Impact of Amyloid on the Aging Brain

描述(申请人提供)：淀粉样蛋白(A)沉积在临床正常的老年人中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，65岁以上认知正常的人中有相当一部分(超过30%)患有明显的淀粉样变性，可通过PIB-PET成像检测到，其模式与阿尔茨海默病(AD)相似。我们的初步数据表明，淀粉样蛋白的存在与细微的功能、结构和认知改变有关，即使在筛查测试中被认为是临床正常的个体也是如此。我们试图确定无症状、淀粉样蛋白负荷高的老年人是否正在走向临床AD的轨道上，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，以前对“正常”认知老化的研究可能包括了许多处于前驱AD非常早期阶段的个体，在没有淀粉样蛋白病理的情况下，表征与年龄相关的认知、脑结构和功能变化是重要的。哈佛大学淀粉样蛋白和老年脑PPG将研究300名临床正常的老年人，采用分子、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指标的新颖组合，以：1)表征存在与不存在淀粉样蛋白的大脑和认知衰老的特征；2)研究淀粉样蛋白病理在从正常衰老向前驱AD转变中的作用。我们提出了四个高度整合的项目，并得到四个基本核心的支持。项目1将检查衰老过程中的执行功能，使用敏感的成像方法来评估额顶叶网络和白质束的完整性。项目2将使用功能性核磁共振和挑战性的情景记忆测试来研究淀粉样蛋白对记忆网络的影响。项目3将表征血浆和脑脊液中A？和tau的标志物，使用新的分析方法来检测可溶性A？寡聚体，并利用先进的电生理和解剖学方法来量化它们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公认的AD成像标记物(包括FDG-PET和容量磁共振成像)的关系，以及与功能和认知能力下降的关系。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卓越的多学科团队，致力于探索淀粉样蛋白对老化大脑的影响。

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.