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

阿尔茨海默病中的重复启动缺陷和蓝斑功能障碍

• 批准号: 10480896
• 负责人: Denis Smirnov
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2023-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480896
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Arousal; Attention; Basal Ganglia; Biological; Brain; Brain Stem; Cell Nucleus; Cells; Characteristics; Clinical; Cognitive; Conscious; Detection; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dissociation; Entropy; Event; Exposure to; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Hippocampus (Brain); Huntington Disease; Image; Imaging Techniques; Impairment; Inferior; Learning Skill; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Medial; Mediating; Memory; Memory impairment; Metabolism; Methods; Modality; Modification; Motor; Motor Cortex; Multimodal Imaging; Nature; Neocortex; Neurosciences Research; Norepinephrine; Optics; Parkinson Disease; Participant; Pathologic; Pathology; Pathway interactions; Patients; Performance; Pontine structure; Population; Property; Proxy; Rest; Salivary; Semantics; Signal Transduction; Source; Stimulus; Structure; System; Techniques; Temporal Lobe; Testing; Unconscious State; Visual; Visual Cortex; Visualization; Work; alpha-amylase; base; cognitive function; cognitive load; cognitive skill; diffusion weighted; experience; functional MRI scan; geometric methodologies; imaging study; implicit memory; in vivo; locus ceruleus structure; memory process; mild cognitive impairment; multidisciplinary; neocortical; neuroimaging; neuromelanin; neuron loss; neuroregulation; norepinephrine system; novel; pre-clinical; preservation; relating to nervous system; response; skills; stem; tau Proteins; theories; tractography

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.

项目总结/摘要 除了对事实或过去事件的外显记忆的特征性缺陷外， 阿尔茨海默氏症还表现出重复启动的一种重要形式， 内隐记忆启动是指仅仅由于重复暴露而发生的性能增强 对刺激，并发生没有有意识的回忆的刺激。预充在以下患者中得以保留 内颞叶（MTL）外显记忆受损导致的外显记忆缺陷 系统（例如患者“H.M.”），但以特定方式受损， 处理这种模式。虽然AD病理学在AD的后期阶段广泛地遍布整个皮质， 疾病进展时，启动障碍出现在轻度认知障碍患者中（ AD），甚至在疾病的临床前阶段-早在病理学已经扩散到影响其他皮质 功能协调发展的或者，最近的研究表明，在影响皮层之前，AD病理学开始于大脑皮层。 脑干核，如蓝斑（LC）-大多数人的去甲肾上腺素（NE）的唯一来源。 新皮层--调节唤醒和注意力，并提供稳定的“皮层紧张”水平。它有 有人提出，AD患者LC-NE系统的早期皮质下损伤损害了这种紧张性皮质 激活到某种程度，无法支持在疾病的初始阶段启动，但直到最近探测 NE系统在体内的完整性在技术上具有挑战性。 快速自旋回波（FSE）T1加权磁共振成像技术的最新发展， NE代谢产物神经黑色素的天然对比特性允许可靠的鉴定 的LC在体内。FSE MRI上结构的神经黑色素对比强度已被病理学证实 被验证为LC细胞损失的量度，并且已经发现与AD中的认知功能相关。同样地， 认知负荷下的瞳孔反应和唾液α-淀粉酶（SAA）的测量最近被 作为网元系统功能和完整性的代理。我建议利用这些新技术来测试 假设启动赤字在AD源于早期LC功能障碍，通过管理知觉开放， 向参与者提供封闭图形启动任务，沿着概念词干完成启动任务 正在参与LC的多模态成像和瞳孔测量研究的老年-MCI-AD谱。 利用最新的扩散加权和静息扩散加权的采集和分析技术， 状态功能MRI，我将进一步测试是否LC的结构和功能连接到模态- 涉及概念和知觉重复启动的特定皮层区域分别与我们的 概念和知觉任务。这项工作不仅将扩大我们对生物学基础的理解， 内隐记忆，而且还进一步表征了这种早期病理性破坏的性质。 阿尔茨海默病早期内隐记忆过程的低估