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.

项目摘要/摘要 除了事实或过去事件的明确记忆中的特征定义外，患者 阿尔茨海默氏病还表明，重复启动的损害不足，这是一种必不可少的形式 隐式内存。启动是指仅由于反复暴露而发生的性能提高 进行刺激，并在没有有意识地回忆刺激的情况下发生。在患者中保存启动 明确的内存定义由于对内侧临时叶（MTL）显式内存的损害而定义 系统（例如患者“ H.M.”），但以特定于模态的方式受损，并具有支持皮质的病变 处理这种方式。而AD病理在后期的阶段广泛传播到整个皮质 疾病进展，启动障碍出现在轻度认知障碍的患者中 AD），甚至在疾病的临床前阶段 - 早在病理传播之前就影响其他皮质 功能。近期，最近的工作表明，在影响皮层之前，AD病理开始于 脑干核，例如基因座（LC） - 大多数去甲肾上腺素（NE）的唯一来源 新皮层 - 控制唤醒和注意力，并提供稳态的“皮质泡沫”。它有 有人提出对该LC-NE系统的早期皮层损害在AD中损害这种滋补皮质 激活的程度无法在疾病的初始阶段支持启动，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。 快速自旋回声（FSE）T1加权MR成像技术的最新发展用于利用 NE NEMELANIN（NE代谢的产物）的自然对比特性已允许可靠的鉴定 lc in Vivo。 FSE MRI上该结构的神经苯胺对比强度在病理上一直是 被验证为LC细胞损失的量度，并已发现与AD中的认知功能有关。相似地， 在认知载荷和唾液α-淀粉酶（SAA）的测量下的瞳孔反应已是最近 用作NE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 假设通过管理感知性开放 - 封闭的图形启动任务以及概念单词式完成启动任务给参与者 参加多模式成像和LC的化学成像研究的老化MCI-AD光谱。 利用技术的最新进步来获取和分析扩散加权和静止 状态功能MRI，我将进一步测试LC与模态的结构和功能连通性是否存在 在概念和感知重复启动中实施的特定皮质区域与我们的 概念和感知任务。这项工作不仅会扩大我们对生物学基础的理解 隐性记忆，但也进一步描述了早期病理破坏的性质 阿尔茨海默氏病早期的隐式记忆过程不足。