Temporal sequence, anatomic progression, and interaction of amyloid-beta and tau (Project 1)

摘要：项目1-淀粉样蛋白和TAU PET β和tau沉积的轨迹现在可以相互关联，也可以与临床前的其他生物标记物相关。 AD以及临床终点。最近的治疗试验失败突显了对更好的 了解病理水平的变化如何相互关联以及与临床结果的关系。不幸的是， 这些关系是复杂的，允许稳健跟踪动态的优化措施仍然存在 不发达，对高效、快速地取得成功的治疗方法构成了障碍。关于…的初步研究 HABS的这些轨迹表明，早期β的增加是可以检测到的，但与 认知下降，直到较晚的观察期，在此期间，下降是由同时发生的 牛磺酸蓄积的量度。在拟议的哈布斯周期3中，项目1将侧重于进展和 β和tau病变的相互关系动力学评价--从成像核心获取的正电子发射计算机断层扫描 病变进展的各个阶段。我们将利用HABS样本，使用9年的淀粉样蛋白和4年的 Tau PET随访和纵向神经心理学数据表征进展阶段 时间术语(目标1)和空间术语(目标2)，以及探索这些表现的新的血浆测量方法 阶段(探索性目标3)。具体地说，HABS参与者将接受11C匹兹堡的系列成像 目标1的化合物B和18F Flortaucipir PET，以表征每种病理的时间轨迹， 将这些轨迹相互关联，识别每个轨迹之间的动态联系 间隔时间，并将这些发现与年龄、性别和载脂蛋白E基因型联系起来；目标2，确定 基于一系列测量的β和tau级数；以及目标3(探索性)，调查β的关联 以及用正电子发射计算机断层扫描测量的tau水平和变化与用血液生物标志物测量的结果之间的相关性 一旦发现，就会进行脑部尸检。项目1将有助于实现总体计划目标： 我们将一起评估调节因素(项目2)以及功能链接(项目3)的影响 将病理变化与临床表型联系起来(项目4)。总而言之，这项研究最终将得到改进 临床试验和治疗靶向策略的抽样。

SUMMARY: PROJECT 1- AMYLOID AND TAU PET Trajectories of aβ and tau deposition can now be related to each other and to other biomarkers of preclinical AD as well as to clinical endpoints. Recent therapeutic trial failures highlight the critical need for a better understanding of how changing levels of pathology relate to each other and to clinical outcomes. Unfortunately, these relationships are complex, and optimized measures permitting robust tracking of dynamics remain underdeveloped, posing a barrier to efficient, rapid progress toward successful therapeutics. Initial study of these trajectories in HABS indicated that earlier aβ increase was detectable but was not associated with cognitive decline until a later observation period, during which time the decline was mediated by concurrent measures of tau accumulation. In the proposed HABS Cycle 3, Project 1 will focus on the progression and interrelated dynamics of aβ and tau pathologies assessed with PET acquired in the Imaging Core to identify stages of pathologic progression. We will leverage the HABS sample, with 9 years of amyloid and 4 years of tau PET follow up along with longitudinal neuropsychological data to characterize stages of progression in terms of time (Aim 1) and space (Aim 2), as well as explore novel plasma measures for manifestations of these stages (exploratory Aim 3). Specifically, HABS participants will undergo serial imaging with 11C Pittsburgh Compound B and 18F Flortaucipir PET with Aim 1, to characterize the temporal trajectory of each pathology, relate these trajectories to each other, identify dynamic connections between each that progress in successive intervals, and relate these findings to age, sex, and APOE genotype; Aim 2, to identify the specific anatomy of aβ and tau progression based on serial measures; and Aim 3 (Exploratory), investigate the associations of aβ and tau level and change measured with PET to measures obtained with blood biomarkers, and to correlate findings with autopsy brains as they become available. Project 1 will contribute to the overall Program goals: together we will assess the impact of modulating factors (Project 2) as well as the functional links (Project 3) that relate pathologic change to clinical phenotype (Project 4). Together, this research will ultimately improve sampling for clinical trials and therapeutic targeting strategies.