How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

本补充材料的目的是了解 HIV 感染与神经认知能力下降之间的关系 感染艾滋病毒的老年人。这是在更大的项目背景下了解个体差异如何 蓝斑（LC）的结构和功能调节老年人群的感知和记忆。 有大量证据表明，LC 回路在认知过程和神经元损失中发挥着核心作用。 已知 LC 会发生在 ADRD 和 PD 等神经退行性疾病中。 LC 神经元的完整性是 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， 缺乏表征 LC 完整性差异效应或详细关系的研究 老年人的 LC 完整性和认知功能之间的关系。关于 LC 如何进行的信息就更少了 艾滋病毒感染者 (PLWHIV) 的年龄。更一般地说，LC 活动与认知过程之间的联系 在人类中尚未得到很好的表征。造成这种情况的历史原因是 LC 很难成像 由于其体积小，因此大多数人类研究通过瞳孔扩张来推断 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 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 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。总的来说，这项研究将提供重要且急需的理解 LC 完整性如何导致老年人（包括 PLWHIV 感染者）认知能力下降。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，我们希望发现 以前无法访问的体内 LC 调制机制，并生成一个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，以及这在老年人中有何变化 感染和未感染 HIV 的成年人以及 LC 和认知之间关系的普遍化程度或 针对特定领域进行个性化。由此产生的对 LC 电路的理解可以帮助解释功能失调是如何发生的 调节回路可能会导致认知能力下降或与正常衰老、感染艾滋病毒和艾滋病毒的人的衰老有关。 阿尔茨海默氏症和阿尔茨海默氏症相关疾病。反过来，这有可能支持非侵入性方法 诊断与 LC 下降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.