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.

拟议的研究检查进行了编码和存储的基础记忆的基础机制，以定义 通过描述淀粉样蛋白的特定作用，在轻度认知障碍阶段的典型和非典型广告 tau和皮质萎缩是这种障碍的潜在驱动因素，无论是在横截面还是纵向上。 研究计划的长期目标是通过通过 扩展我们对整个广告频谱中编码损害的记忆机制的了解， 专注于更好地表征AD的非典型表现（即，皮质萎缩； PCA和PCA和 徽标变体主要渐进式失语症； LVPPA）。该提案以初步证据为基础 显示内存编码与内存存储相反，依赖于媒体外的皮质网络 在典型和非典型广告中的临时爱情，听觉语言的工作记忆定义了影响编码的影响 在PCA中检索但不存储。候选人的初步工作也证明了视觉空间 面部感知定义了可能是记忆编码的关键因素，对ad-敏感 PCA和LVPPA的视觉关联区域中相关的TAU和萎缩。我们将以这项初步工作为基础 通过检查这些过程与内存的不同阶段（编码与存储）以及有关 成像AD病理学的生物标志物。第一个目的是检查视觉或听觉语言的影响 处理与tau和淀粉样病理学有关的关联记忆编码和存储的处理障碍， 跨前驱AD范围。第二个目的是研究皮质萎缩的介导作用 和调节因素，包括症状发作的年龄，可以解释tau之间的这种关系 病理和记忆。这些目标的短期培训目标包括获得TAU和淀粉样蛋白的专业知识 宠物加工将进一步使用候选人的长期目标，即利用多模式神经影像 整个AD表型谱系的预后疾病病程的认知结果指标。第三 目的是确定tau蔓延对萎缩和渐进记忆力下降的纵向影响 前驱AD的光谱。实现此目标的培训将把候选人的专业知识扩展到纵向 生物统计分析，包括形态计量分析，以量化和控制灰质损失的影响 在前驱广告中。所有目标都将利用从新颖的关联内存任务中收集的数据 在拟议的项目中概述了。所有其他临床和神经影像学数据将由初级提供 Menor的NIH资助研究。马萨诸塞州综合医院和哈佛医疗的培训 学校社区允许在必要的特定技术中访问资源和指导 拟议的目标以及候选人的培训和职业目标的完成。