Impact of Amyloid on the Aging Brain

淀粉样蛋白对大脑衰老的影响

• 批准号: 7871772
• 负责人: REISA A. SPERLING
• 金额: $ 217.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871772
• 关键词: Impact; Amyloid; Aging; Brain

DESCRIPTION (provided by applicant): The biological and clinical significance of amyloid ¿-protein (A¿) deposition in clinically normal older individuals remains to be elucidated. Consistent with prior autopsy studies, we and others have found that a substantial proportion (over 30%) of cognitively intact individuals over age 65 harbor significant amyloid pathology, detectable with PiB-PET imaging, in a similar pattern to that seen in Alzheimer's disease (AD). Our preliminary data indicate that the presence of amyloid is associated with subtle functional, structural and cognitive alterations, even among individuals who are considered clinically normal on screening tests. We seek to determine if asymptomatic older individuals with high amyloid burden are on a trajectory towards clinical AD, as this will open a critical time window for maximally effective therapeutic intervention. Furthermore, we believe that previous studies of "normal" cognitive aging have likely included many individuals in very early stages of prodromal AD, and that it is important to characterize age-related changes in cognition, brain structure and function in the absence of amyloid pathology. The Harvard Amyloid and Aging Brain PPG will study 300 clinically normal older individuals with a novel combination of molecular, functional, and structural imaging, plasma and CSF markers, and sensitive neuropsychological measures, to: 1) characterize brain and cognitive aging in the presence vs. absence of amyloid and 2) investigate the role of amyloid pathology in the transition from normal aging to prodromal AD. We propose four highly integrated projects, supported by four essential cores. Project 1 will examine executive function in aging, using sensitive imaging measures to assess the integrity of fronto-parietal networks and white matter tracts. Project 2 will investigate the impact of amyloid on memory networks, using functional MRI and challenging tests of episodic memory. Project 3 will characterize plasma and CSF markers of A¿ and tau, using novel assays to detect soluble A¿ oligomers and quantify their effects on synaptic structure and function with advanced electrophysiological and anatomical methods. Project 4 will investigate longitudinal accumulation of amyloid and its relationship to well-established imaging markers of AD, including FDG-PET and volumetric MRI, and to functional and cognitive decline. This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. PUBLIC HEALTH RELEVANCE: This Program Project will improve our understanding of the aging brain and determine the role of brain amyloid, one of the key brain lesions seen in Alzheimer's disease, in predicting cognitive decline among clinically normal older individuals. We hope to detect the earliest brain changes associated with Alzheimer's disease, even before there is significant cognitive impairment, as this is likely to be the point when treatment would likely be most effective in slowing cognitive decline and preventing dementia. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE; Dr. Reisa Sperling, Core Leader (CL) DESCRIPTION (provided by applicant): The Administrative Core will provide the leadership, coordination, and administrative oversight to achieve the programmatic goals of the Harvard Amyloid and Aging Brain Program Project Grant (PPG). The Administrative Core will strive to ensure optimal integration among the four Cores and the four Research Projects of the PPG to achieve maximal scientific productivity. The Administrative Core consists of the Principal Investigator (Sperling), Co-investigator (Rentz) and Program Administrator (Houghton), and will work closely with the co-PIs of the PPG (Buckner and Johnson) to enhance the coordination among all components of the PPG. The Administrative Core will provide administrative and scientific oversight of the PPG (Aim 1), and will coordinate monthly meetings of the Executive Committee, and yearly meetings of the external Scientific Advisory Committee (to be named at the time of grant funding). The Administrative Core will facilitate the efficient communication and integration between all components of the PPG, provide oversight of timely data transfer from all Cores and Projects to Core D: Analytic Core to achieve maximal scientific productivity, and track all scientific publications (Aim 2). The Administrative Core will prepare NIH progress reports, interface with Core B: Clinical to prepare IRB documentation and annual continuing review, and with Core C: Imaging Core to prepare annual reports to the MGH Radioactive Drug Research Committee (Aim 3). The Administrative Core will oversee all aspects of the PPG finances to assure fiscal responsibility (Aim 4). The Administrative Core will prepare all budgets, and interface with the MGH Research Administration to monitor all financial and regulatory aspects of the PPG. The Administrative Core will also serve to facilitate coordination with the Massachusetts Alzheimer's Disease Research Center (MADRC), the Martinos Center for Biomedical Imaging at MGH, and other local resources available to the PPG at Harvard. The Administrative Core will oversee an outstanding multidisciplinary group of investigators with a strong record of collaboration and scientific productivity, and a common interest in elucidating the role of amyloid in the transition from normal aging to prodromal AD. PUBLIC HEALTH RELEVANCE: This Core will provide the administrative support to achieve the overall goals of the Project to improve our understanding of the aging brain and the role of amyloid pathology in predicting cognitive decline. We hope to differentiate the brain changes seen in normal aging from the earliest brain abnormalities associated with Alzheimer's disease, in order to enable treatment before the onset of dementia.

