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.

项目摘要 本提案的总体目标是了解结构中的个体差异如何 老年人人群中核座（LC）中等感知和记忆的功能。有 LC电路在认知过程中起着核心作用的大量证据，LC中的神经元丧失是 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 在正常衰老期间也调解了认知能力的保留。但是，到目前为止，存在一个 缺乏表征LC完整性差异效应或详细介绍LC之间关系的研究 老年人的完整性和认知功能。更一般地，LC活动与认知之间的联系 在人类中，过程尚未得到很好的特征。历史原因是LC很困难 由于其尺寸较小，因此大多数人类研究都会通过使用学生来推断LC功能 扩张作为替代措施。为了克服该领域的现有限制，我们提出了一系列详细的 对老年人的心理物理和基于MRI的研究，旨在表征LC的结构和功能 调节行为，进而由中间大脑区域的活动介导的行为，这是如何介导的 参与感知过程和记忆过程。我们进一步提出了计算方法来表征 LC电路完整性如何与不同的认知表现模式相关的个体差异 任务以及先进的神经影像学方法来本地化和图像LC，这已被我们开创 团体。使用基于MRI的方法，我们将使用高分辨率神经元素敏感的LC完整性检查LC完整性 结构成像，拖拉术和功能连通性。这种方法将使我们能够确定候选人 LC电路完整性的生物标志物。我们将使用一系列受试者内部设计，我们可以操纵LC活动 并检查LC与行为与大脑区域之间的关系是否被认为是为了调解这些人的 行为在不同的感知方式和内存任务之间是一致的。总体而言，这项研究 将为LC诚信如何在认知下降的基础上提供重要且急需的理解 老年人。通过结合先进的神经影像学，控制良好的行为评估和计算 分析，我们期望以前无法访问LC调制的体内机制，并产生A 独特的数据集解决了LC完整性如何缓和认知的基本机理问题，如何 这在老年人之间各不相同，LC和认知之间的关系在多大程度上被普遍化 或个性化到特定领域。对LC电路的最终理解可以帮助解释如何 功能失调的调节电路可能会导致认知下降或与正常衰老和年龄有关 相关疾病，例如阿尔茨海默氏症和阿尔茨海默氏症相关疾病。反过来，这有可能支持 用于诊断与LC下降和开发新疗法相关的病理学的非侵入性方法。