Vascular and Metabolic Mechanisms in Alzheimer's Disease

阿尔茨海默病的血管和代谢机制

• 批准号: 6901500
• 负责人: WILLIAM J POWERS
• 金额: $ 10.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901500
• 关键词: Alzheimer' s disease; amyloid proteins; autonomic nervous system; bioenergetics; blood brain barrier; blood vessel disorder; brain circulation; brain metabolism; cerebral cortex; clinical research; dementia; magnetic resonance imaging; neuroimaging; oxidative stress; pathologic process; positron emission tomography; protein transport; psychometrics

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.

描述(申请人提供)：阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。在认识到蛋白质异常沉积在AD发病机制中的重要作用的同时，大量证据表明脑血管和脑代谢机制在病理性AD的发生发展和病理性AD患者痴呆的发生发展中起着重要作用。这个项目将解决AD中这些机制的3个具体方面。具体目标1将检验这一假设，即临床诊断为AD的患者已经损害了脑血流的自动调节，导致全身平均动脉压降低。特定目标2将检验临床诊断为AD的患者存在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用C-11标记合成淀粉样多肽A-β(1-40)的方法，并进行动物实验，为最终在人类受试者身上的研究做准备。我们将测试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。为了弥合实验室和患者之间的差距，我们将通过精心设计的研究，在人体内严格测试这些假说。这种转换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。我们将使用精确、准确和经过充分验证的技术来测量脑血流和新陈代谢，以及创新的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。这项提案汇集了阿尔茨海默病研究中心和放射科学部的资深研究人员，他们拥有互补的专业知识。通过使用华盛顿大学医学中心的独特资源和人员，我们有机会为AD的重要临床和机械性问题提供答案。