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

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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."