描述（由申请人提供）：临床正常老年人体内淀粉样β-蛋白（Aβ）沉积的生物学和临床意义仍有待阐明。与之前的尸检研究一致，我们和其他人发现，相当大比例（超过 30%）的 65 岁以上认知完整的个体具有明显的淀粉样蛋白病理，可以​​通过 PiB-PET 成像检测到，其模式与阿尔茨海默氏病 (AD) 中所见的模式相似。我们的初步数据表明，淀粉样蛋白的存在与微妙的功能、结构和认知改变有关，即使是在筛选测试中被认为临床正常的个体中也是如此。我们试图确定淀粉样蛋白负荷高的无症状老年人是否正在走向临床 AD，因为这将为最有效的治疗干预打开一个关键的时间窗口。此外，我们认为，之前对“正常”认知衰老的研究可能包括许多处于 AD 前驱期的个体，并且在没有淀粉样蛋白病理的情况下，表征认知、大脑结构和功能的年龄相关变化非常重要。哈佛淀粉样蛋白和衰老大脑 PPG 将通过分子、功能和结构成像、血浆和脑脊液标记物以及敏感的神经心理学测量的新颖组合来研究 300 名临床正常的老年人，以：1）在存在和不存在淀粉样蛋白的情况下表征大脑和认知老化；2）研究淀粉样蛋白病理学在从正常衰老到前驱 AD 的转变中的作用。我们提出了四个高度集成的项目，由四个基本核心支持。项目 1 将检查衰老过程中的执行功能，使用敏感的成像测量来评估额顶叶网络和白质束的完整性。项目 2 将利用功能性 MRI 和情景记忆的挑战性测试来研究淀粉样蛋白对记忆网络的影响。项目 3 将表征 A¿ 和 tau 的血浆和脑脊液标记物，使用新颖的检测方法来检测可溶性 A¿ 寡聚体，并通过先进的电生理学和解剖学方法量化其对突触结构和功能的影响。项目 4 将研究淀粉样蛋白的纵向积累及其与 AD 成熟成像标志物（包括 FDG-PET 和体积 MRI）以及功能和认知能力下降的关系。该 PPG 汇集了一支由临床、统计学、认知神经科学、成像和实验室研究人员组成的杰出多学科团队，致力于探索淀粉样蛋白对衰老大脑的影响。 公共健康相关性：该计划项目将提高我们对衰老大脑的了解，并确定大脑淀粉样蛋白（阿尔茨海默病中发现的关键脑部病变之一）在预测临床正常老年人认知能力下降方面的作用。我们希望甚至在出现明显的认知障碍之前就检测到与阿尔茨海默病相关的最早的大脑变化，因为这可能是治疗最有效地减缓认知衰退和预防痴呆的时刻。 计划项目各个组成部分的审查 核心A：行政核心； Reisa Sperling 博士，核心领导者 (CL) 描述（由申请人提供）：行政核心将提供领导、协调和行政监督，以实现哈佛淀粉样蛋白和衰老大脑计划项目拨款 (PPG) 的计划目标。行政核心将努力确保 PPG 的四个核心和四个研究项目之间的最佳整合，以实现最大的科学生产力。行政核心由首席研究员 (Sperling)、联合研究员 (Rentz) 和项目管理员 (Houghton) 组成，并将与 PPG 的联合 PI（Buckner 和 Johnson）密切合作，以加强 PPG 所有组成部分之间的协调。行政核心将为 PPG 提供行政和科学监督（目标 1），并将协调执行委员会的每月会议和外部科学咨询委员会（将在拨款时命名）的年度会议。管理核心将促进 PPG 所有组成部分之间的高效沟通和集成，监督从所有核心和项目到核心 D：分析核心的及时数据传输，以实现最大的科学生产力，并跟踪所有科学出版物（目标 2）。行政核心将准备 NIH 进度报告，与核心 B：临床接口以准备 IRB 文件和年度持续审查，并与核心 C：成像核心接口，为 MGH 放射性药物研究委员会准备年度报告（目标 3）。行政核心将监督 PPG 财务的各个方面，以确保财务责任（目标 4）。行政核心将准备所有预算，并与 MGH 研究管理部门联系，以监督 PPG 的所有财务和监管方面。行政核心还将促进与马萨诸塞州阿尔茨海默病研究中心 (MADRC)、麻省总医院马蒂诺斯生物医学成像中心以及哈佛大学 PPG 可用的其他本​​地资源的协调。行政核心将监督一支杰出的多学科研究人员小组，他们具有良好的合作记录和科学生产力，并且对阐明淀粉样蛋白在从正常衰老到前驱 AD 转变中的作用有着共同的兴趣。 公共健康相关性：该核心将为实现该项目的总体目标提供行政支持，以提高我们对衰老大脑以及淀粉样蛋白病理学在预测认知衰退中的作用的理解。我们希望将正常衰老过程中出现的大脑变化与与阿尔茨海默病相关的最早的大脑异常区分开来，以便在痴呆症发作之前进行治疗。