Tracking the origin of tau pathology

摘要 阿尔茨海默病（AD）的标志性神经病理学病变是淀粉样蛋白-β（Aβ）和tau沉积。 这些沉积物可以在临床正常成人中观察到，平均在认知功能障碍发作前20年。 损伤尽管在成像和生物标记方面取得了相当大的进展，但研究人员还不能确定 预期在显示任何病理之前积累病理的个体。随着临床试验的发展， 早期干预将更准确地选择有累积AD病理风险的参与者， 至关重要的.该提案的首要目标是评估体内蓝斑（LC）的完整性作为衡量标准 根据其与Aβ、tau积累的早期相关性，从临床前AD中识别认知衰老 认知能力下降的模式和轨迹。我们目标的总体科学前提是， 表明，在80%的40岁病例中，可以在LC中检测到第一个tau病变，并且LC完整性 与认知相关，即使在没有病理的人身上。tau蛋白示踪剂和新型tau蛋白的研究进展 详细可视化LC的方法现在提供了研究LC之间的关联的机会， 完整性、年龄、Aβ、tau和认知。中心假设是LC完整性可以预测区域tau Aβ水平较低的个体在中年时已经出现了累积和认知能力下降。系列Aβ和tau 将进行PET测量、系列3 T MRI、系列认知评估和专用基线7 T LC-MRI扫描， 从人类连接组计划中精心挑选的36-56岁的个体中收集。这 数据将被利用到另一个纵向队列，哈佛老龄化大脑研究和我们现有的患者 问题研究三个特定领域，可能会确定个人的轨迹，以临床前AD将是 解决：1）确定年龄，性别和LC完整性之间的横截面关联的个人在 Aβ和tau病理的不同阶段以及不同的认知障碍水平，这将有助于 评估LC完整性作为AD病理学的生物标志物（目的1）; 2）LC完整性范围的定量 完整性水平预测临床正常个体中的区域tau积累和记忆衰退， 这将阐明与LC完整性相关的空间tau模式， 在认知老化的轨迹上与那些朝向临床前AD的轨迹（目的2）; 3）研究潜在的 通过将结构连接性和功能活动在敏感的 记忆任务与tau累积速率的关系（目标3）。本申请中提出的研究具有创新性 因为它将早期检测转移到年轻的成年人群体（<60岁），这将提供有关 LC完整性在临床前AD和认知老化中的作用。此外，建立潜在的 病理学进展将与新药的开发相关。最终，能够 从AD相关轨迹中辨别出正常年龄相关的轨迹具有显著的早期检测移动的潜力， 在Aβ较低或尚未检测到的时间范围内进行干预，使预防性试验更成功。

ABSTRACT The hallmark neuropathologic lesions of Alzheimer's disease (AD) are amyloid-beta (Aβ) and tau deposits. These deposits can be observed in clinically normal adults, on average 20 years before the onset of cognitive impairment. Despite considerable advance in imaging and biomarkers, researchers are not yet able to identify individuals expected to accumulate pathology prior to showing any pathology. As clinical trials are moving to earlier intervention a more accurate selection of participants at risk for accumulating AD pathology will be crucial. The overarching goal of this proposal is to evaluate in vivo locus coeruleus (LC) integrity as a gauge discerning cognitive aging from preclinical AD based on its very early associations with Aβ, tau accumulation patterns and trajectories of cognitive decline. The overall scientific premise for our goal is that autopsy studies indicated that the first tau lesions can be detected in the LC in 80% of the 40-year old cases, and LC integrity correlates with cognition, even in persons with no pathology. The recent development of tau tracers and novel methods to visualize the LC in detail provide now the opportunity to investigate associations between LC integrity, age, Aβ, tau and cognition. The central hypothesis is that LC integrity can predict regional tau accumulations and cognitive decline in individuals with lower levels of Aβ, already at midlife. Serial Aβ and tau PET measures, serial 3T MRI, serial cognitive assessments and dedicated baseline 7T LC-MRI scans will be collected in individuals between 36-56 years old carefully selected from the Human Connectome Project. This data will be leveraged to another longitudinal cohort, the Harvard Aging Brain Study and our existing patient studies. Three specific areas that could potentially identify individuals on a trajectory to preclinical AD will be addressed: 1) to identify cross-sectional associations between age, sex and LC integrity for individuals at different stages of Aβ and tau pathology and different cognitive impairment levels, which will contribute to the assessment of LC integrity as a biomarker for AD pathology (Aim 1); 2) the quantification of the range of LC integrity levels that predict regional tau accumulation and memory decline in clinically normal individuals, which will elucidate the spatial tau patterns associated with LC integrity and may help in discerning individuals on a trajectory of cognitive aging versus those towards preclinical AD (Aim 2); 3) to investigate underlying mechanisms of spread of pathology by relating structural connectivity and functional activity during a sensitive memory task to rates of tau accumulation (Aim 3). The research proposed in this application is innovative because it moves early detection to a younger adult group (<60 years), which will provide information on the role of LC integrity in preclinical AD and in cognitive aging. In addition, establishing potential mechanisms of pathology progression will be relevant for the development of new pharmaceuticals. Ultimately, being able to discern normal age-related from AD-related trajectories has a significant potential to move early detection and intervention to time frames where Aβ is low or not yet detectable, rendering preventive trials more successful.