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

这项拟议的研究考察了内存编码与存储缺陷之间的潜在机制， 在典型和非典型阿尔茨海默病轻度认知障碍阶段，通过勾画 淀粉样蛋白、tau蛋白和皮质萎缩是这种损害的潜在驱动因素 纵向的。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知识来监测结果 跨AD频谱，重点是更好地表征AD的非典型呈现(即， 后部皮质萎缩；前列腺癌和对数变异的原发进行性失语；lvPPA)。这项建议 初步证据表明，与记忆存储相比，记忆编码依赖于 典型和非典型阿尔茨海默病患者内侧颞叶外皮质网络的研究 工作记忆缺陷会影响PCA的编码和提取，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，这可能是关键 记忆编码的贡献者，对AD相关的tau和视觉联想萎缩敏感 PCA和LvPPA中的区域。我们将在这一初步工作的基础上，在 与记忆的不同阶段(编码与存储)的关系，以及与AD的成像生物标志物的关系 病理学。第一个目标是检查视觉或听觉-语言加工障碍对 关联记忆编码和存储，与tau和淀粉样蛋白病理有关，跨光谱 前驱症状的AD。第二个目的是研究大脑皮层萎缩和调节的调节作用 因素，包括症状开始时的年龄，可能解释tau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PET的专业知识。 这将促进候选人的长期目标，即利用多模式神经成像 认知结果测量以预测整个AD表型谱的病程。这个 第三个目的是确定tau扩散对萎缩和进行性记忆衰退的纵向影响 在前驱AD的谱系中。针对这一目标的培训将把应聘者的专业知识扩展到 纵向生物统计分析，包括形态计量分析，以量化和控制效果 阿尔茨海默病前驱人群中灰质丢失的可能性。所有AIMS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 由主要导师的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访问资源和指导 完成拟议目标和候选人培训所需的具体技术，以及 职业目标。

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.