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

摘要--总体。哈佛大学衰老大脑研究(HABS)成立于九年前，目的是阐明 阿尔茨海默病(AD)的标志性蛋白病变，即淀粉样β蛋白(aβ)和tau，AS的影响 在临床正常的老年人中，通过PET成像进行评估。这是一个与之竞争的续订申请 HABS计划项目赠款(PPG)的第三个周期，以继续我们的纵向认知和多模式 对一组非常专注和表型丰富的参与者(目前51岁- 94，种族和社会经济地位的多样性)，并利用创新技术来推动我们的 寻求更好地了解认知老化和临床前阿尔茨海默病。我们在实现以下目标方面取得了很大进展 我们第二个赠款周期的科学目标，在过去四年中发表了100多篇研究论文 为正在进行的预防试验设计和关于AD和其他疾病的研究的国际倡议提供了信息 与年龄相关的病理。我们在这次更新中的总体目标是：1)更早：调查最早的阶段 β和tau的积聚，评估进展的特定解剖模式以及它们之间的相互作用 阿尔茨海默病“临床前”阶段的病理学。2)更广泛：调查潜在的调节因素，如 血管风险、体力活动和全身性炎症可能独立地促进认知 下降，并与β和tau相互作用，加速认知下降。3)更深入：探索新的措施 突触完整性和利用多方面的数字技术来捕捉认知的特定变化 流程。4)速度更快：实现对成像和认知变化的更快速、更高效的评估 在较短的时间间隔内进行测量，并最终预测具有临床意义的结果的进展。我们 提议五个核心，包括一个新的Biomarker核心，将支持四个项目：项目1：调查 Aβ和tau PET的纵向关系及在病程中可检测到的活体病理解剖分期 临床前阿尔茨海默病项目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记物。项目 3.评价突触功能的纵向多模式成像方法，并探索一种新的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 新的数字化测量，并建立了早期认知变化的临床意义。这是哈布斯PPG 续签将利用一批出色的多学科调查人员，获得尖端成像 和认知评估技术，以及一些最长tau的特征非常好的队列 宠物后续服务。额外的纵向评估将使我们能够确定以下因素 促进健康的大脑老化，而不是那些容易积累β和tau的人，以及那些易受伤害的人 早期AD病理背景下认知功能下降的恢复力对比，最终目标是加速 临床前阿尔茨海默病患者认知功能减退的有效预防进展。

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.