How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

项目摘要 本提案的首要目标是了解结构和结构中的个体差异 蓝斑(LC)在老年人群中的适度感知和记忆功能。的确有 大量证据表明LC环路在LC的认知过程和神经元丢失中发挥核心作用 已知发生在神经退行性疾病中，如ADRD和PD。假设LC神经元的完整性 在正常衰老过程中调节认知能力的保存。然而，到目前为止，存在着一种 缺乏研究来描述LC完整性的不同影响或LC之间的详细关系 老年人的完整性和认知功能。更广泛地说，LC活动和认知之间的联系 人类的过程并没有得到很好的描述。造成这种情况的历史原因是，立法会一直很难 由于其体积很小，因此大多数人类研究都是利用瞳孔来推断LC的功能 作为替代措施的扩张。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。我们将使用一系列主题内设计，在这些设计中我们操作LC活动 并研究LC与行为和大脑区域之间的关系是否调节了这些 不同知觉通道和记忆任务之间的行为是否一致。总体来说，这项研究 将提供一个重要的和迫切需要的理解，即LC的完整性是如何导致认知能力下降的 上了年纪的人。通过结合先进的神经成像、良好控制的行为评估和计算 分析，我们希望发现以前无法在体内获得的LC调制机制，并产生一种 独特的数据集，用于解决LC完整性如何调节认知、如何 这在老年人中是不同的，在LC和认知之间的关系被概括的程度也不同 或针对特定领域进行个性化。由此产生的对LC电路的理解有助于解释 功能失调的调节回路可能会导致认知能力下降，或者与正常衰老和衰老有关- 相关疾病，如阿尔茨海默氏症和阿尔茨海默氏症相关疾病。反过来，这又有可能支持 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。

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.