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: 9909017
• 负责人: Denis Smirnov
• 金额: $ 3.75万
• 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/9909017
• 关键词: Affect; Aging; Alzheimer' s Disease; 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; Imagery; Imaging Techniques; Impairment; Inferior; Learning Skill; Lesion; MRI Scans; 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; Work; alpha-amylase; base; cognitive function; cognitive load; cognitive skill; diffusion weighted; experience; 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.

项目概要/摘要 除了对事实或过去事件的外显记忆的特征性缺陷外，患者 阿尔茨海默病还表现出重复启动（一种重要形式）的损伤，这一点被低估了 内隐记忆的启动是指仅仅由于重复暴露而发生的性能增强。 的刺激，并且在患者没有有意识地回忆刺激的情况下发生。 由于内侧颞叶（MTL）外显记忆受到限制性损伤而导致外显记忆缺陷 系统（例如患者“H.M.”），但由于皮质支持损伤而以特定方式受损 AD 病理学在后期的整个皮质中广泛传播。 随着疾病进展，轻度认知障碍（认知障碍的先兆）患者出现启动障碍 AD），甚至在疾病的临床前阶段 - 早在病理学扩散到影响其他皮质之前 另外，最近的研究表明，AD 病理学在影响皮质之前就开始了。 脑干核，例如蓝斑 (LC)——大多数人去甲肾上腺素 (NE) 的唯一来源 新皮质——调节唤醒和注意力，并提供稳态水平的“皮质张力”。 有人提出，AD 中这种 LC-NE 系统的早期皮质下损伤会损害这种强直皮质 激活程度无法支持疾病初始阶段的启动，但直到最近才进行探索 体内 NE 系统的完整性在技术上具有挑战性。 最近开发的快速自旋回波 (FSE) T1 加权 MR 成像技术利用 神经黑色素（NE 代谢的产物）的天然对比特性使得可靠的识别成为可能 FSE MRI 上的 LC 结构的神经黑色素对比强度是病理性的。 经验证可作为 LC 细胞损失的衡量标准，并且已被发现与 AD 中的认知功能类似地相关， 最近研究了认知负荷下的瞳孔反应和唾液α-淀粉酶（SAA）的测量 我建议利用这些新技术来测试 NE 系统功能和完整性。 假设 AD 中的启动缺陷源于早期 LC 功能障碍，通过给予知觉开放 封闭图形启动任务以及概念词干完成启动任务给参与者 参与 LC 多模态成像和瞳孔测量研究的老化-MCI-AD 谱。 利用最新的技术进展来采集和分析扩散加权和静息信号 状态功能 MRI，我将进一步测试 LC 与模态的结构和功能连接是否- 与概念和知觉重复启动有关的特定皮层区域分别与我们的 这项工作不仅会扩展我们对生物学基础的理解。 内隐记忆，还进一步表征了这种早期病理性破坏的本质 早期阿尔茨海默病中的内隐记忆过程未被充分认识。