Repetition Priming Deficits and Locus Coeruleus Dysfunction in Alzheimer's Disease

项目摘要/摘要 除了对事实或过去事件的外显记忆的特征缺陷外，患有 阿尔茨海默病还表现出一种被低估的重复启动障碍，重复启动是一种基本形式 内隐记忆。引爆指的是仅仅由于重复暴露而产生的性能提升 一种刺激，并且在没有意识到刺激的情况下发生。引爆剂被保存在患有 内侧颞叶(MTL)外显记忆局限性损害所致的外显记忆缺陷 系统(例如，患者“H.M.”)，但以特定方式受损，皮质支持损害 对该通道的处理。而阿尔茨海默病的病理在晚期广泛蔓延到整个大脑皮层 轻度认知障碍患者出现疾病进展、启动障碍(先兆 AD)，甚至在疾病的临床前阶段--在病理扩散到影响其他皮质之前很久 功能。或者，最近的研究表明，在影响皮质之前，AD病理开始于 脑干核团，如蓝斑(LC)--去甲肾上腺素(NE)的唯一来源 新大脑皮层调节唤醒和注意力，并提供稳定水平的“皮质紧张感”。它有 有人提出，AD时对LC-NE系统的早期皮质下损害会损害这种紧张性皮质 激活到不能在疾病的初始阶段支持启动的程度，但直到最近才被探测到 体内NE系统的完整性在技术上是具有挑战性的。 快速自旋回波(FSE)T1加权磁共振成像技术的最新进展 神经黑色素是去甲肾上腺素代谢的产物，其自然对比特性使可靠的鉴定成为可能。 在活体内的LC。FSE MRI上结构的神经黑色素对比强度已被病理证实 被证实是LC细胞丢失的一种衡量标准，并已被发现与AD的认知功能有关。同样， 认知负荷下的瞳孔反应和唾液α-淀粉酶(SAA)的测定最近被认为是 作为网元系统功能和完整性的代理。我建议利用这些新颖的技术来测试 假设AD的启动缺陷源于早期LC功能障碍，通过给予知觉开放- 封闭式图形启动任务和概念词干完成启动任务 正在参与LC的多模式成像和瞳孔测量研究的老年人-MCI-AD频谱。 利用技术的最新进展来获取和分析扩散加权和静息- 根据功能磁共振成像，我将进一步测试LC的结构和功能与通道的连接性- 概念和知觉重复启动所涉及的特定皮质区域分别与我们的 概念性和感知性任务。这项工作不仅将扩大我们对糖尿病的生物学基础的理解 内隐记忆，也进一步表征了这一早期病理中断的性质 早期阿尔茨海默病患者的内隐记忆过程被低估。

Project Summary/Abstract In addition to the characteristic deficits in explicit memory for facts or past events, patients with Alzheimer's disease also demonstrate an underappreciated impairment in repetition priming, an essential form of implicit memory. Priming refers to a performance enhancement that occurs simply due to repeated exposure to a stimulus, and occurs without conscious recollection of the stimulus. Priming is preserved in patients with explicit memory deficits due to circumscribed damage to the medial temporal lobe (MTL) explicit memory system (e.g. patient “H.M.”), but is impaired in a modality-specific manner with lesions of cortex supporting processing of that modality. While AD pathology spreads widely throughout the cortex in the later stages of disease progression, priming impairments appear in patients with Mild Cognitive Impairment (a precursor to AD) and even in the preclinical stages of disease - long before pathology has spread to affect other cortical functions. Alternatively, recent work suggests that before affecting the cortex, AD pathology begins in brainstem nuclei such as the locus coeruleus (LC) – the sole source of norepinephrine (NE) for the majority of the neocortex – regulating arousal and attention, and providing a steady-state level of “cortical tonus.” It has been proposed that early subcortical damage to this LC-NE system in AD compromises this tonic cortical activation to a degree that is unable to support priming in the initial stages of disease, but until recently probing the integrity of the NE system in vivo was technically challenging. The recent development of Fast Spin Echo (FSE) T1-weighted MR imaging techniques to utilize the natural contrast properties of neuromelanin, a product of NE metabolism, has allowed the reliable identification of the LC in vivo. The neuromelanin contrast intensity of the structure on FSE MRI has been pathologically validated as a measure of LC cell loss, and has been found to relate to cognitive function in AD. Similarly, pupillary response under cognitive load and measurement of salivary alpha-amylase (SAA) have recently been used as proxies of NE system function and integrity. I propose to utilize these novel techniques to test the hypothesis that the priming deficit in AD stems from early LC dysfunction by administering a perceptual open- closed figure priming task along with a conceptual word-stem completion priming task to participants on the aging-MCI-AD spectrum who are participating in a multi-modal imaging and pupillometry studies of the LC. Using recent advances in techniques for the acquisition and analysis of both diffusion-weighted and resting- state functional MRI, I will further test whether the structural and functional connectivity of the LC to modality- specific cortical regions implicated in conceptual and perceptual repetition priming are separately related to our conceptual and perceptual tasks. This work will not only expand our understanding of the biological basis of implicit memory, but also further characterize the nature of the early pathologic disruption of this underappreciated implicit memory process in early Alzheimer's disease.