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: 10577894
• 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/10577894
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Anatomy; Atrophic; Auditory; Behavioral; Biometry; Clinical; Clinical Data; Cognitive; Cognitive deficits; Communities; Data; Data Analyses; Diagnosis; Disease; Dissociation; 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; disease prognosis; 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; verbal

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.

这项拟议中的研究探讨了记忆编码与存储缺陷的潜在机制， 在轻度认知障碍阶段的典型和非典型AD，通过描述淀粉样蛋白的特定作用， tau蛋白和皮质萎缩是横截面和纵向损伤的潜在驱动因素。一 该研究项目的长期目标是通过以下方式改善临床诊断和结局监测 扩展了我们对整个AD谱的记忆编码损伤机制的知识， 专注于更好地表征AD的非典型表现（即，后皮质萎缩; PCA，和 逻辑缺失变异型原发性进行性失语症。这项建议是以初步证据为基础的 这表明，与记忆存储相反，记忆编码依赖于内侧皮层以外的皮层网络， 典型和非典型AD患者颞叶及言语工作记忆缺陷对编码的影响 和检索，但不是存储，在PCA中。候选人的前期工作也证明了视觉空间 和面部知觉缺陷，这可能是关键的贡献者记忆编码，是敏感的AD- PCA和lvPPA中视觉关联区域的相关tau和萎缩。我们将在这一初步工作的基础上 通过研究这些过程与记忆的不同阶段（编码与存储）的关系，以及与 AD病理学的成像生物标志物。第一个目的是检查视觉或语言的影响 处理与tau和淀粉样蛋白病理学相关的关联记忆编码和存储的损伤， 在前驱AD的范围内。第二个目的是研究皮层萎缩的中介作用 和调节因素，包括症状发作时的年龄，这可能解释tau蛋白与 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处理将进一步促进候选人利用多模态神经成像的长期目标， 认知结果测量，以明确整个AD表型谱的病程。第三 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AD的症状谱。为此目的的培训将使候选人的专业知识扩展到纵向 生物统计学分析，包括定量和控制灰质损失影响的形态学分析 在前驱AD人群中。所有目标将利用从新的联想记忆任务中收集的数据 在拟议的项目中。所有其他临床和神经影像学数据将由主要研究人员提供。 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具体技术方面的资源和指导， 完成拟议的目标和候选人的培训和职业目标。