How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

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。

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.