Tracking the origin of tau pathology

摘要 阿尔茨海默病(AD)的标志性神经病理损害是淀粉样β蛋白(Aβ)和tau沉积。 这些沉积可以在临床正常的成年人中观察到，平均在认知障碍发作前20年。 减损。尽管在成像和生物标记物方面取得了相当大的进步，但研究人员还无法识别 希望在表现出任何病理之前积累病理的个人。随着临床试验向 更早的干预更准确地选择有累积AD病理风险的参与者 至关重要。这项建议的首要目标是评估体内蓝斑(LC)的完整性作为一种衡量标准 基于AD与A-β、tau积聚的早期关联区分认知老化与临床前AD 认知衰退的模式和轨迹。我们目标的总体科学前提是尸检研究 结果表明，在40岁以上的患者中，80%的患者可以检测到首发tau病变，且LC完好率较高 与认知相关，即使在没有病理的人中也是如此。Tau示踪剂和小说的最新发展 对LC进行详细可视化的方法现在为研究LC之间的关联提供了机会 正直、年龄、Aβ、tau和认知。中心假设是LC的完整性可以预测区域tau Aβ水平较低的人，已经到了中年，他们的积聚和认知能力下降。系列Aβ和Tau 将进行PET测量、系列3T磁共振成像、系列认知评估和专用基线7T LC-MRI扫描 收集的个人年龄在36-56岁之间，精心挑选自人类连接组项目。这 数据将被用于另一个纵向队列，即哈佛大学老龄化大脑研究和我们现有的患者 学习。有三个特定领域可能会识别处于临床前AD发展轨迹上的个体 解决：1)在以下位置确定个人的年龄、性别和LC完整性之间的横向关联 Aβ和tau病理的不同阶段和不同的认知损害程度，将有助于 评估LC完整性作为AD病理的生物标志物(目标1)；2)LC范围的量化 预测临床正常个体局部tau蓄积和记忆力下降的完整性水平， 这将阐明与LC完整性相关的空间tau模式，并可能有助于区分个体 关于认知老化与临床前阿尔茨海默病的轨迹(目标2)；3)调查潜在的 通过将结构连通性和功能活动联系起来的病理传播机制 记忆任务对tau积累率的影响(目标3)。本申请中提出的研究具有创新性。 因为它将早期发现转移到更年轻的成人群体(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，建立潜在的机制 病理进展将与新药的开发相关。最终，能够 从阿尔茨海默病相关的轨迹中辨别正常的年龄相关轨迹具有很大的潜力，可以早期发现和 对Aβ低或尚未检测到的时间段进行干预，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.