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， 典型和非典型AD在轻度认知损害阶段，通过描绘淀粉样蛋白的特定作用， Tau和皮质萎缩是这种损伤的潜在驱动因素，无论是横断面还是纵向。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 通过AD频谱扩展我们对记忆编码损伤机制的知识， 侧重于更好地描述AD的非典型表现(即，皮质后部萎缩；Pca和 对数型变异型原发进行性失语(LvPPA)。这项建议建立在初步证据的基础上。 研究表明，与记忆存储相比，记忆编码依赖于内侧大脑皮质网络。 典型和非典型AD患者的颞叶，以及听觉-语言工作记忆缺陷对编码的影响 和检索，但不是存储，在PCA中。候选人的初步工作也证明了视觉空间 面孔感知缺陷可能是记忆编码的关键因素，对AD- Pca和LvPPA视觉关联区的相关tau和萎缩。我们将在这项前期工作的基础上再接再厉 通过检查这些过程与记忆的不同阶段(编码与存储)的关系，以及与 涉及AD病理的成像生物标记物。第一个目标是检查视觉或听觉语言的影响 与tau和淀粉样蛋白病理相关的联想记忆编码和存储处理障碍， 在前驱AD的谱系中。第二个目的是研究皮质萎缩的调节作用。 缓和因素，包括症状出现时的年龄，可能解释tau之间的这种关系 病理学和记忆力。这些目标的短期培训目标包括获得tau和淀粉样蛋白方面的专业知识。 宠物处理，将促进候选人的长期目标，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。第三 目的是确定tau扩散对脑萎缩和进行性记忆衰退的纵向影响。 前驱AD的谱图。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，以量化和控制灰质丢失的影响 在阿尔茨海默病的前驱人群中。所有AIMS将利用从新的联想记忆任务中收集的数据 在拟议的项目中概述。所有其他临床和神经影像数据将由初级 门托国家卫生研究院资助的研究。在马萨诸塞州综合医院和哈佛医学院提供培训 学校社区允许访问资源并在必要的特定技术方面进行指导 完成拟议的目标以及候选人的培训和职业目标。

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 to the completion of the proposed aims and the candidate's training and career goals.