How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

老年人的 LC 完整性如何调节知觉和记忆过程

• 批准号: 10213521
• 负责人: XIAOPING P HU
• 金额: $ 196.67万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213521
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amygdaloid structure; Arousal; Attention; Auditory; Auditory area; Behavior; Behavior assessment; Behavioral; Biological Markers; Brain region; Cerebellum; Cognition; Computer Analysis; Data Set; Detection; Diagnosis; Disease; Elderly; Evaluation; Exertion; Goals; Hand; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; Individual Differences; Intervention; Learning; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Methods; Mission; Modality; Mydriasis; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Neocortex; Neurodegenerative Disorders; Neurons; Norepinephrine; Parkinson Disease; Pathology; Pattern; Perception; Performance; Play; Pontine structure; Population; Psychophysics; Public Health; Research; Resolution; Role; Series; Source; Stimulus; Stress; Structure; Task Performances; Tegmentum Mesencephali; Testing; Thalamic structure; United States National Institutes of Health; Vision; Visual; Visual Cortex; Visual Perception; age related; base; candidate marker; cognitive ability; cognitive function; cognitive performance; cognitive process; design; grasp; in vivo; interest; locus ceruleus structure; memory process; neuroimaging; neuromelanin; neuron loss; normal aging; novel therapeutics; preservation; stem; stressor; tractography; visual memory

Project Summary The overarching goal of the present proposal is to understand how individual differences in the structure and function of Locus Coeruleus (LC) moderate perception and memory in an older adult population. There is substantial evidence that the LC circuit plays a central role in cognitive processes and neuronal loss in LC is known to occur in neurodegenerative disorders such as ADRD and PD. Integrity of LC neurons is hypothesized to mediate the preservation of cognitive abilities during normal aging as well. To date, however, there exists a dearth of research that either characterizes differential effects of LC integrity or details relationships between LC integrity and cognitive function in older adult humans. More generally, the link between LC activity and cognitive processes has not been well characterized in humans. Historical reasons for this is that the LC has been difficult to image due to its small size and thus most human research makes inferences about LC function by using pupil dilation as a surrogate measure. To overcome existing limitations in the field, we propose a series of detailed psychophysical and MRI-based studies in older adults aimed to characterize how LC structure and function moderates behavior and in turn how this is mediated by activity in intermediate brain regions known to be involved in perceptual and memory processes. We further propose computational approaches to characterize individual differences in how LC circuit integrity relates to different patterns of cognitive performance across tasks, and advanced neuroimaging methods to localize and image the LC, which have been pioneered by our group. Using MRI-based methods, we will examine LC integrity using high-resolution neuromelanin-sensitive structural imaging, tractography and functional connectivity. This approach will allow us to identify candidate biomarkers of LC circuit integrity. We will use a series of within-subject designs where we manipulate LC activity and examine whether relationships between LC and behavior and brain regions thought to mediate those behaviors are consistent or not between different perceptual modalities and memory tasks. Overall this study will provide an important and much needed understanding of how LC integrity underlies cognitive declines in older adults. By combining advanced neuroimaging, well-controlled behavioral assessment, and computational analysis, we expect to uncover previously inaccessible in vivo mechanisms of LC modulation and generate a unique dataset to address fundamental mechanistic questions of how the LC integrity moderates cognition, how this varies across older adults and the extent to which relationships between LC and cognition are generalized or individualized to particular domains. The resulting understanding of LC circuit can help explain how dysfunctional modulatory circuits may generate cognitive declines or be implicated in normal aging and age- related disorders such as Alzheimer's and Alzheimer's related disorders. This, in turn, has potential to support non-invasive methods for diagnosing pathologies associated with LC decline and developing new treatments.

项目概要 本提案的总体目标是了解结构和结构中的个体差异如何 蓝斑（LC）的功能调节老年人群的感知和记忆。有 大量证据表明 LC 回路在认知过程中发挥着核心作用，并且 LC 中的神经元损失 已知发生在 ADRD 和 PD 等神经退行性疾病中。假设 LC 神经元的完整性 也能在正常衰老过程中调节认知能力的保存。然而迄今为止，存在一种 缺乏表征 LC 完整性差异效应或详细了解 LC 之间关系的研究 老年人的完整性和认知功能。更一般地说，LC 活动与认知之间的联系 人类的过程尚未得到很好的表征。造成这种情况的历史原因是LC一直很困难 由于其尺寸小，无法成像，因此大多数人类研究通过使用瞳孔来推断 LC 功能 扩张作为替代措施。为了克服该领域现有的局限性，我们提出了一系列详细的 基于心理物理学和 MRI 的老年人研究旨在描述 LC 的结构和功能 调节行为，进而调节行为如何由已知的中间大脑区域的活动介导 参与知觉和记忆过程。我们进一步提出计算方法来表征 LC 电路完整性与认知表现的不同模式之间存在个体差异 任务，以及先进的神经成像方法来定位和成像 LC，这是我们首创的 团体。使用基于 MRI 的方法，我们将使用高分辨率神经黑色素敏感技术检查 LC 完整性 结构成像、纤维束成像和功能连接。这种方法将使我们能够识别候选人 LC 电路完整性的生物标志物。我们将使用一系列受试者内设计来操纵 LC 活性 并检查 LC 与行为以及调节这些行为的大脑区域之间是否存在关系 不同的感知方式和记忆任务之间的行为是否一致。总体而言本研究 将提供关于 LC 完整性如何导致认知能力下降的重要且急需的理解 老年人。通过结合先进的神经影像学、良好控制的行为评估和计算 分析后，我们期望揭示以前无法实现的体内 LC 调制机制，并生成 独特的数据集，用于解决 LC 完整性如何调节认知、如何 这对于老年人来说是不同的，而且 LC 和认知之间关系的普遍化程度也不同 或针对特定领域进行个性化。由此产生的对 LC 电路的理解有助于解释如何 调节回路功能失调可能会导致认知能力下降或与正常衰老和年龄增长有关。 相关疾病，例如阿尔茨海默病和阿尔茨海默病相关疾病。反过来，这有可能支持 用于诊断与 LC 下降相关的病理学并开发新疗法的非侵入性方法。