Pharmaconeuropathology of Brain Aging and Dementia

脑衰老和痴呆的药物神经病理学

• 批准号: 6988686
• 负责人: Thomas J Montine
• 金额: $ 29.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988686
• 关键词: Alzheimer' s disease; Lewy body; antihypertensive agents; antioxidants; brain disorder diagnosis; clinical research; dementia; drug discovery /isolation; drug screening /evaluation; gas chromatography mass spectrometry; histopathology; hormone therapy; human data; isotope dilution method; longitudinal human study; neural degeneration; neuritic plaques; neurofibrillary tangles; neuropathology; neuropharmacology; neuroprotectants; nonsteroidal antiinflammatory agent; postmortem; therapy design /development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common dementing disorder in the United States. AD already is a major public health burden that is poised to burgeon in the next generation. There is a clear therapeutic imperative for AD and a critical need to quickly and robustly validate candidate protectants from observational studies to insure that the best possible agents advance to randomized clinical trials, and to discover new and safe neuroprotectants. The long-term objective of this project is to provide pathological and biochemical validation of candidate protectants and to aid in the discovery of new candidates for AD. The Adult Changes in Thought (ACT) study is an ongoing large population-based longitudinal study involving approximately 3,200 elderly individuals who were cognitively intact when enrolled. A unique and powerful feature of ACT is its extensive pharmacy database that extends back to 1986. We propose to use this pharmacy database to test the hypothesis that some commonly used therapeutics suppress pathological features of AD-type neurodegeneration in elderly individuals without dementia, individuals with prodromal dementia, and patients with incident AD. We will test this hypothesis by determining associations between documented exposure to therapeutics and pathologic endpoints obtained in this project. Therapeutics to be evaluated include antihypertensives, antioxidants, non-steroidal anti-inflammatory drugs, hormone replacement therapy in women, and emerging candidate protectants identified during the course of this project. Pathologic endpoints to be determined in multiple brain regions obtained by rapid autopsy protocol are: (1) magnitude of oxidative damage to neuronal membranes (2) dendritic and synaptic degeneration (3) protein insolubility (4) density and staging of histopathologic structures, viz., neuritic plaques, neurofibrillary tangles, and Lewy bodies. This study offers a unique opportunity to discover and validate candidate protectants from among commonly used therapeutics, an endeavor unlikely to be pursued by pharmaceutical industry, and will provide needed rational either for or against the advancement of candidate protectants in randomized clinical trials for prevention of AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）是美国最常见的痴呆症。广告已经是一个重大的公共卫生负担，有望在下一代中繁忙。 AD有明确的治疗势力，并且迫切需要快速，牢固地验证候选者免受观察性研究的影响，以确保最好的药物可以前进到随机临床试验，并发现新的和安全的神经保护剂。该项目的长期目标是提供候选保护剂的病理和生化验证，并帮助发现新的AD候选人。成人思想变化（ACT）研究是一项持续的大型基于人群的纵向研究，涉及大约3200个老年人，他们在入学时就完好​​无损。 ACT的一个独特而有力的功能是其广泛的药房数据库，它可以追溯到1986年。我们建议使用该药房数据库来测试以下假设：某些常用的治疗疗法抑制了无痴呆痴呆症患者的AD型神经变性的病理学特征，患有痴呆症患者，患有痴呆痴呆症患者和入射AD。我们将通过确定该项目中获得的治疗剂和病理终点之间的关联来检验这一假设。待评估的治疗剂包括抗高血压，抗氧化剂，非甾体类抗炎药，女性的激素替代疗法以及在本项目过程中确定的新兴候选保护剂。在通过快速尸检方案获得的多个大脑区域中要确定的病理终点是：（1）神经元膜的氧化损伤的大小（2）树突状和突触变性（3）蛋白质不溶性（4）密度和分布，组织病理结构，组织病学结构，viz。，neuritic plaques。这项研究提供了一个独特的机会，可以发现和验证候选者免受常用治疗学的侵害，这是制药行业不太可能追求的努力，并将为在随机临床试验中的候选保护剂的发展提供必要的理性，以预防AD的随机临床试验。