Dissociating the mechanisms of Tau PET and cortical atrophy underlying memory deficits in typical and atypical prodromal Alzheimer's disease

解析典型和非典型阿尔茨海默病前驱期记忆缺陷中 Tau PET 和皮质萎缩的机制

• 批准号: 10319376
• 负责人: Deepti Putcha
• 金额: $ 5.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319376
• 关键词: Age; Alzheimer' s disease pathology; Amyloid; Atrophic; Auditory; Biometry; Clinical; Cognitive; Communities; Data; Disease; Funding; General Hospitals; Goals; Impairment; Knowledge; Massachusetts; Medial; Mediating; Memory; Memory Loss; Memory impairment; Mentors; Mentorship; Monitor; Outcome; Outcome Measure; Pathology; Phenotype; Population; Positron-Emission Tomography; Primary Progressive Aphasia; Process; Research; Resources; Retrieval; Role; Short-Term Memory; Space Perception; Symptoms; Techniques; Temporal Lobe; Training; United States National Institutes of Health; Variant; Visual; Work; amyloid pathology; career; cerebral atrophy; face perception; gray matter; imaging biomarker; improved; medical schools; memory encoding; mild cognitive impairment; multimodality; neuroimaging; novel; prodromal Alzheimer' s disease; prognostic; programs; tau Proteins

The proposed research examines the mechanisms underlying memory encoding versus storage deficits, in typical and atypical AD at the stage of mild cognitive impairment, by delineating the specific roles of amyloid, tau, and cortical atrophy as potential drivers of this impairment both cross-sectionally and longitudinally. A long-term goal of the research program is to improve clinical prognostication and outcomes monitoring by expanding our knowledge of the mechanisms of memory encoding impairment across the AD spectrum, with a focus on better characterizing the atypical presentations of AD (i.e., posterior cortical atrophy; PCA, and logopenic variant primary progressive aphasia; lvPPA). The proposal builds upon preliminary evidence showing that memory encoding, in contrast to memory storage, relies on cortical networks outside the medial temporal lobes in typical and atypical AD, and that auditory-verbal working memory deficits impact encoding and retrieval, but not storage, in PCA. The candidate’s preliminary work also demonstrated that visual space and face perception deficits, which may be critical contributors to memory encoding, are sensitive to AD-related tau and atrophy in visual association regions in PCA and lvPPA. We will build on this preliminary work by examining these processes in relation to different stages of memory (encoding vs storage), and in relation to imaging biomarkers of AD pathology. The first aim is to examine the impact of visual or auditory-verbal processing impairment on associative memory encoding and storage, in relation to tau and amyloid pathology, across the spectrum of prodromal AD. The second aim is to investigate the mediating effect of cortical atrophy and moderating factors, including age at symptom onset, that may explain this relationship between tau pathology and memory. Short-term training goals for these aims include obtaining expertise in tau and amyloid PET processing that will further the candidate's long-term goal of utilizing multimodal neuroimaging with cognitive outcome measures to prognosticate disease course across the AD phenotypic spectrum. The third aim is to determine the longitudinal impact of tau spread on atrophy and progressive memory decline across the spectrum of prodromal AD. Training for this aim will extend the candidate's expertise into longitudinal biostatistical analysis, including morphometric analyses to quantify and control for the effect of gray matter loss in the prodromal AD population. All aims will utilize data collected from the novel associative memory tasks outlined in the proposed project. All other clinical and neuroimaging data will be provided by the primary mentor’s NIH-funded studies. Training available at Massachusetts General Hospital and the Harvard Medical School community allows access to resources and mentorship in the specific techniques necessary for the completion of the proposed aims and the candidate's training and career goals.

拟议的研究考试进行了编码和存储的基础机制定义， 在轻度认知障碍阶段的典型和非典型广告中，通过描述特定作用 淀粉样蛋白，tau和皮质萎缩，作为这种障碍的潜在驱动因素，无论 纵向。研究计划的长期目标是改善临床节目和 结果通过扩展我们对记忆机制编码障碍的机制的了解来监视 在整个AD频谱中，重点是更好地表征AD的非典型表现（即 后皮质萎缩； PCA和徽标变体主要进行性失语症； LVPPA）。提案 基于初步证据，表明记忆编码与内存存储相反 在典型和非典型广告中内侧临时爱之外的皮质网络上 工作记忆定义了PCA中的影响编码和检索，但不存储。候选人的 初步工作还表明，视觉空间和面部感知可以定义，这可能很关键 记忆编码的贡献者，对与广告相关的tau和视觉关联中的萎缩敏感 PCA和LVPPA的区域。我们将通过研究这些过程来建立这项初步工作 与不同的内存阶段（编码与存储）以及与AD的生物标志物有关的关系 病理。第一个目的是检查视觉或听觉语言处理障碍对 相关记忆编码和存储，与TAU和淀粉样病理学有关，跨光谱 前序广告。第二个目的是研究皮质萎缩和调节的介导作用 因素，包括症状发作的年龄，可以解释tau病理学与 记忆。这些目标的短期培训目标包括获得TAU和淀粉样蛋白宠物的专业知识 处理将进一步加强候选人使用多模式神经影像的长期目标 在整个AD表型谱系中，认知结果措施预测疾病病程。这 第三个目的是确定tau扩散对萎缩和渐进记忆下降的纵向影响 跨前驱AD范围。实现此目标的培训将把候选人的专业知识扩展到 纵向生物统计学分析，包括形态分析以量化和控制效果 前驱AD人群中的灰质损失。所有目标都将利用从小说中收集的数据 拟议项目中概述的关联内存任务。所有其他临床和神经影像学数据将是 由主要导师的NIH资助研究提供。马萨诸塞州一般培训 医院和哈佛医学院社区允许在 完成拟议的目标以及候选人的培训所必需的具体技术 职业目标。