Impact of Amyloid on the Aging Brain

描述（申请人提供）：淀粉样蛋白-蛋白(A)沉积在临床正常老年人中的生物学和临床意义仍有待阐明。与先前的尸检研究一致，我们和其他人发现，相当大比例（超过30%）的65岁以上认知完好的个体具有明显的淀粉样蛋白病理，PiB-PET成像可检测到，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，即使在筛查试验中被认为临床正常的个体中也是如此。我们试图确定具有高淀粉样蛋白负担的无症状老年人是否处于临床AD的发展轨道上，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，之前对“正常”认知衰老的研究可能包括许多处于前驱AD早期阶段的个体，因此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是很重要的。哈佛淀粉样蛋白和衰老大脑PPG将对300名临床正常老年人进行研究，采用分子、功能和结构成像、血浆和脑脊液标志物以及敏感的神经心理学测量方法的新组合，以：1)表征淀粉样蛋白存在与不存在时的大脑和认知衰老；2)研究淀粉样蛋白病理在从正常衰老到前驱AD转变中的作用。我们提出了四个高度整合的项目，以四个基本核心为支撑。项目1将研究衰老过程中的执行功能，使用敏感成像方法评估额顶叶网络和白质束的完整性。项目2将研究淀粉样蛋白对记忆网络的影响，使用功能性核磁共振成像和情景记忆的挑战性测试。项目3将对A¿和tau的血浆和脑脊液标记物进行表征，使用新的检测方法检测可溶性A¿低聚物，并使用先进的电生理和解剖学方法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AD影像学标志物的关系，包括FDG-PET和体积MRI，以及与功能和认知能力下降的关系。这个PPG汇集了一个杰出的多学科团队，包括临床、统计学、认知神经科学、成像和实验室研究人员，致力于探索淀粉样蛋白对衰老大脑的影响。

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.