Longitudinal multicenter head-to-head harmonization of tau PET tracers

项目摘要/摘要： Tau正电子发射断层扫描(PET)示踪剂的发展为更好地 了解tau蓄积与阿尔茨海默病(AD)的发展相关，改善 AD的诊断准确性，并测试治疗干预对tau沉积的影响。我们的团队和 其他研究表明，[18F]Flortaucipir的分布模式与尸检报告的相似 并显示尽管脑白质中有偏离靶点的信号，tau随着时间的推移仍有显著的积累率 神经节和脉络丛。[18F]第二代tau示踪剂MK-6240对tau的亲和力提高了约6倍 比[18F]Flortaucipir更复杂，大脑偏离目标的信号可以忽略不计。然而，[18F]MK-6240具有非靶向摄取 在与整个皮质相邻的脑膜中，这可能会影响大脑区域内的信号。我们有 结果表明，[18F]MK-6240的摄取模式与尸检和[18F]Flortaucipir的研究相似。然而， [18F]MK-6240具有更高的动态范围，尽管在不同的队列中测量，但tau的年变化 使用[18F]MK-6240似乎比使用[18F]Flortaucipir测量的变化更大。到目前为止，超过 在美国进行tau PET研究的站点中，95%都在使用这些示踪剂之一。尽管这两种示踪剂都提供了 稳健的tau估计，它们之间在结合特征上的巨大差异可能会导致误导 对其结果的解释，排除了使用简单的转换方法合并其数据集的可能性。 因此，一项强大的纵向研究评估了[18F]Flortaucipir和[18F]MK-6240扫描 潜在的：(1)标准化他们的分析，允许合并数据集，(2)比较他们的比率 纵向沉积，以阐明它们在研究、试验和实践中的优势和局限性，以及(3) 制定供科学界使用的基准数据集，以开发PET量化方法 和和谐性。在这里，我们提出了一项多点纵向研究，在该研究中，620名受试者(40名青年对照， 280名认知正常的老年人，200名轻度认知障碍，100名阿尔茨海默病患者)将接受[18F]Flortaucipir 和[18F]MK6240在基线和18个月后进行扫描。在每个时间点，受试者也会有一个淀粉样蛋白- β(Aβ)正电子发射计算机断层扫描、磁共振成像、认知测试和抽血进行血浆tau分析。 方法将与ADNI和ADRC计划协调。在目标1中，我们将(1)将流程标准化 方法，(2)转换为普通量表，(3)比较与Aβ、萎缩和认知的联系，以及(4) 使用横断面数据比较两种tau示踪剂的Braak分期。在目标2中，我们将(1)确定最优 纵向分析的处理方法和(2)Tau示踪剂和Tau示踪剂纵向累积的比较 它与Aβ、萎缩和认知的变化有关。正如我们小组和其他人最近的结果 显示新的p-tau血浆分析确定了脑tau的病理，在探索性目标3中，我们将比较 血浆p-tau结果的横断面和纵向[18F]Flortaucipir和[18F]MK6240估计。

Project Summary/Abstract: The development of tau positron emission tomography (PET) tracers has yielded the opportunity to better understand the tau accumulation associated with the development of Alzheimer’s disease (AD), improve the diagnostic accuracy of AD, and test the effects of therapeutic interventions in tau deposition. Our group and others have shown that [18F]Flortaucipir has distribution patterns similar to those reported in postmortem studies and shows significant rates of tau accumulation over time despite brain off-target signal in white matter, basal ganglia, and choroid plexus. [18F]MK-6240, a second-generation tau tracer, has ~6-fold greater affinity for tau tangles than [18F]Flortaucipir and negligible brain off-target signal. However, [18F]MK-6240 has off-target uptake in the meninges adjacent to the entire cortex, which can compromise the signal within brain regions. We have shown that [18F]MK-6240 has similar patterns of uptake as postmortem and [18F]Flortaucipir studies. However, [18F]MK-6240 has a higher dynamic range and, although measured in different cohorts, the annual change in tau using [18F]MK-6240 appears to be greater than changes measured using [18F]Flortaucipir. To date, more than 95% of sites in the US performing tau PET studies are using one of these tracers. Although both tracers offer robust tau estimates, these large differences in binding characteristics between them can lead to misleading interpretations of their outcomes and preclude the merging of their datasets using simple conversion methods. Thus, a well-powered longitudinal study assessing head-to-head [18F]Flortaucipir and [18F]MK-6240 scans has the potential to: (1) standardize their analysis, allowing datasets to be combined, (2) compare their rates of longitudinal deposition to elucidate their advantages and limitations for research, trials, and practice, and (3) produce a benchmark dataset to be used by the scientific community to develop methods for PET quantification and harmonization. Here, we propose a multi-site longitudinal study in which 620 subjects (40 young controls, 280 cognitively unimpaired elderly, 200 mild cognitive impairment, 100 AD dementia) will receive [18F]Flortaucipir and [18F]MK6240 scans at baseline and 18 months later. At each time point, subjects will also have an amyloid- β (Aβ) PET scan, magnetic resonance imaging, cognitive tests, and a blood draw for plasma tau analyses. Methods will be harmonized with ADNI and the ADRC program. In Aim 1, we will (1) standardize processing methods, (2) convert to a common scale, (3) compare associations with Aβ, atrophy, and cognition, and (4) compare Braak staging between tau tracers using cross-sectional data. In Aim 2, we will (1) ascertain the optimal processing method for longitudinal analysis and (2) compare longitudinal accumulation between tau tracers and its associations with changes in Aβ, atrophy, and cognition. As recent results from our group and others have shown that the new p-tau plasma assays identify brain tau pathology, in exploratory Aim 3, we will compare cross-sectional and longitudinal [18F]Flortaucipir and [18F]MK6240 estimates with plasma p-tau outcomes.