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

项目总结 在衰老和阿尔茨海默病(AD)中，过度磷酸化形式的tau蛋白优先 在海马区的CA1亚区内发育。海马体对正常的记忆功能至关重要， 因此，tau在CA1中的沉积可能会导致与年龄和疾病相关的记忆力下降。然而， 海马tau在CA1功能障碍和记忆障碍的行为表达中的作用 此前曾接受过调查。本研究旨在确定海马tau区病理改变对大鼠脑缺血再灌注损伤的影响。 用多模式神经成像方法研究记忆过程中CA1的激活和行为表现 认知正常的老年人。Tau病理将用正电子发射断层扫描(PET)和 新型第二代tau-PET示踪剂[18F]MK-6240，能够可靠地定量 首次在海马区发出tau-PET信号。我们将使用功能磁共振成像(FMRI)来 评估记忆处理过程中的CA1激活。最近的研究表明，CA1特异性地 支持统计学习，这是一种记忆，在这种记忆中，经验之间的规律被学习。更老的 因此，成年人将在fMRI获取过程中执行统计学习任务，以得出CA1激活的测量 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 并将CA1体积与结构MRI相结合，探讨这些因素的附加贡献。在目标1中，我们将 通过以下方法确定统计学习行为表现与衰老过程中CA1激活的关系 比较高表现和低表现老年人之间的激活，并模拟激活的变化 这项任务。在目标2中，我们将确定海马区的tau病理如何与CA1的激活有关 和统计学习行为表现。最后，在目标3中，我们将测量功能连通性 在统计学习任务期间，在海马亚区和内嗅皮层之间，并确定 Tau病理对这种连通性的影响。这项研究的发现将有助于阐明海马体的作用 Tau病理上的增龄和疾病相关的记忆力下降。此外，统计上的行为表现 学习任务可能成为早期海马tau病理的敏感生物标志物。已完成的 建议的研究将直接支持申请者的培训目标，包括(1)功能磁共振实验设计 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) 记忆的认知神经科学中的概念发展，以及(4)支持学术的技能的增长 职业生涯。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级的神经成像设备。发起人迈克尔·亚萨博士是一名 在用多模式神经成像研究与年龄相关的记忆衰退方面处于领先地位。这两种技术的结合 拟议的研究和培训计划将为申请者提供一个全面的基础，以便 建立一个研究事业，使用多模式神经成像来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.