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

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以起病隐匿为特征的神经认知功能障碍 以及进行性记忆衰退和其他认知领域（如工作记忆）的缺陷。 最近，AD研究集中在疾病的临床前检测和治疗上， 检测和干预可能使我们停止或减缓AD发病机制。先前的研究发现， 早期症状性AD患者的工作记忆困难，表明这一认知领域的变化可能 发生在情节性记忆障碍之前或与情节性记忆障碍同时发生。使用休息和基于任务的激活， 功能磁共振成像（fMRI）上的连通性是表征大脑标记物的新方法 以及在临床前AD中支持工作记忆表现的机制。神经心理测验 工作记忆的变化可能只揭示了临床前AD患者和 但工作记忆相关网络中的任务和静息fMRI激活和连接可能 能够识别异常模式，区分个体的风险为AD。有可能网络 工作记忆相关区域的中断也可能缓和AD大脑之间观察到的关系， 病理学（皮质淀粉样蛋白β和内侧颞叶tau）和情景记忆表现， AD的临床前阶段。本研究将探讨（1）工作记忆相关的功能磁共振成像激活， 临床前ADAD的连接;（2）工作记忆，情景记忆和AD大脑之间的关系 临床前ADAD和散发性AD的病理学;和（3）工作中的静息态脑网络完整性 记忆相关网络及其与临床前散发性AD和临床前AD脑病理的关系 常染色体显性阿尔茨海默病（ADAD）。AIM 1将利用年轻的、认知未受损的突变 来自哥伦比亚ADAD家族的携带者和非携带者家族成员;该突变的携带者 （早老素1 E280 A）几乎肯定会在40多岁时发展为AD所致的痴呆。目标2和3将 同样招募哥伦比亚亲属携带者和非携带者，以及认知正常的老年人在风险 对于基于AD病理学分子标志物升高的散发性AD，参见正电子发射断层扫描 (PET)在大脑中。通过这个项目，申请人将（1）获得成像和神经心理学方面的专业知识 与研究临床前ADAD和临床前ADAD中工作记忆的神经相关性有关的方法 散发性AD，（2）接受有关认知和成像实验设计的培训和指导 研究神经退行性疾病，（3）与经验丰富的专业人士建立专业关系 研究人员和合作者谁将装备他的技能过渡到职业独立。

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.