Tau PET/CT for Early Detection of Alzheimer’s Disease Pathology

项目摘要 阿尔茨海默病（AD）是一种异质性神经退行性疾病，其特征在于： 淀粉样蛋白-β斑块和由tau组成的神经纤维缠结（NFT）的异常积累。 重要的初步数据表明，tau PET与定量分析可以区分Braak III 对比IV NFT病理学。然而，在知识方面存在差距，参与者人数有限 已经用早期Braak NFT阶段（I-IV）进行了评价。我们将利用1779年的数据库 在过去6年中接受过tau PET的参与者，他们提供了一个良好表征的队列， 这项研究节省了大量的费用。我们的假设是，评估tau PET的新方法 将与早期Braak NFT阶段（I-IV）和认知测试异常相关。我们将测试我们的 三个目标的假设： 目的1：表征与早期NFT相关的tau PET测量。 我们将使用创新的tau PET分析方法来预测大样本中的早期Braak NFT阶段。 早期Braak NFT阶段的参与者。我们将使用一种新的定量tau PET评估方法， 改进现有方法并测试tau PET与早期Braak NFT阶段的关联。 目的2：表征与认知测试结果相关的tau PET特征。 我们将使用tau PET来预测CU参与者的认知测试结果。认知测试结果 与MRI或淀粉样蛋白PET相比，在这方面与tau PET相关性最好，tau PET可能是最佳的 治疗生物标志物。我们将使用创新的tau PET成像分析方法来预测早期 认知测试结果在大样本的CU。 目的3：确定不同tau PET放射性示踪剂与早期神经病理性tau蛋白的相关性 过度磷酸化和认知测试。 替代的tau PET放射性示踪剂可以为早期NFT病理和早期NFT病理提供改善的灵敏度。 CU参与者的认知发现。我们将测试另一种tau PET的鉴别能力 成像药物预测早期Braak NFT阶段，并证明与认知测试的关联。 这项工作将提供一个严格的评估tau PET信号的生物学意义。它将有一个 通过鉴定具有早期tau沉积的子集对治疗算法产生显著影响， 与仅怀疑淀粉样病变的患者相比，发生AD痴呆的风险更高。这里我们 提出一种多管齐下的方法来定义早期NFT的tau PET成像及其与认知功能的相关性。 在认知未受损个体中的测试结果。这一建议是变革性的，考虑到 采用最先进的体内PET和新方法在早期检测NFT的新概念 和病理相关性，可以为无症状预防试验提供见解。

PROJECT SUMMARY Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder characterized by the abnormal accumulation of amyloid-β plaques and neurofibrillary tangles (NFT) composed of tau. Important preliminary data has shown that tau PET with quantitative analysis can distinguish Braak III vs IV NFT pathology. However, there is a gap in knowledge and only limited numbers of participants have been evaluated with early Braak NFT stages (I-IV). We will leverage our database of 1779 participants who have had tau PET over the past 6 years who provide a well characterized cohort for this study at substantial cost savings. Our hypotheses are that novel methods of assessing tau PET will be associated with early Braak NFT stages (I-IV) and cognitive test abnormalities. We will test our hypotheses in three aims: Aim 1: Characterize tau PET measurements that are associated with early NFT. We will use innovative tau PET analysis methods to predict early Braak NFT stage in a large sample of early Braak NFT stage participants. We will use a novel method of quantitative tau PET assessment to improve on prior methodologies and test tau PET for association with early Braak NFT stages. Aim 2: Characterize tau PET features associated with cognitive test findings. We will use tau PET to predict cognitive test findings in CU participants. Cognitive test findings correlate best with tau PET in this regard vs MRI or amyloid PET and tau PET could be an optimal therapeutic biomarker. We will use innovative tau PET imaging analysis methods to predict early cognitive test findings in a large sample of CU. Aim 3: Identify associations of different tau PET radiotracers with early neuropathologic tau hyperphosphorylation and cognitive testing. Alternative tau PET radiotracers may provide improved sensitivity for early NFT pathology and early cognitive findings in CU participants. We will test the differential ability of an alternative tau PET imaging drug to predict early Braak NFT stages and demonstrate association with cognitive tests. This work will provide a rigorous assessment of the biological meaning of tau PET signal. It will have a dramatic impact on treatment algorithms by identifying a subset with early tau deposition and therefore higher risk for developing AD dementia than those with only suspected amyloid pathology. Here we propose a multipronged approach to define tau PET imaging of early NFT and correlation with cognitive test findings in cognitively unimpaired individuals. This proposal is transformative, considering the novel concept of detecting NFT at early stages with state-of-art in vivo PET with novel methods and pathologic correlation that could provide insight for asymptomatic prevention trials.