No rest for research; sleep studies shift from mice models to human trials
It was nearly 10 years ago, when Jeffrey Iliff, PhD, and his research team peered into the brain of a living mouse, deep among the neurons and blood vessels, to discover an elegant sanitation system that clears away brain toxic (neurotoxic) waste…
Using the most advanced imaging and microscopy techniques, Iliff, then a postdoc at the University of Rochester Medical Center, observed waves of cerebrospinal fluid flowing around and through the brain, collecting waste from cells and flushing them out to the circulatory system.
And there was the kicker: the team found that this waste pick-up service for neurons goes into action during sleep. It turns off during the day when the brain is busy with other tasks.
The discovery by Iliff and his mentor at the time, Maiken Nedergaard, that this brain-wide network, called the “glymphatic system,” cleans the brain during sleep was one of Science magazine’s “Top 10 Breakthroughs” of 2013.
The research not only shined a light on the newly described glymphatic system, but also on the connection between sleep and brain health. Does the system work similarly in humans as it does in mice? Does the sanitation system in the brain clog or break down when sleep is impaired? If so, does waste that doesn’t get cleaned out of the brain trigger disease?
The discovery by Iliff and his mentor at the time, Maiken Nedergaard, that this brain-wide network, called the “glymphatic system,” cleans the brain during sleep was one of Science magazine’s “Top 10 Breakthroughs” of 2013.
The research not only shined a light on the newly described glymphatic system, but also on the connection between sleep and brain health. Does the system work similarly in humans as it does in mice? Does the sanitation system in the brain clog or break down when sleep is impaired? If so, does waste that doesn’t get cleaned out of the brain trigger disease?
Piecing the puzzle
In the past several years, Iliff – now an SIBCR-supported scientist, the University of Washington School of Medicine’s Arthur J. and Marcella McCaffery Professor in Alzheimer’s Disease, and Associate Director for Research at the VISN20 NW Mental Illness Research, Education, and Clinical Center (MIRECC) at the VA Puget Sound – has helped to piece together much of the puzzle.
In their studies in mice, Iliff and his research team have demonstrated that the glymphatic system, when working properly, indeed clears proteins implicated in neurodegenerative diseases such as Parkinson’s and Alzheimer’s. “In healthy people, these proteins are naturally produced and removed at near-equal rates,” he said. “But when this cleaning system is impaired, these proteins can pile up, spread and cause trouble.”
Iliff’s research group also found that in older mice and those with brain injuries, the cleaning system slowed, leading to the build-up of some of those same neurotoxic proteins.
And it’s no coincidence that a hallmark symptom of aging, traumatic brain injury and some neurodegenerative diseases is poor sleep.
The Alzheimer’s link
Notably, Iliff has found that among the wastes that accumulate in the brain when the glymphatic system is faulty, is amyloid beta, which has been implicated in Alzheimer’s disease. Moreover, other researchers have found that losing just a single night of sleep can increase amyloid in the brain.
So, should sleep and the glymphatic system be targets to treat or prevent neurodegenerative diseases? Iliff believes so, particularly for Alzheimer’s. Currently-approved therapies, including the amyloid-focused drug aducanumab have been iffy at best and quite expensive. In the meantime, there are proven therapies, with or without drugs, to improve sleep.
Move to human trials
While Iliff’s lab will continue to study the glymphatic system in mice, more and more of his research has begun to focus on people. That’s just how successful science progresses.
Last fall, the US Department of Defense awarded $4.3 million for a three-year clinical trial of a device to speed up the natural system of brain cleansing that occurs with sleep. On the study, Iliff is working with University of Washington School of Medicine Department of Radiology researcher Dr. Swati Rane, along with collaborators at the University of North Carolina, Brain Electrophysiology Lab, the Oregon Health and Science University, and Montana State University.
“Our lab’s research over the past eight years on brain-waste clearance in animals has helped define glymphatic biology,” said Iliff. “Now we hope to see if we can use what we’ve learned to help people overcome poor or interrupted sleep and the brain dysfunction that follows.”
The technology in this study involves an easy-to-use, wireless, combined electrical brain wave monitoring (EEG)/stimulation headband that can be applied before sleep to monitor and improve deep sleep and glymphatic waste clearance.
Veterans’ research participation
Veterans will play an important role in Iliff’s future collaborative clinical studies. In the NW MIRECC at the VA Puget Sound, he works closely with Elaine Peskind, MD, and Murray Raskind, MD, both SIBCR scientists.
Dr. Peskind has been investigating mild traumatic brain injury in Iraq and Afghanistan war Veterans, while Dr. Raskind has pioneered the use of the drug prazosin, a medication approved for treatment of high blood pressure, for use in post-traumatic stress disorder (PTSD). While Dr. Iliff’s work in mice has shown that traumatic brain injury impairs brain waste clearance, and that the drug prazosin can improve sleep and glymphatic function, this team of SIBCR scientists now plans to extend these studies into Veteran populations to test whether prazosin can improve outcomes after traumatic brain injury by supporting brain waste clearance.
In parallel, Drs. Iliff, Rane and Peskind are conducting studies to develop better ways to measure these processes in the human brain, and to figure out if changes in waste clearance are reflected in spinal fluid biomarkers for brain toxic proteins implicated in neurodegenerative diseases. An initial study using these approaches to test the effects of poor sleep in young healthy volunteers is planned for the coming spring.
While it may be years before these studies yield new therapies for preventing and treating neurodegenerative disease, Iliff’s research supports some age-old advice: Get a good night’s sleep.
