Working Memory in Preclinical Alzheimer's Disease: a Neuropsychological and Neuroimaging Investigation

项目摘要/摘要 阿尔茨海默病(AD)是一种以潜伏性发病为特征的衰弱神经认知障碍 以及记忆力下降和其他认知领域的缺陷的进行性过程，如工作记忆。 最近，AD的研究已经集中在疾病的临床前检测和治疗上，就像以前一样 检测和干预可能使我们停止或延缓AD的发病。之前的研究已经确定 早期症状性AD的工作记忆困难，提示这一认知领域的变化可能 出现在间歇性记忆损害之前或同时发生。使用休息和基于任务的激活和 功能性磁共振成像(FMRI)上的连通性是表征大脑标志物的一种新方法 以及支持临床前阿尔茨海默病工作记忆表现的机制。神经心理测量 可能只揭示了临床前AD和AD患者之间的细微行为差异 健康成年人，但工作记忆相关网络中任务和静息fMRI的激活和连接可能 能够识别异常模式，区分有AD风险的个体。该网络有可能 工作记忆相关区域的破坏也可能缓和已观察到的阿尔茨海默病大脑之间的关系 病理学(皮质淀粉样β蛋白和内侧颞叶tau)和情景记忆表现 阿尔茨海默病临床前期。本项目将研究(1)与工作记忆相关的任务fMRI激活和 临床前ADAD的连接性；(2)工作记忆、情景记忆与AD脑的关系 临床前ADAD和散发性AD的病理学；(3)工作中静息状态脑网络的完整性 临床前散发性阿尔茨海默病和临床前阿尔茨海默病的记忆相关网络及其与AD脑病理的关系 常染色体显性遗传阿尔茨海默病(ADAD)。目标1将利用年轻的、认知能力未受损的突变 来自哥伦比亚ADAD家族的携带者和非携带者家庭成员；该突变的携带者 (早老素E280A)几乎肯定会在他们快40岁的时候因AD而患上痴呆症。目标2和目标3将 同样，招募哥伦比亚亲属携带者和非携带者，以及认知正常的有风险的老年人 基于AD病理分子标志物升高的散发性AD，请参阅正电子发射断层扫描 (宠物)在大脑中。通过这个项目，申请者将(1)获得成像和神经心理学方面的专业知识 临床前ADAD与临床前工作记忆神经相关研究方法 零星AD，(2)接受与认知和成像有关的实验设计方面的培训和指导 研究神经退行性疾病，以及(3)与有经验的人建立专业关系 研究人员和合作者，他们将为他提供过渡到职业独立的技能。

PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD) is a debilitating neurocognitive disorder that is characterized by an insidious onset and progressive course of memory decline and deficits in other cognitive domains, such as working memory. Recently, AD research has focused on the preclinical detection and treatment of the disease, as earlier detection and intervention may allow us to halt or slow AD pathogenesis. Previous research has identified working memory difficulties in early symptomatic AD, suggesting that changes in this cognitive domain may precede or co-occur with episodic memory impairment. Using resting and task-based activation and connectivity on functional magnetic resonance imaging (fMRI) is a novel way to characterize the brain markers and mechanisms that underpin working memory performance in preclinical AD. Neuropsychological measures of working memory may reveal only subtle behavioral differences between individuals with preclinical AD and healthy adults, but task and resting fMRI activation and connectivity in working-memory related networks may be able to identify aberrant patterns that distinguish individuals at risk for AD. It is possible that network disruption in working memory-related areas may also moderate the observed relation between AD brain pathology (cortical amyloid-beta and medial temporal lobe tau) and episodic memory performance in the preclinical stage of AD. This project will investigate (1) working memory-related task fMRI activation and connectivity in preclinical ADAD; (2) the relation between working memory, episodic memory, and AD brain pathology in preclinical ADAD and sporadic AD; and (3) resting-state brain network integrity in working memory-related networks and its relations to AD brain pathology in preclinical sporadic AD and preclinical autosomal dominant Alzheimer's disease (ADAD). Aim 1 will draw on young, cognitively unimpaired mutation carriers and non-carrier family members from the Colombian ADAD kindred; carriers of this mutation (presenilin1 E280A) are virtually guaranteed to develop dementia due to AD by their late 40s. Aims 2 and 3 will similarly recruit Colombian kindred carriers and non-carriers, as well as cognitively normal older adults at risk for sporadic AD based on elevated molecular markers of AD pathology see on positron emission tomography (PET) in the brain. Through this project the applicant will (1) gain expertise in imaging and neuropsychological methods related to investigating the neural correlates of working memory in preclinical ADAD and preclinical sporadic AD, (2) receive training and mentorship on experimental design pertaining to cognitive and imaging research on neurodegenerative diseases, and (3) establish professional relationships with experienced researchers and collaborators who will equip him with the skills to transition to career independence.