Clinical Trial Evaluating the Impact of Sleep and Sleep Deprivation on the Cerebral Glymphatic System
Abstract
Sleep is exhibited by all mammals, and sleep-like behavior is seen in birds, reptiles,amphibians, and even insects. Insufficient sleep leads to marked degradation in attention,memory consolidation, decision-making, mood, and other cognitive functions, and if continuedover days or weeks, insufficient sleep has adverse effects on metabolism, immune, andcardiovascular function. Indeed, sleep is so critical to life that studies in rats demonstrate that 2-4weeks of total or selective REM sleep deprivation results in death. Despite several decades ofstudy, however, we still do not understand how sleep restores the brain and what transpiresduring sleep that is critical for waking functions.Nedergaard recently reported that in mice there is a 60% relative increase of brain interstitialspace during sleep compared with wake, resulting in two times faster clearance of beta-amyloid.If such a change also occurs in humans, it could advance our understanding of one of the criticalroles of sleep and the mechanisms by which poor sleep quality and/or insufficient sleep durationlead to short- and long-term cognitive changes and why treatments for sleep disorders alter thetrajectory of cognitive decline.Unlike other organs, the brain has no lymphatic vessels. In mice, homeostasis between thecerebrospinal fluid and the interstitial fluid in the space between the cells of the brainparenchyma drains neurotoxic catabolites. Nedergaard named this system glymphatic due tothe crucial role of glia in fluid exchanges between brain compartments and because ofsimilarities with the lymphatic system. They hypothesized that impaired glymphatic clearancecontributes to accumulation of neurotoxic proteins, including beta-amyloid in AlzheimersDisease (AD); hyperphosphorylated tau in AD, fronto-temporal dementia and traumaticencephalopathy; and alpha-synuclein in Parkinsons Disease and Lewy Body Dementia, whichare all diseases associated with disrupted sleep.MRI is a reliable tool to assess the cerebral interstitial space in humans. Perivascular spaces,also known as Virchow-Robin spaces (VRs), are extensions of the interstitial space that followthe course of the penetrating vessels and are visible on conventional MRI. Although the presenceof enlarged VRs is not considered per se pathological, larger or more numerous VRs areassociated with aging, traumatic brain injury, AD and cerebrovascular disease. Physiologicalfluctuations of VRs volume have not been studied in healthy individuals. Therefore, the aims ofour project are to carry out studies to determine if the volume of Virchow-Robin spaces (VRs) islarger during sleep than during wakefulness, and if the VRs volume differs between the nonREMand REM sleep states. Deliverables will consist of pilot data consisting of a quantitativeassessment of VRs volume during sleep vs. wake from healthy study participants. Because VRsvolume reflects the volume of the interstitial space, quantitative assessment of VRs in sleep vs.wake will allow us to determine whether the glymphatic system described in mice followssimilar sleep-wake dynamics in humans. If so, this would have profound implications for ourunderstanding of one of the core functions of sleep.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 08, 2020
- Source ID
- N000141912239
Entities
People
- Charles Czeisler
Organizations
- Office of Naval Research
- United States Navy