Effect of hippocampal tau pathology on CA1 function and memory processing in aging

项目摘要 在衰老和阿尔茨海默病（AD）中，tau蛋白的过度磷酸化形式优先 在海马体的CA 1子区内发展。海马体对正常的记忆功能至关重要， 因此CA 1内的tau沉积可能导致与年龄和疾病相关的记忆衰退。但 海马tau蛋白对CA 1功能障碍和记忆障碍的行为表达的作用还没有 以前被调查过。目前的研究旨在确定海马tau蛋白病理学对 使用多模式神经成像方法研究记忆过程中的CA 1激活和行为表现 认知正常的老年人。将用正电子发射断层扫描（PET）测量Tau病理学， 新型第二代tau-PET示踪剂[18F] MK-6240，能够可靠地定量 海马tau-PET信号。我们将使用功能性磁共振成像（fMRI）， 在记忆处理过程中评估CA 1激活。最近的研究表明，CA 1特异性 支持统计学习，这是一种记忆类型，在这种记忆中，经验之间的联系被学习。老年 因此，成年人将在fMRI采集期间执行统计学习任务，以获得CA 1激活的测量值 和统计学习行为表现。我们还将使用[18F] Florbetapir PET测量淀粉样蛋白-β 和CA 1体积与结构MRI，以探讨这些因素的其他贡献。在目标1中，我们 确定统计学习行为表现和老化中CA 1激活之间的关系， 比较高绩效和低绩效老年人之间的激活，并对不同年龄段的激活变化进行建模。 任务。在目标2中，我们将确定海马内的tau病理学如何与CA 1激活 和统计学习行为表现。最后，在目标3中，我们将测量功能连接性 在统计学习任务中海马子场和内嗅皮层之间的关系，并确定 tau病理学对这种连接性的影响。这项研究的发现将有助于阐明海马神经元在脑内的作用。 tau病理学对年龄和疾病相关记忆衰退的影响。此外，统计上的行为表现 学习任务可能成为早期海马tau病理学的敏感生物标志物。完成 拟议的研究将直接支持申请人的培训目标，包括（1）fMRI实验设计 和高级分析，（2）使用新示踪剂和高分辨率量化的额外PET培训，（3） 在记忆的认知神经科学的概念发展，和（4）技能的增长，以支持学术 事业加州大学欧文分校提供了一个创新的认知神经科学网络， 阿尔茨海默氏症研究人员拥有世界一流的神经成像设备。迈克尔·亚萨博士，赞助商，是一个 在研究与年龄相关的记忆衰退与多模态神经成像的领导者。的组合 拟议的研究和培训计划将为申请人提供全面的基础， 建立一个研究生涯，使用多模态神经成像研究衰老和疾病中的记忆障碍。

PROJECT SUMMARY In both aging and Alzheimer's disease (AD), hyperphosphorylated forms of the tau protein preferentially develop within the CA1 subfield of the hippocampus. The hippocampus is critical to normal memory function, and thus tau deposition within CA1 may lead to age- and disease-related memory decline. However, the contribution of hippocampal tau to CA1 dysfunction and behavioral expression of memory impairment has not previously been investigated. The current study aims to determine the effects of hippocampal tau pathology on CA1 activation and behavioral performance during memory using a multimodal neuroimaging approach in cognitively normal older adults. Tau pathology will be measured with positron emission tomography (PET) and the novel second-generation tau-PET tracer [18F] MK-6240, which enables reliable quantification of hippocampal tau-PET signal for the first time. We will use functional magnetic resonance imaging (fMRI) to assess CA1 activation during memory processing. Recent studies have proposed that CA1 specifically supports statistical learning, a type of memory in which regularities between experiences are learned. Older adults will thus perform a statistical learning task during fMRI acquisition to derive measures of CA1 activation and statistical learning behavioral performance. We will also measure amyloid-β with [18F] Florbetapir PET and CA1 volume with structural MRI to explore the additional contribution of these factors. In Aim 1, we will determine the relationship between statistical learning behavioral performance and CA1 activation in aging by comparing activation between high- and low-performing older adults, and modeling activation changes across the task. In Aim 2, we will identify how tau pathology within the hippocampus is related to both CA1 activation and statistical learning behavioral performance. Finally, in Aim 3, we will measure functional connectivity between hippocampal subfields and the entorhinal cortex during the statistical learning task, and determine the effects of tau pathology on this connectivity. Findings from this study will help elucidate the role of hippocampal tau pathology on age- and disease-related memory decline. Additionally, behavioral performance on statistical learning tasks may emerge as a sensitive biomarker for early hippocampal tau pathology. Completion of the proposed research will directly support the applicant's training goals, including (1) fMRI experimental design and advanced analysis, (2) additional PET training with new tracers and high-resolution quantification, (3) conceptual development in cognitive neuroscience of memory, and (4) growth of skills to support an academic career. The University of California, Irvine provides a network of innovative cognitive neuroscience and Alzheimer's researchers with world-class facilities for neuroimaging. Dr. Michael Yassa, the sponsor, is a leader in studying age-related memory decline with multimodal neuroimaging. The combination of the proposed research and training plan will provide the applicant with a comprehensive foundation on which to build a research career using multimodal neuroimaging to study memory impairment in aging and disease.