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（由应用提供）：淀粉样蛋白（a蛋白（A�）在临床正常老年人中的沉积的生物学和临床意义仍然有待阐明。与先前的尸检研究一致，我们和其他人发现，在65岁以上的认知完整个体中，有很大的比例（超过30％）具有与PIB-PET成像可检测到的显着淀粉样蛋白病理学，其模式与阿尔茨海默氏病（AD）相似的模式。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，即使是在筛查测试中被认为在临床上正常的个体中。我们试图确定具有高淀粉样蛋白伯恩的非对称老年人是否朝着临床AD的轨迹，因为这将打开关键的时间窗口，以最大程度地有效治疗干预。此外，我们认为先前对“正常”认知衰老的研究可能包括许多人在前驱AD的早期阶段，并且在没有淀粉样病理学的情况下表征与年龄相关的认知，脑结构和功能的变化很重要。 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.我们提出了四个高度集成的项目，并得到了四个基本核心的支持。项目1将使用敏感的成像指标来检查衰老中的执行功能，以评估额叶网络和白质区域的完整性。项目2将使用功能性MRI和情节记忆测试来研究淀粉样蛋白对内存网络的影响。项目3将使用新颖的测定法来检测A和TAU的等离子体和CSF标记，以检测固体A寡聚物，并使用先进的电生理和解剖学方法量化其对合成结构和功能的影响。项目4将研究淀粉样蛋白的纵向积累及其与AD的良好成像标记的关系，包括FDG-PET和体积MRI，以及功能和认知能力下降。该PPG汇集了一个临床，统计，认知神经科学，成像和实验室研究人员的特殊多学科团队，致力于探索淀粉样蛋白对衰老大脑的影响。 公共卫生相关性：该计划项目将提高我们对衰老大脑的理解，并确定大脑淀粉样蛋白的作用，这是阿尔茨海默氏病在预测临床正常老年人的认知能力下降方面所见的关键大脑病变之一。我们希望能够检测到与阿尔茨海默氏病有关的最早的大脑变化，甚至在严重的认知障碍之前，因为这可能是治疗在减慢认知能力下降和预防痴呆症方面最有效的关键。 审查程序项目的各个组件 核心A：行政核心；核心负责人Reisa Sperling博士（CL） 描述（由应用程序提供）：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的大脑计划项目赠款（PPG）的程序化目标。行政核心将努力确保四个内核和PPG的四个研究项目之间的最佳整合，以实现最大的科学产品。行政核心由首席研究员（Sperling），共同投资者（Rentz）和计划管理员（Houghton）组成，并将与PPG（Buckner and Johnson）的Co-PI紧密合作，以增强PPG所有组件的协调。行政核心将提供对PPG的行政和科学监督（AIM 1），并将协调执行委员会的每月会议，以及外部科学咨询委员会的年度会议（在授予资助时命名）。行政核心将准备PPG的所有组件之间的有效沟通和集成，从而监督从所有内核和项目到核心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（AIM 2）。行政核心将准备NIH进度报告，与核心B：临床互动以准备IRB文档和年度持续审查，以及核心C：Imaging Core，以准备向MGH放射性药物研究委员会的年度报告（AIM 3）。行政核心将监督PPG财务的各个方面，以确保财政责任（AIM 4）。行政核心将准备所有预算，并与MGH研究管理局进行交互，以监视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氏病研究中心（MADRC），MARTINOS生物医学成像中心的协调，以及MGH的其他本地资源，可用于哈佛大学的PPG。行政核心将监督一个杰出的多学科研究人员，具有很强的协作和科学生产力的记录，并且对阐明淀粉样蛋白在从正常衰老到前驱AD的过渡中的作用方面具有共同的兴趣。 公共卫生相关性：该核心将提供行政支持，以实现该项目的总体目标，以提高我们对衰老大脑的理解以及淀粉样病理学在预测认知能力下降中的作用。我们希望将正常衰老的大脑变化与与阿尔茨海默氏病有关的最早的大脑异常区分，以便在痴呆症发作之前进行治疗。