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.

拟议的研究探讨了记忆编码与存储缺陷之间的机制， 在轻度认知障碍阶段的典型和非典型 AD 中，通过描述 淀粉样蛋白、tau 蛋白和皮质萎缩是这种损伤的潜在驱动因素，无论是横截面还是 纵向。该研究计划的长期目标是改善临床预测和 通过扩展我们对记忆编码损伤机制的了解来监测结果 整个 AD 谱系，重点是更好地描述 AD 的非典型表现（即， 后皮质萎缩； PCA 和语言减少变异型原发性进行性失语症； LVPPA）。提案 初步证据表明，与记忆存储相比，记忆编码依赖于 典型和非典型 AD 中内侧颞叶外的皮质网络，以及听觉语言 工作记忆缺陷会影响 PCA 中的编码和检索，但不会影响存储。候选人的 初步工作还表明，视觉空间和面部感知缺陷可能是至关重要的 记忆编码的贡献者，对 AD 相关的 tau 蛋白和视觉关联萎缩敏感 PCA 和 lvPPA 中的区域。我们将通过检查这些过程来建立这项初步工作 与记忆的不同阶段（编码与存储）以及 AD 的成像生物标志物的关系 病理。第一个目的是检查视觉或听觉语言处理障碍对 与 tau 蛋白和淀粉样蛋白病理学相关的联想记忆编码和存储 前驱期AD。第二个目的是研究皮质萎缩和调节的中介作用 一些因素，包括症状出现时的年龄，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 蛋白和淀粉样蛋白 PET 方面的专业知识 处理将进一步促进候选人利用多模式神经影像的长期目标 认知结果测量可预测整个 AD 表型谱的疾病进程。这 第三个目标是确定 tau 蛋白扩散对萎缩和进行性记忆衰退的纵向影响 整个前驱期 AD 的范围。为此目的进行的培训将把候选人的专业知识扩展到 纵向生物统计分析，包括形态测量分析以量化和控制效果 AD 人群前驱期灰质损失的研究。所有目标都将利用从小说中收集的数据 拟议项目中概述的联想记忆任务。所有其他临床和神经影像数据将 由主要导师 NIH 资助的研究提供。马萨诸塞州综合医院提供培训 医院和哈佛医学院社区允许获得相关资源和指导 完成拟议目标和候选人培训所需的具体技术和 职业目标。