How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

本补充的目的是了解艾滋病毒感染和神经认知能力下降之间的关系， 艾滋病病毒携带者这是在更大的项目背景下，了解个体差异如何在 蓝斑（LC）结构和功能调节老年人的知觉和记忆。 有大量证据表明，LC回路在认知过程和神经元损失中起着核心作用。 已知LC发生于神经退行性疾病，如ADRD和PD。LC神经元的完整性 假设在正常衰老过程中也能介导认知能力的保存。然而，迄今为止， 缺乏研究来描述LC完整性的差异效应或详细的关系 LC完整性和老年人认知功能之间的关系。关于LC如何使用的信息更少 艾滋病毒感染者（PLWHIV）的年龄。更一般地说，LC活动和认知过程之间的联系 在人类身上还没有得到很好的表征。历史原因是立法会一直难以形象化 由于其体积小，因此大多数人类研究通过使用瞳孔扩张来推断LC功能 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 在老年人中进行的心理物理学和基于MRI的研究旨在表征LC的结构和功能 调节行为，反过来又如何通过已知的中间大脑区域的活动来介导， 参与感知和记忆过程。我们进一步提出了计算方法来表征 LC电路完整性与不同认知表现模式之间的个体差异 任务和先进的神经影像学方法来定位和成像LC，这是我们的 组使用基于MRI的方法，我们将使用高分辨率神经黑色素敏感的 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回路完整性的生物标志物。总的来说，这项研究将提供一个重要的和急需的理解 LC完整性如何成为老年人认知能力下降的基础，包括PLWHIV。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，我们希望能发现 以前无法获得的LC调制的体内机制，并生成独特的数据集来解决 LC完整性如何调节认知的基本机制问题，这在老年人中如何变化， 有和没有艾滋病毒的成年人以及LC和认知之间的关系被泛化的程度， 个性化到特定领域。由此产生的对LC电路的理解可以帮助解释为什么功能失调 调节回路可能导致认知能力下降，或与正常衰老有关， 阿尔茨海默氏症和阿尔茨海默氏症相关疾病。这反过来又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。

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.