Vascular and Metabolic Mechanisms in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症最常见的原因。虽然承认异常蛋白沉积在AD发病机制中的重要作用，但存在大量证据表明脑血管和脑代谢机制在病理性AD的发展中以及在患有病理性AD的受试者中痴呆的发展中起作用。本项目将解决AD中这些机制的3个具体方面。具体目标1将检验以下假设：临床诊断为AD的患者的脑血流自动调节受损，导致全身平均动脉压降低。具体目标2将检验临床诊断为AD的患者脑氧化能量代谢异常的假设。在具体目标3中，我们将开发和优化一种方法，用C-11标记合成的淀粉样肽A-β（1-40），并进行动物研究，为最终在人类受试者中的研究做准备。我们将检验的假设是基于动物模型和人体组织体外研究中描述的机制。为了弥合实验室工作台和患者之间的差距，我们将通过精心设计的研究在人体AD中严格测试这些假设。这种翻译方法将使我们能够确定这些机制在人类疾病中的重要性，并可能为设计未来的治疗策略提供必要的信息。我们将采用精确，准确和经过充分验证的技术来测量脑血流和代谢，以及创新的新神经成像技术来评估脑淀粉样蛋白沉积和淀粉样蛋白的BBB运输。这项提案汇集了来自阿尔茨海默病研究中心和放射科学部的有成就的研究人员，他们具有互补的专业知识。通过利用华盛顿大学医学中心独特的资源和人员，我们有机会为AD的重要临床和机制问题提供答案。

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most common cause of dementia in the elderly. While acknowledging the important role of abnormal protein deposition in the pathogenesis of AD, there exists a considerable body of evidence indicating that both cerebral vascular and cerebral metabolic mechanisms play a role in the development of pathological AD and in the development of dementia in subjects with pathological AD. This project will address 3 specific aspects of these mechanisms in AD. Specific Aim 1 will test the hypothesis that patients with clinically diagnosed AD have impaired autoregulation of cerebral blood flow to reductions in systemic mean arterial pressure. Specific Aim 2 will test the hypothesis that patients with clinically diagnosed AD have an abnormality in cerebral oxidative energy metabolism. In Specific Aim 3 we will develop and optimize a method to label the synthetic amyloid peptide A-beta (1-40) with C-11 and perform animal studies to prepare for eventual studies in human subjects. The hypotheses that we will test are soundly based on mechanisms described in animal models and in vitro studies of human tissue. To bridge the gap between the laboratory bench and the patient, we will rigorously test these hypotheses in human AD in vivo by well-designed studies. This translational approach will allow us to determine the importance of these mechanisms in the human disease and potentially provide the information necessary for designing future treatment strategies. We will employ precise, accurate and well-validated techniques to measure cerebral blood flow and metabolism as well as innovative new neuroimaging techniques to evaluate brain amyloid deposition and BBB transport of amyloid. This proposal brings together accomplished investigators from the Alzheimer's Disease Research Center and the Division of Radiological Sciences with complementary expertise. Through the use of the unique resources and personnel at Washington University Medical Center, we have the opportunity to provide answers to important clinical and mechanistic questions in AD.