Impact of Amyloid and Tau on the Aging Brain: The Harvard Aging Brain Study

总结-总体情况。哈佛大脑老化研究（HABS）成立于9年前， 阿尔茨海默病（AD）的标志性蛋白质病的影响，即，淀粉样蛋白-β（aβ）和tau，如 通过PET成像评估，在临床正常的老年人中。这是一个竞争性的续期申请， HABS计划项目补助金（PPG）的第三个周期，以继续我们的纵向认知和多模态 对一组非常专注和表型丰富的参与者（目前年龄51- 94，种族和社会经济地位的多样性），并利用创新技术来推进我们的 寻求更好地了解认知老化和临床前AD。我们已经取得了很大的进展， 我们第二个资助周期的科学目标，在过去四年中发表了100多篇研究论文 这为正在进行的预防试验设计和关于AD和其他疾病研究的国际倡议提供了信息， 与年龄有关的疾病我们在这次更新中的总体目标是：1）更早：调查最早的阶段 aβ和tau积累，评估进展的特定解剖模式，以及这些之间的相互作用 AD的“临床前”阶段的病理学。2)扩大范围：调查潜在的调节因素，如 作为血管风险，体力活动和全身炎症，可能独立地导致认知功能障碍， 下降，并与aβ和tau相互作用以加速认知能力下降。3)深入：探索新的措施， 突触的完整性，并利用多方面的数字技术来捕捉特定的认知变化， 流程. 4)更快：能够更快速、更有效地评估成像和认知变化 在较短的时间间隔内测量，并最终预测临床有意义的结果的进展。我们 提出了五个核心，包括一个新的生物标志物核心，将支持四个项目：项目1：调查 纵向aβ和tau PET关系，并确定在该过程中可检测的体内病理解剖学阶段 临床前AD项目2：调查调节临床下降的其他因素的贡献，包括 血管疾病、体力活动以及神经损伤和炎症的探索性血液生物标志物。项目 3：评估突触功能的纵向多模态成像测量，并探索新型PET示踪剂 突触的完整性项目4：调查认知能力下降的决定因素，优化快速检测， 新的数字测量，并建立早期认知变化的临床意义。HABS PPG 更新将利用一组优秀的多学科研究人员，获得尖端的成像 和认知评估技术，以及一个非常特征化的队列， PET随访存在。额外的纵向评估将使我们能够确定 促进健康的大脑老化，而不是那些容易积累aβ和tau的大脑老化， vs.在早期AD病理学背景下对认知能力下降的恢复力，最终目标是加速 沿着临床前AD的轨迹，朝着有效预防认知下降的方向取得进展。

SUMMARY—OVERALL. The Harvard Aging Brain Study (HABS) was established nine years ago to elucidate the impact of the hallmark proteinopathies of Alzheimer’s disease (AD), i.e., amyloid-beta (aβ) and tau, as assessed by PET imaging, in clinically normal older individuals. This is a competing renewal application for a third cycle of the HABS Program Project Grant (PPG) to continue our longitudinal cognitive and multi-modality imaging assessments of an extremely dedicated and richly phenotyped cohort of participants (currently age 51- 94, with diversity in ethnicity and socioeconomic status), and to leverage innovative technology to advance our quest to better understand cognitive aging and preclinical AD. We have made excellent progress in achieving the scientific goals of our second grant cycle, with over 100 research publications during the past four years that have informed ongoing prevention trial designs and international initiatives on the study of AD and other age-related pathologies. Our overall goals in this renewal are to: 1) Go earlier: investigate the earliest stages of aβ and tau accumulation, evaluating specific anatomic patterns of progression, and the interactions of these pathologies in the “pre-preclinical” phase of AD. 2) Go broader: investigate potential modulating factors, such as vascular risk, physical activity, and systemic inflammation that may independently contribute to cognitive decline, and interact with aβ and tau to accelerate cognitive decline. 3) Go deeper: explore novel measures of synaptic integrity and utilize multifaceted digital technology to capture specific alterations in cognitive processes. 4) Go faster: enable more rapid and efficient assessment of change in imaging and cognitive measures over shorter time intervals, and ultimately predict progression on clinically meaningful outcomes. We propose five Cores, including a new Biomarker Core, that will support four Projects: Project 1: Investigate longitudinal aβ and tau PET relationships and identify in vivo pathoanatomic stages detectable over the course of preclinical AD. Project 2: Investigate the contribution of other factors that modulate clinical decline, including vascular disease, physical activity, and exploratory blood biomarkers of neural injury and inflammation. Project 3: Evaluate longitudinal multi-modality imaging measures of synaptic function and explore a novel PET tracer of synaptic integrity. Project 4: Investigate the determinants of cognitive decline, optimize rapid detection with novel digital measures, and establish the clinical meaningfulness of early cognitive changes. This HABS PPG renewal will leverage an outstanding group of multidisciplinary investigators, access to cutting-edge imaging and cognitive assessment technology, and an extremely well-characterized cohort with some of the longest tau PET follow up in existence. The additional longitudinal assessments will allow us to determine the factors that promote healthy brain aging vs. those that confer susceptibility to accumulating aβ and tau, and vulnerability vs. resilience to cognitive decline in the setting of early AD pathology, with the ultimate goal of accelerating progress towards the effective prevention of cognitive decline along the trajectory of preclinical AD.