力下降中发挥主要作用，从而成为治疗痴呆和AD的关键新靶点。这是一个包含多个项目、核心、机构和调查人员的项目申请。它代表着一个整体，远远大于其各部分的总和。每个项目和核心相互补充，从而实现了它们之间的协同关系，共同关注该计划的目标，即测试AD的神经血管假说。这一假说认为，脑血管功能障碍和神经血管完整性的破坏是认知功能衰退发生和发展的基础，并有助于认知功能衰退的发生和发展。我们招募了现有的临床和转化研究小组，这些小组在研究计划的所有方面都带来了重要的专业知识，每个小组都在多年来为痴呆症和阿尔茨海默病的研究做出了富有成效的贡献。为了验证“神经血管假说”，参与的研究人员将应用尖端的分子和成像方法。我们将在两个AD遗传风险组中采用类似的方法进行平行研究，这些研究具有晚发性AD的主要遗传风险因素，即载脂蛋白E-ε4基因和早发性常染色体显性AD，即早老素1(PSEN1)突变，它们同时发展为早期血管功能障碍和显著的脑血管病理，并在AD大鼠模型(品系TgF344-AD)中进行平行研究，真实地概括了人类AD丰富的临床病理谱，包括早期血管功能障碍和脑血管病理的存在。我们的方法的核心是我们致力于采取一个新的研究方向，总体目标是为更广泛的问题提供答案，即血管系统在痴呆症和阿尔茨海默病的发病机制中所起的作用，以及神经血管分子和成像生物标记物在预测认知能力下降方面的预后和诊断价值。神经血管完整性、大脑连通性和认知功能之间的关系尚未被探索。研究人员的集体专业知识、总体环境、初步结果以及每个项目和支持核心的实验设计为该计划的成功提供了巨大的希望。我们相信，拟议的研究将对我们理解痴呆症和AD的发病机制、治疗和早期预防产生重大影响。

 DESCRIPTION (provided by applicant): Age related diseases causing dementia are an increasing global, social and economic catastrophe that mandates broad and aggressive research. Alzheimer's disease (AD) is the most common cause of cognitive impairment in older adults and affects over 5 million people in the US alone. Vascular contributions to dementia and AD are increasingly recognized. However, the role of the cerebrovascular system in the pathogenesis of dementia and AD, and the underlying neurovascular mechanisms remain, to date, largely unknown and under researched, representing a critical barrier in the field. The overall goals of this program are to advance current knowledge on the vascular contributions to dementia and AD, and establish whether the neurovasculature plays a major role in cognitive decline, and therefore is a key new therapeutic target to treat dementia and AD. This is a program project application with multiple projects, cores, institutions and investigators. It represents an integrated whole far greater than the sum of its parts. Each project and core complements the others so that a synergistic relationship among them is achieved with a common focus on goals of the program, namely to test the neurovascular hypothesis of AD. This hypothesis holds that cerebrovascular dysfunction and disruption in the neurovascular integrity underlies and contributes to the onset and progression of cognitive decline. We have enlisted the established clinical and translational research groups that collectively bring significant expertise in all aspects of the research plan and each have contributed productively over many years to the study of dementia and AD. To test the 'neurovascular hypothesis', the participating investigators will apply cutting-edge molecular and imaging methods. We will perform parallel studies with analogous measures in humans and rats in two AD genetic risk groups with the major genetic risk factors for late-onset AD, i.e., apolipoprotein E-ε4 (APOE4) gene and early-onset autosomal dominant AD (ADAD), i.e., presenilin 1 (PSEN1) mutations that both develop early vascular dysfunction and significant cerebrovascular pathology, and in the rat model of AD (line TgF344-AD) that faithfully recapitulates the rich clinico-pathological spectrum of human AD including the presence of early vascular dysfunction and cerebrovascular pathology. Central to our approach is our commitment to take a new research direction with the overarching goal to provide an answer to the broader question; 'what is the role of the vascular system in the pathogenesis of dementia and AD', and 'what is the prognostic and diagnostic value of neurovascular molecular and imaging biomarkers in predicting cognitive decline'. The relationship between neurovascular integrity, brain connectivity and cognitive function has not been explored. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores hold tremendous promise for the success of this program. We are confident that the proposed studies will have a significant impact on our understanding of pathogenesis, treatment, and early prevention of dementia and AD.