Associative Memory and Transitive Inference in Aging and Preclinical AD

描述（由申请人提供）：情景记忆衰退通常在“正常”衰老过程中报告，但经常引起对早期阿尔茨海默病（AD）的关注。在阿尔茨海默病的病理生理过程中，了解记忆衰退的早期神经基础对于促进早期诊断、跟踪疾病进展和评估潜在治疗的疗效至关重要。功能性神经影像学已经显示，年轻人、正常老年人和阿尔茨海默氏症患者在情景记忆任务，特别是联想记忆方面存在显著差异。最近，我的赞助人的小组发现了阿尔茨海默病临床正常老年人的早期功能和行为改变的证据（例如淀粉样蛋白沉积），这表明这些人可能处于阿尔茨海默病的临床前阶段。临床前AD记忆功能障碍的神经基础仍有待更充分的阐明，特别是淀粉样蛋白-¿对海马功能的影响。本项目的总体目标是开发一种新的fMRI范式，结合面孔-名称和面孔-职业对的联想和传递记忆来探测海马功能，这可能有助于更好地消除临床前AD早期阶段“正常”衰老过程的歧义。这种结合将更好地表征情景记忆的神经基础。该实验设计利用了两个关键思想：(1)面孔-名字对的联想记忆对衰老效应敏感，而面孔-职业缺陷可能表明淀粉样蛋白相关功能障碍；(2)传递记忆的损害将是AD相关病理的一个更具体的标志，并且受年龄的影响较小。第一个具体目标是验证神经成像任务表征了年轻人联想记忆和传递记忆之间的神经差异。第二个具体目的是通过比较年轻人和老年人在PiB-PET淀粉样蛋白成像上没有淀粉样蛋白沉积的证据，评估在情景记忆和/或传递记忆的神经基础上是否存在“正常”的衰老相关变化。第三个具体目标是通过比较有和没有淀粉样蛋白沉积的个体，评估在情景记忆、联想记忆和/或传递记忆的神经基础中是否存在淀粉样蛋白依赖的变化。该项目将有助于我们进一步了解“正常”衰老过程中情景记忆的神经机制，以及可能代表阿尔茨海默病临床前阶段的记忆功能改变。

DESCRIPTION (provided by applicant): Episodic memory decline is commonly reported in the course of "normal" aging but often raises concern about incipient Alzheimer's disease (AD). Understanding the neural basis for memory decline early in the AD pathophysiological process is critical to facilitate earlier diagnosis, track disease progression and to evaluate the efficacyof potential therapies. Functional neuroimaging has already shown significant differences between young adults, normal elderly and patients with AD dementia in episodic memory tasks, particularly associative memory. More recently, my sponsor's group has found evidence of early functional and behavioral alterations in clinically normal older individuals with Alzheimer's pathology (e.g. amyloid-¿ deposition) that suggest these individuals may be in the preclinical stages of AD. The neural underpinnings of memory dysfunction in preclinical AD remain to be more fully elucidated, particularly the influence of amyloid-¿ on hippocampal function. The overall objective of this project to develop a novel fMRI paradigm that combines associative and transitive memory of face-name and face-occupation pairs to probe hippocampal function, and that may serve to better disambiguate the process of "normal" aging from the early stages of preclinical AD. This combination will better characterize the neural basis of episodic memory. This experimental design leverages two key ideas: (1) associative memory for face-name pairs is sensitive to aging effects, while face-occupation deficits may be indicative of amyloid-¿ related dysfunction; and (2) impairment of transitive memory will be a more specific marker of AD related pathology, and will be less affected by age. The first specific aim is to validate that the neuroimaging task characterizes the neural differences between associative and transitive memory in young adults. The second specific aim assesses whether there are "normal" aging-related changes in the neural basis of episodic memory for associative memory and/or transitive memory by comparing young adults to older adults without evidence of amyloid-¿ deposition on PiB-PET amyloid imaging. The third specific aim is to assess whether there are amyloid-dependent changes in the neural basis of episodic memory for associative memory and/or transitive memory by comparing individuals with and without any amyloid-¿ deposition. The proposed project should serve to further our understanding of the neural mechanisms underlying episodic memory in the process of "normal" aging and the alterations in memory function that may represent preclinical stages of AD.