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

Tau PET/CT 用于早期检测阿尔茨海默病病理学

基本信息

批准号：
10273696
负责人：
VAL JOHN LOWE
金额：
$ 39.65万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273696
关键词：
Aging Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Amyloid Autopsy Autoradiography Biological Clinic Clinical Cognitive Cohort Studies Cost Savings Data Data Correlations Databases Dementia Deposition Early Diagnosis Goals Immunohistochemistry Individual Knowledge Magnetic Resonance Imaging Measurement Methodology Methods Neurodegenerative Disorders Neurofibrillary Tangles Participant Pathologic Pathology Patients Pattern Pharmaceutical Preparations Phenotype Positron-Emission Tomography Prevention trial Research Research Personnel Sampling Scanning Selection for Treatments Senile Plaques Severities Severity of illness Signal Transduction Subjects Selections Symptoms Testing Tracer Validation Work abeta accumulation amyloid pathology cognitive testing cohort detection method high risk improved in vivo indexing innovation insight interest novel radiotracer tau Proteins therapeutic biomarker treatment trial uptake

项目摘要

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.

项目概要阿尔茨海默病（AD）是一种异质性神经退行性疾病，其特征是 β 淀粉样蛋白斑块和由 tau 蛋白组成的神经原纤维缠结 (NFT) 的异常积累。重要的初步数据表明，tau PET 定量分析可以区分 Braak III VS IV NFT 病理学然而，知识上存在差距，而且参与者数量有限。已通过早期 Braak NFT 阶段 (I-IV) 进行了评估，我们将利用 1779 年的数据库。过去 6 年接受过 tau PET 治疗的参与者为我们的假设是评估 tau PET 的新方法可以节省大量成本。将与早期 Braak NFT 阶段 (I-IV) 和认知测试异常相关。三个目标的假设：目标 1：表征与早期 NFT 相关的 tau PET 测量结果。我们将使用创新的 tau PET 分析方法来预测大样本中的早期 Braak NFT 阶段我们将使用一种新的定量 tau PET 评估方法来评估早期 Braak NFT 阶段的参与者。改进先前的方法并测试 tau PET 与早期 Braak NFT 阶段的关联。目标 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。在这方面，与 MRI 或淀粉样蛋白 PET 相比，与 tau PET 相关性最好，并且 tau PET 可能是最佳选择我们将使用创新的 tau PET 成像分析方法来进行早期预测。大样本 CU 的认知测试结果。目标 3：确定不同 tau PET 放射性示踪剂与早期神经病理性 tau 的关联过度磷酸化和认知测试。替代 tau PET 放射性示踪剂可能会提高早期 NFT 病理学和早期 NFT 病理学的灵敏度。我们将测试另一种 tau PET 的差异能力。成像药物可预测早期 Braak NFT 阶段并证明与认知测试的关联。这项工作将对 tau PET 信号的生物学意义进行严格的评估。通过识别具有早期 tau 沉积的子集，对治疗算法产生巨大影响，因此与仅患有淀粉样蛋白病理的患者相比，患 AD 痴呆的风险更高。提出一种多管齐下的方法来定义早期 NFT 的 tau PET 成像及其与认知的相关性考虑到认知未受损的个体的测试结果，该提议具有变革性。利用最先进的体内 PET 和新方法在早期阶段检测 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。