The perivascular space: A structural link between inadequate sleep, glymphatic dysfunction, and neurocognitive outcomes in adolescents

项目摘要 这项建议的总体目标是定义睡眠不佳、臀部疼痛之间的关系 损害和青少年的神经认知功能。青少年睡眠不足是一种严重的 全球范围内的健康风险。此外，睡眠不佳与运动功能、注意力、记忆力、 和冲动控制，影响青少年的基本领域，如驾驶和学习功能。 几项研究已经将睡眠不良与青少年的神经认知功能受损联系起来。然而， 这种联系背后的生物学机制仍然知之甚少。其中一种机制可以 参与淋巴通路，这是一个支持大脑废物清除的血管周围空间网络。 在清醒时，大脑会产生大量的废物，这些废物至少部分通过大脑的 睡眠中的淋巴通路。这种废物的清除对于大脑正常运作是必不可少的。在这 提案中，我们假设睡眠不佳会导致淋巴功能障碍、废物堆积和 青少年的神经认知功能障碍。最近，可见的血管周围间隙(PVS)的数量 脑MRI已被认为是一种无创的淋巴功能指标。我们的初步数据显示 睡眠不佳患者的PVS数量增加。此外，在一项对美国陆军退伍军人的研究中，我们有 观察到PVS数量和神经认知功能，特别是运动能力之间的关联。 这些初步发现表明，在睡眠质量差和睡眠质量下降之间的关系中，淋巴通路起着重要作用。 神经认知功能。 为了验证我们的假设，我们提出了以下目标：1)定义自我报告和 客观测量睡眠时间和质量对正常青少年PVS负荷的影响 调整其他协变量；2)确定PVS负担在两者之间的关系中的中介作用 青少年的睡眠时间和质量，以及神经认知功能。为了实现我们的目标，我们将采取 我们团队开发的新技术的优势，使我们能够大规模测量PVS， 健康青少年和年轻人的纵向队列。我们希望观察到两者之间的直接关联 睡眠时间和PVS负荷。我们还希望PVS负荷，表明淋巴功能障碍，调解 睡眠与神经认知功能的关系。 这项研究的发现将为提高我们对穷人之间联系的科学知识奠定基础 青少年的睡眠、淋巴功能障碍和神经认知结果。推进临床护理和 关于青少年睡眠的研究与2021年国家心肺血液研究所睡眠研究是一致的 “阐明健康和疾病背后的睡眠和昼夜节律机制”的障碍研究计划 以及“开发工具和/或方法，用于睡眠不足和睡眠的早期预测和检测[…]。 儿童和青少年的昼夜节律紊乱，以促进终身健康和福祉，并预防疾病。

Project Summary The overall objective of this proposal is to define the relationship between poor sleep, glymphatic impairment, and neurocognitive function in adolescents. Insufficient sleep in adolescents is a severe health risk worldwide. In addition, poor sleep is associated with deficits in motor function, attention, memory, and impulse control, impacting adolescents in essential areas such as driving and academic functioning. Several studies have linked poor sleep with impaired neurocognitive function in adolescents. However, the biological mechanisms underlying this association remain poorly understood. One of those mechanisms may involve the glymphatic pathway, a network of perivascular spaces that support cerebral waste clearance. During wakefulness, the brain generates considerable amounts of waste, cleared at least in part via the glymphatic pathway during sleep. This waste removal is essential for the brain to function appropriately. In this proposal, we hypothesize that poor sleep leads to glymphatic dysfunction, waste accumulation, and neurocognitive dysfunction in adolescents. Recently, the number of perivascular spaces (PVS) visible on brain MRI has been proposed as a noninvasive marker of glymphatic function. Our preliminary data show increased PVS numbers in patients with poor sleep. Moreover, in a study of US Army Veterans, we have observed an association between PVS number and neurocognitive function, specifically motor performance. These initial findings suggest a role of the glymphatic pathway in the association between poor sleep and neurocognitive function. To test our hypothesis, we propose the following aims: 1) Define the association between self-reported and objective measures of sleep duration and quality on PVS burden in normal adolescents over time after adjusting for other covariates; and 2) determine the mediating effect of PVS burden in the relationship between sleep duration and quality, and neurocognitive function in adolescents. To achieve our aims, we will take advantage of novel technology developed by our group that will allow us to measure PVS in a large, longitudinal cohort of healthy adolescents and young adults. We expect to observe a direct correlation between sleep duration and PVS burden. We also expect PVS burden, indicating glymphatic dysfunction, to mediate the relation between sleep and neurocognitive function. Findings from this study will be foundational for improving our scientific knowledge of the link between poor sleep, glymphatic dysfunction, and neurocognitive outcomes in adolescents. Advancing clinical care and research for sleep in adolescents is in line with the 2021 National Heart, Lung, and Blood Institute Sleep Disorders Research Plan to "elucidate the sleep and circadian mechanisms underlying health and disease" and "develop tools and/or methods for the early prediction, and detection […] of sleep deficiency and sleep and circadian disorders in children and adolescents to promote lifelong health and wellbeing and prevent disease."