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

海马 tau 蛋白病理学对衰老过程中 CA1 功能和记忆加工的影响

• 批准号: 10516028
• 负责人: Jenna Nicole Adams
• 金额: $ 6.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516028
• 关键词: Academic support; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Anatomy; Basal Ganglia; Behavioral; Binding; California; Clinical; Cognitive; Data; Deposition; Development; Disease; Elderly; Experimental Designs; Failure; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Goals; Growth; Hippocampus (Brain); Impairment; Lead; Lesion; Magnetic Resonance Imaging; Measures; Medial; Memory; Memory Loss; Memory impairment; Modeling; Neocortex; Nerve Degeneration; Output; Pathologic; Pathology; Pathway interactions; Pattern; Performance; Positron-Emission Tomography; Predisposition; Research; Research Personnel; Research Training; Resolution; Role; Sampling; Scientist; Signal Transduction; Specificity; Stimulus; Structure of choroid plexus; Symptoms; System; Temporal Lobe; Time; Tracer; Training; Universities; age related; artificial neural network; association cortex; beta amyloid pathology; career; cognitive neuroscience; dentate gyrus; early detection biomarkers; entorhinal cortex; experience; innovation; insight; memory process; multimodal neuroimaging; neuroimaging; neuropathology; normal aging; novel; pre-clinical; prevent; response; skills; statistical learning; tau Proteins; tau aggregation; young adult

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.

项目摘要 在衰老和阿尔茨海默氏病（AD）中，tau蛋白的高磷酸化形式优选 在海马的CA1子场内发展。海马对于正常内存功能至关重要， 因此，CA1内的TAU沉积可能会导致与年龄和疾病相关的记忆下降。但是， 海马TAU对CA1功能障碍和记忆障碍的行为表达的贡献尚未 先前已经研究了。当前的研究旨在确定海马tau病理对 CA1在记忆过程中使用多模式神经影像学方法的CA1激活和行为表现 认知正常的老年人。 TAU病理将通过正电子发射断层扫描（PET）和 新型的第二代tau-pet示踪剂[18F] MK-6240，可靠地量化 海马tau-pet首次信号。我们将使用功能性磁共振成像（fMRI） 评估记忆处理过程中的CA1激活。最近的研究提出了CA1专门 支持统计学习，这是一种学习经验之间规律性的记忆。年龄较大 因此，成人将在fMRI获取期间执行统计学习任务，以得出CA1激活的测量 和统计学习行为表现。我们还将用[18F] Florbetapir PET测量淀粉样蛋白-β 和带有结构性MRI的CA1体积，以探索这些因素的其他贡献。在AIM 1中，我们将 确定通过 比较高性能和低表现的老年人之间的激活，并在整个 任务。在AIM 2中，我们将确定海马内的TAU病理与两种CA1激活有关 和统计学习行为表现。最后，在AIM 3中，我们将衡量功能连接性 在统计学习任务期间，海马子场和内嗅皮层之间 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的作用 与年龄和疾病有关的记忆下降的TAU病理学。另外，统计上的行为表现 学习任务可能会成为早期海马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）使用新的示踪剂和高分辨率定量的额外宠物培训，（3） 记忆认知神经科学的概念发展，以及（4）支持学术的技能的增长 职业。加州大学尔湾分校提供了创新的认知神经科学网络和 阿尔茨海默氏症的研究人员拥有世界一流的神经影像学设施。赞助商Michael Yassa博士是 通过多模式神经影像学研究与年龄相关的记忆下降的领导者。结合 拟议的研究和培训计划将为申请人提供全面的基础 使用多模式神经影像学来研究衰老和疾病的记忆障碍。