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

项目总结 阿尔茨海默病(AD)是一种异质性神经退行性疾病，其特征是 淀粉样蛋白-β斑块和由tau组成的神经原纤维缠结(NFT)异常聚集。 重要的初步数据已经表明，tau PET结合定量分析可以区分Braak III VS IV NFT病理。然而，在知识方面存在差距，参与者人数有限。 已通过Braak NFT早期阶段(I-IV)进行了评估。我们将利用我们1779年的数据库 在过去6年内接受tau PET的参与者，他们提供了一个具有良好特征的队列 这项研究节省了大量的成本。我们的假设是评估tau PET的新方法 将与早期Braak NFT分期(I-IV)和认知测试异常有关。我们将测试我们的 三个目标中的假设： 目的1：描述与早期NFT相关的tau PET测量结果。 我们将使用创新的tau PET分析方法在大样本中预测Braak NFT的早期阶段 布拉克早期NFT阶段的参与者。我们将使用一种新的tau PET定量评估方法来 改进以前的方法并测试tau PET，以便与Braak NFT早期阶段相关联。 目的2：描述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 在这方面与tau PET的相关性最好，而MRI或淀粉样蛋白PET和tau PET可能是最佳选择 治疗性生物标志物。我们将使用创新的tau PET成像分析方法来预测早期 认知测试在CU的大样本中发现。 目的3：确定不同的tau PET放射性示踪剂与早期神经病理性tau的关系 过度磷酸化和认知测试。 替代的tau PET放射性示踪剂可提高早期NFT病理和早期诊断的敏感性 康奈尔大学参与者的认知发现。我们将测试替代tau PET的区分能力 预测Braak NFT早期阶段的成像药物，并证明与认知测试的相关性。 这项工作将为tau PET信号的生物学意义提供严格的评估。它将有一个 通过识别具有早期tau沉积的子集来显著影响治疗算法，因此 与那些仅怀疑患有淀粉样变性的人相比，患上阿尔茨海默病的风险更高。在这里我们 提出一种多管齐下的方法来确定早期NFT的tau PET成像及其与认知功能的相关性 在认知能力正常的个体身上进行测试。这项提议具有变革性，考虑到 用新方法在体PET检测早期NFT的新概念 以及病理相关性，可为无症状预防试验提供洞察力。

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.