Associative Memory and Transitive Inference in Aging and Preclinical AD

描述(申请人提供)：间歇性记忆减退通常在“正常”衰老过程中被报道，但经常引起人们对早期阿尔茨海默病(AD)的关注。在AD的病理生理过程中早期了解记忆下降的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方法的有效性至关重要。功能神经成像已经显示出年轻人、正常老年人和阿尔茨海默病患者在情景记忆任务，特别是联想记忆任务上的显著差异。最近，我的赞助商小组发现了临床正常的阿尔茨海默病老年患者早期功能和行为改变的证据，表明这些人可能处于AD的临床前阶段。临床前阿尔茨海默病患者记忆障碍的神经基础仍有待更充分的阐明，尤其是淀粉样蛋白对海马区功能的影响。该项目的总体目标是开发一种新的fMRI范式，该范式结合了对面孔名称和面孔职业对的联想和传递性记忆来探测海马区的功能，这可能有助于更好地消除临床前阿尔茨海默病早期“正常”衰老过程的歧义。这种结合将更好地描述情节记忆的神经基础。这项实验设计利用了两个关键概念：(1)面孔-名字对的联想记忆对衰老效应敏感，而面孔占用缺陷可能表明淀粉样蛋白相关的功能障碍；(2)传递性记忆障碍将是AD相关病理的更特异的标志，受年龄的影响较小。第一个具体目标是验证神经成像任务是否表征了年轻人的联想记忆和传递性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淀粉样蛋白成像中没有淀粉样蛋白沉积的证据，来评估联想记忆和/或传递性记忆的情景记忆的神经基础是否存在与衰老有关的“正常”变化。第三个具体目的是通过比较有和没有任何淀粉样蛋白沉积的个体来评估联想记忆和/或传递性记忆的情景记忆的神经基础是否存在淀粉样蛋白依赖性的变化。这项研究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AD临床前阶段的记忆功能的变化。

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.