AGING BRAIN: VASCULATURE, ISCHEMIA, AND BEHAVIOR

大脑老化：血管、缺血和行为

• 批准号: 6905495
• 负责人: HELENA Chang CHUI
• 金额: $ 230.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905495
• 关键词: Alzheimer' s disease; aging; cerebral ischemia /hypoxia; cerebrovascular disorders; clinical research; human subject

DESCRIPTION (provided by applicant): This is a competing renewal application for a multi-institutional Program Project Grant (PPG) that focuses on cognitive impairment due to small-vessel cerebrovascular disease (s-CVD). The long-term goals of this program Project are to 1) improve our understanding of the pathogenesis of subcortical ischemic vascular dementia (SIVD) and its interactions with Alzheimer's disease (AD), and 2) to develop and validate clinical and imaging markers that inform clinical diagnosis and prognosis. Previous findings from this Project have shown that both SIVD and AD are associated with changes in cerebral cortex, including atrophy, glucose hypometabolism, and loss of n-acetyl aspartate [NAA]. We hypothesize, however, that the mechanisms leading to these cortical and cognitive changes differ in these two disorders. Because s-CVD and Alzheimer disease frequently co-exist in persons over age 65 years, we propose to develop continuous, rather than binary, measures that describe the relative contributions of s-CVD and AD to cognitive impairment. Three Cores and four Projects are built around a prospective longitudinal study design and complementary multi-modal measures of brain structure and function. The Central Coordinating Core (CCC) recruits and follows over 500 subjects representing a spectrum of cognitive impairment attributed to either s-CVD or AD, as well as normal controls. The Imaging Core (Weiner) quantifies volumes of lacunes [L], white matter lesions [WML], cortical gray matter [cGM], and hippocampus [HV] over time. The Pathology Core (Vinters) determines the nature and severity of neurodegenerative, ischemic, and cerebrovascular pathology for each autopsy case. Project 1 (Reed) tests structural-functional-behavioral relationships associated with regional glucose hypometabolism (measured by FDG-PET) in the dorsolateral frontal vs. temporal-parietal lobes. Project 2 (Weiner) tests for differences in brain-metabolic-behavioral relationships in SIVD and AD, using N-acetylaspartate [NAA] and myoinositol from MRSI, as well as perfusion- and diffusion-tensor MR. Project 3 (Chui) seeks the pathological correlates of hippocampal and cortical atrophy, WML, and lacunes, using computerized co-registration of post-mortem brain with in vivo MRI. Project 5 (Mungas) uses multi-variate random effects analyses to model, over time, the neuropsychological and structural MRI correlates of dementia in s-CVD and AD. By integrating multidimensional data obtained using state-of the art methods, we propose to advance understanding of the pathogenesis of cognitive impairment associated with s-CVD and AD and to provide quantitative tools for diagnosis and prognosis.

描述（由申请人提供）：这是一个多机构计划项目资助（PPG）的竞争性续期申请，重点是小血管脑血管疾病（s-CVD）引起的认知障碍。该项目的长期目标是：1）提高我们对皮质下缺血性血管性痴呆（SIVD）发病机制及其与阿尔茨海默病（AD）相互作用的理解，2）开发和验证临床和成像标记物，为临床诊断和预后提供信息。该项目的既往研究结果表明，SIVD和AD均与大脑皮层的变化相关，包括萎缩、葡萄糖代谢低下和n-乙酰天冬氨酸[NAA]的丢失。然而，我们假设，导致这些皮质和认知变化的机制在这两种疾病中是不同的。由于s-CVD和阿尔茨海默病经常在65岁以上的人群中共存，我们建议开发连续的，而不是二元的，描述s-CVD和AD对认知障碍的相对贡献的措施。 三个核心和四个项目是围绕前瞻性纵向研究设计和大脑结构和功能的补充多模式措施而建立的。中央协调核心（CCC）招募并随访了500多名受试者，这些受试者代表了归因于s-CVD或AD的认知障碍谱，以及正常对照。Imaging Core（Weiner）定量了随时间推移的腔隙[L]、白色病变[WML]、皮质灰质[CGM]和海马[HV]体积。病理学核心（Vinters）确定每个尸检病例的神经退行性、缺血性和脑血管病理学的性质和严重程度。项目1（Reed）测试了与背外侧额叶与颞顶叶区域葡萄糖代谢低下（通过FDG-PET测量）相关的结构-功能-行为关系。项目2（Weiner）使用N-乙酰天冬氨酸[NAA]和来自MRSI的肌醇以及灌注和扩散张量MR测试SIVD和AD中脑代谢行为关系的差异。项目3（Chui）使用死后大脑与体内MRI的计算机化共配准寻找海马和皮质萎缩、WML和腔隙的病理相关性。项目5（Mungas）使用多变量随机效应分析来建模，随着时间的推移，s-CVD和AD中痴呆的神经心理学和结构MRI相关性。通过整合使用最先进的方法获得的多维数据，我们提出了进一步了解与s-CVD和AD相关的认知障碍的发病机制，并提供诊断和预后的定量工具。