Impact of Amyloid on the Aging Brain

淀粉样蛋白对大脑衰老的影响

• 批准号: 8686697
• 负责人: REISA A. SPERLING
• 金额: $ 205.29万
• 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/8686697
• 关键词: Administrative Coordination; Administrator; Advisory Committees; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid Proteins; Amyloid deposition; Anatomy; Annual Reports; Autopsy; Behavioral; Biological; Biological Assay; Biological Markers; Biological Neural Networks; Boxing; Brain; Brain Diseases; Budgets; Cerebrospinal Fluid; Clinical; Clinical assessments; Cognition; Cognitive; Cognitive aging; Collaborations; Commit; Communication; Data; Dementia; Deposition; Detection; Development; Disease; Documentation; Elderly; Ensure; Episodic memory; Executive Dysfunction; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Genetic; Goals; Grant; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Institutional Review Boards; Intervention; Laboratories; Leadership; Lesion; Link; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Massachusetts; Measures; Mediating; Memory; Methods; Molecular; Monitor; Names; Nerve Degeneration; Neuronal Dysfunction; Neurons; Neuropsychological Tests; Neurotransmitters; Outcome; Parietal; Pathology; Patients; Pattern; Phase; Pike fish; Pittsburgh Compound-B; Plasma; Positron-Emission Tomography; Predisposition; Principal Investigator; Productivity; Program Research Project Grants; Progress Reports; Publications; Radiopharmaceuticals; Recruitment Activity; Reporting; Research; Research Personnel; Research Project Grants; Resources; Retrieval; Risk; Role; Staging; Structure; Symptoms; Synapses; Technology; Testing; Therapeutic Intervention; Time; Toxic effect; United States National Institutes of Health; Work; age related; aging brain; amyloid imaging; amyloid pathology; base; bioimaging; cerebral atrophy; clinical Diagnosis; clinically significant; cognitive neuroscience; cognitive reserve; cohort; comparison group; data management; endophenotype; executive function; functional decline; hippocampal atrophy; improved; interest; meetings; molecular marker; multidisciplinary; neuroimaging; neuron loss; neuropsychological; normal aging; novel; prevent; programs; relating to nervous system; screening; synaptic failure; tau Proteins; white matter

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.

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。