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: 10343772
• 负责人: Deepti Putcha
• 金额: $ 18.02万
• 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/10343772
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Anatomy; Atrophic; Auditory; Behavioral; Biological; Biometry; Clinical; Clinical Data; Cognitive; Cognitive deficits; Communities; Data; Data Analyses; Diagnosis; Disease; Dorsal; Episodic memory; Face; Foundations; Funding; General Hospitals; Goals; Impaired cognition; Impairment; Individual; Inferior; Investigation; Knowledge; Language; Link; Lobule; Location; MRI Scans; Magnetic Resonance Imaging; Massachusetts; Medial; Mediating; Memory; Memory Loss; Memory impairment; Mentors; Mentorship; Methods; Monitor; Multimodal Imaging; Occipital lobe; Outcome; Outcome Measure; Parents; Parietal; Pathology; Performance; Population; Positron-Emission Tomography; Primary Progressive Aphasia; Process; Research; Resources; Retrieval; Role; Short-Term Memory; Solid; Space Perception; Symptoms; Techniques; Temporal Lobe; Time; Training; United States National Institutes of Health; Variant; Visual; Work; age related; amyloid pathology; career; cerebral atrophy; cognitive testing; cohort; diagnostic criteria; disease phenotype; face perception; gray matter; imaging biomarker; improved; medical schools; memory encoding; mild cognitive impairment; multimodal neuroimaging; neuroimaging; novel; prodromal Alzheimer' s disease; prognostication; programs; semantic processing; skills; tau Proteins; tau aggregation

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 to 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的潜在机制， 通过描述淀粉样蛋白的具体作用，区分轻度认知障碍阶段的典型和非典型 AD， tau 蛋白和皮质萎缩是这种横向和纵向损伤的潜在驱动因素。一个 该研究计划的长期目标是通过以下方式改善临床预测和结果监测 扩展我们对 AD 谱系中记忆编码损伤机制的了解， 重点更好地描述 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； LVPPA）。该提案建立在初步证据的基础上 表明与记忆存储相比，记忆编码依赖于内侧皮质网络 典型和非典型 AD 中的颞叶，听觉语言工作记忆缺陷会影响编码 在 PCA 中，可以进行检索，但不能进行存储。候选人的初步工作还表明，视觉空间 和面部知觉缺陷，这可能是记忆编码的关键因素，对AD-敏感 PCA 和 lvPPA 中视觉关联区域的相关 tau 蛋白和萎缩。我们将在此基础上开展前期工作 通过检查这些过程与内存不同阶段（编码与存储）的关系，以及 AD 病理学的成像生物标志物。第一个目的是检查视觉或听觉语言的影响 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的处理损伤， 整个前驱期 AD 的范围。第二个目的是研究皮质萎缩的中介作用 调节因素，包括症状出现时的年龄，可以解释 tau 蛋白之间的这种关系 病理学和记忆。这些目标的短期培训目标包括获得 tau 蛋白和淀粉样蛋白的专业知识 PET 处理将进一步推动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。第三个 目的是确定 tau 蛋白扩散对萎缩和进行性记忆衰退的纵向影响 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领域 生物统计分析，包括形态测量分析，以量化和控制灰质损失的影响 在 AD 前驱人群中。所有目标都将利用从新颖的联想记忆任务中收集的数据 拟议项目中概述。所有其他临床和神经影像数据将由主要提供 导师的 NIH 资助的研究。马萨诸塞州总医院和哈佛医学院提供培训 学校社区允许获得必要的特定技术的资源和指导 完成拟议的目标以及候选人的培训和职业目标。