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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

基本信息

批准号：
10613285
负责人：
XIAOPING P HU
金额：
$ 38.87万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
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/10613285
关键词：
Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amygdaloid structure Arousal Attention Award Awareness Behavior Behavior assessment Behavioral Biological Markers Brain Brain region Cerebellum Cognition Collaborations Computer Analysis Control Groups Data Data Set Diagnosis Disease Elderly Enrollment Exertion Foundations Functional Magnetic Resonance Imaging Funding Gays Goals HIV HIV Infections HIV-associated neurocognitive disorder Hand High Prevalence Hippocampus (Brain)Human Image Impaired cognition Individual 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 Nerve Degeneration Neurocognitive Deficit Neurodegenerative Disorders Neurons Norepinephrine Parkinson Disease Pathology Patient Self-Report Pattern Perception Performance Persons Play Pontine structure Population Psychophysics Public Health Publications Research Research Personnel Research Project Grants Resolution Role Series Services Source Stress Structure Surveys Task Performances Tegmentum Mesencephali Testing Thalamic structure United States National Institutes of Health Woman age stratification base candidate marker cognitive ability cognitive function cognitive neuroscience cognitive performance cognitive process cognitive testing community based research design digital grasp in vivo insight interest locus ceruleus structure memory process men neurobehavioral neuroimaging neuromelanin neuron loss normal aging novel novel therapeutics preservation recruit response stressor tractography

项目摘要

The goal of this supplement is to understand relationships between HIV infection and neurocognitive decline in people aging with HIV. This is in the context of the larger project 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. There is even less information on how the LC ages in people living with HIV (PLWHIV). 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. Overall this study will provide an important and much needed understanding of how LC integrity underlies cognitive declines in older adults, including PLWHIV. 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 with and without HIV 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, those aging with HIV and 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.

本附录的目的是了解HIV感染和神经认知功能下降之间的关系艾滋病毒携带者变老。这是在一个更大的项目的背景下理解个体差异是如何蓝斑(LC)的结构和功能在老年人群中具有中等的感知和记忆能力。有大量证据表明，LC环路在认知过程和神经元丢失中发挥核心作用众所周知，LC可发生在神经退行性疾病中，如ADRD和PD。LC神经元的完整性是假设也是为了在正常衰老过程中调节认知能力的保存。然而，到目前为止，缺乏对LC完整性或细节关系的不同影响进行表征的研究老年人LC完整性和认知功能之间的关系。关于LC的信息甚至更少艾滋病毒感染者(PLWHIV)的年龄。更广泛地说，LC活动和认知过程之间的联系在人类身上并没有很好的特征。这其中的历史原因是，LC一直难以想象由于LC的体积很小，因此大多数人类研究都是通过散瞳来推断LC的功能作为替代措施。为了克服该领域现有的限制，我们提出了一系列详细的老年人的心理物理和基于MRI的研究旨在表征LC的结构和功能缓和行为，进而说明这是如何通过大脑中间区域的活动来调节的参与知觉和记忆过程的。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认知表现模式有关的个体差异任务，以及先进的神经成像方法来定位和成像LC，这是我们的首创一群人。使用基于MRI的方法，我们将使用高分辨率神经黑色素敏感物质来检查LC的完整性结构成像、纤维束成像和功能连接。这种方法将使我们能够确定候选人 LC电路完整性的生物标志物。总体而言，这项研究将提供一个重要的和亟需的理解 LC完整性如何导致包括PLWHIV在内的老年人认知能力下降。通过将高级神经成像、良好控制的行为评估和计算分析，我们预计将发现以前无法获得LC调制的体内机制，并生成唯一的数据集来解决基本的机制问题，即LC完整性如何调节认知，这在老年人中有何不同感染和不感染艾滋病毒的成年人以及LC和认知之间的关系被概括或针对特定领域进行个性化的。由此产生的对LC电路的理解有助于解释为什么调制回路可能会导致认知能力下降或与正常衰老有关，那些感染艾滋病毒和阿尔茨海默氏症和阿尔茨海默氏症相关疾病。这反过来有可能支持非侵入性方法诊断与LC衰退相关的病理并开发新的治疗方法。