Imaging Tauopathy in the Dominanatly Inherited Alzheimer Network (DIAN)

摘要/项目摘要 在这项提案中，我们探讨了从临床前到症状性阿尔茨海默病（AD）的转变， 将新的tau成像示踪剂（[18F]-AV-1451）并入显性免疫缺陷病毒的富含生物标志物的方案中。 遗传性阿尔茨海默病网络（DIAN）我们利用DIAN现有的基础设施，并与 Avid放射性药物在这个独特的队列中启动tau正电子发射断层扫描（PET）成像。 DIAN为AD由临床前阶段组成的假设提供了基本支持，其中 β-淀粉样蛋白（Aβ）斑块和tau神经元缠结（NFT）的积累逐渐导致神经元 功能障碍和认知障碍。然而，在我们对时间的理解方面仍然存在关键的差距， 在从临床前症状到临床症状的过渡期间，Aβ和tau之间发生的空间相互作用。 这项建议通过三个目标回答了这些基本问题。目的1研究时间动力学 tau沉积（使用AV-1451）与估计的症状发作年数（EYO）和现有 DIAN中的生物标志物（包括脑脊液、神经成像和认知表现）。Aim 2研究 tau沉积的空间（局部和分布）变化（使用AV-1451）。目标3研究了 体内tau沉积（使用AV-1451）与神经病理学之间的关系。常染色体特有的 显性AD（ADAD），DIAN参与者的年轻年龄消除了与潜在年龄相关的重叠 神经病理学或tau蛋白病（PART）。我们的总体假设是，从认知正常到 症状性AD可以通过神经成像生物标志物，特别是通过AV-1451 PET准确预测。 该提案的结果对于我们理解PET tau不仅是诊断指标， 同时也是一种治疗标志物，用于评估未来ADAD干预措施的临床疗效。

ABSTRACT/PROJECT SUMMARY In this proposal we explore the transition from preclinical to symptomatic Alzheimer disease (AD) by incorporating the novel tau imaging tracer ([18F]-AV-1451) within the biomarker-rich protocol of the Dominantly Inherited Alzheimer Network (DIAN). We leverage the existing infrastructure of DIAN and a collaboration with Avid Radiopharmaceuticals to initiate tau positron emission tomography (PET) imaging in this unique cohort. DIAN provides fundamental support to the hypothesis that AD consists of a preclinical stage in which accumulation of beta-amyloid (Aβ) plaques and tau neurofibrillary tangle (NFT) gradually lead to neuronal dysfunction and cognitive impairment. However, key gaps remain in our understanding of the temporal and spatial interactions that occur between Aβ and tau during the transition from preclinical to clinical symptoms. This proposal answers these fundamental questions through three aims. Aim 1 studies the temporal dynamics of tau deposition (using AV-1451) in relation to estimated years to symptom onset (EYO) and existing biomarkers in DIAN (including cerebrospinal fluid, neuroimaging, and cognitive performance). Aim 2 studies the spatial (both local and distributed) changes of tau deposition (using AV-1451). Aim 3 studies the relationship between in vivo tau deposition (using AV-1451) and neuropathology. Unique to autosomal dominant AD (ADAD), the young age of the DIAN participants eliminates overlap with potential age-related neuropathology or tauopathy (PART). Our overall hypothesis is that conversion from cognitively normal to symptomatic AD can be accurately predicted by neuroimaging biomarkers, in particular by AV-1451 PET. Results from this proposal are fundamental for our understanding of PET tau as not only a diagnostic indicator of disease but also a therapeutic marker to evaluate the clinical efficacy of future interventions in ADAD.