By Franklin X. Faust
As published in Dimensions Magazine - Fall 2019
Greek philosopher Aristotle once surmised that sleep helps the body to filter its blood at the end of the day, sending dirty blood downwards and pure blood up to the brain. This idea echoes many early intuitions about the cleansing power of sleep. Two thousand years later, we know that getting good quality, consistent sleep makes for a clearer mind, while not getting enough puts you at a greater risk for many chronic medical conditions and age-related cognitive decline. It turns out the ancient minds had the right idea about sleep. Modern scientific approaches to understanding the brain’s refreshing overnight processes could lead to a new preventative therapy for dementia.
The brain stays clean and operational thanks to the glymphatic system, the brain’s biology of exchange. It jumps into action during sleep, acting like an all-in-one delivery and trash pick-up service for neurons. When you are deep asleep, cerebrospinal fluid in the glymphatic system rushes along right next to the brain’s blood vessels, delivering key supplies while clearing away unwanted debris.
Some of this cellular trash is more or less benign, but some of these molecules are toxic and associated with neurodegenerative disease. Fortunately, the trash sitting outside of each cell is picked up by the same cerebrospinal fluid in charge of delivery. The glymphatic system then dumps the molecular trash back into the larger pools of fluid surrounding the brain, where it is cleared via waste disposal checkpoints. This elegant workflow of exchange helps keep the neurons of the brain supplied, clean, and functioning.
Back in 2012, Dr. Jeff Iliff, PhD led the team that initially defined the glymphatic system as the network of pathways that supports the clearance of waste from brain tissue during sleep. At the time, he was a postdoc at the Nedergaard lab at University of Rochester Medical Center. Now, as Professor in the UW Department of Psychiatry and Behavioral Sciences and Lead of the proposed UW ADRC Research Education Component, Iliff brings a greater focus on sleep’s role in dementia risk to our Center. Since this study, we have learned much more about the glymphatic system’s relevance to neurodegenerative disease and a good night’s sleep.
Iliff’s experiments on mice have found that the glymphatic system mediates the transport of Alzheimer’s-associated proteins out of the brain, and that this process appears to slow as animals age and in the presence of vascular and traumatic brain injury. Research from several groups around the world has shown that this same kind of janitorial work is happening in the human brain as well. “The advancements we’ve made in the past five years have given us some of the strongest evidence to date that what we see in animals may also be happening in humans,” says Iliff. For example, researchers at the University of Oslo recently found that patients with dementia caused by normal- pressure hydrocephalus have been shown to have impairments in fluid movement through their brain tissue, suggesting that a weakened glymphatic system contributes to dementia in these patients. “When you’re talking about a very fundamental biological process to brain function, its implications spread to many places and questions; it’s just a matter of understanding the process well enough,” says Iliff. He thinks that the glymphatic system will play an important role in future dementia research.
SLEEP, GLYMPHATIC CLEARANCE, AND DEMENTIA RISK
One piece of the puzzle is how impaired glymphatic clearance can lead to dementia. “Proteins implicated in neurodegenerative diseases exist in healthy people, but they are naturally produced and removed at near-equal rates,” says Iliff. “When this balance is thrown off, these proteins can pile up, spread, and become a problem.” To study this balance, researchers at the Washington University in St. Louis have tagged the building blocks of these toxic proteins with safe radioactive labels, and infused them into human subjects. Scientists can then record how these building blocks appear and then disappear from the fluid surrounding the brain to measure how fast these toxic proteins are produced and cleared in aging and Alzheimer’s disease. “These proteins might build up in two ways,” says Iliff. “They’re either produced too fast or removed too slowly.” Research shows that people with rare genetic mutations causing early-onset Alzheimer’s disease produce more disease-associated protein than the systems can clear. But the vast majority of Alzheimer’s cases are different. One study showed that in cases of the much more common sporadic late-onset version of Alzheimer’s disease, the rate of production doesn’t change, but the rate of clearance slows. Another study found this same pattern in older people without Alzheimer’s disease. These studies suggest that the slowed clearance of these proteins may be a root cause of diseases like Alzheimer’s.
New scientific clues suggest that issues with sleep may cause this slower clearance seen in aging and Alzheimer’s. Researchers found that losing just one night of sleep leads to an increase in amyloid beta, a protein in the brain associated with impaired neuron function and Alzheimer’s disease. An NIH study used positron emission tomography (PET) to scan the brains of 20 healthy participants after a full night’s rest and after 31 hours of sleep deprivation. The study found that the participant’s brains had about 5% more amyloid beta after that single night of sleeplessness. In light of two recent reports out of the Atherosclerosis Risk in Communities Study and the Framingham Heart Study, the connection between sleep and dementia is looking even more convincing. These studies have followed the health of young people for decades, and some of the participants who originally enrolled are now developing dementia. Researchers analyzed this gold-standard data and found that mid-life sleep disruption predicts cognitive decline later in life.
SLOW WAVE SLEEP AND THE AGING BRAIN
Sleep is integrally tied to the brain’s essential biology of clearance and exchange. Recent findings in animals show that the bulk of glymphatic clearance occurs during deep sleep when slow wave activity is most abundant. “It’s well known that people sleep less and less, and more poorly as they get older,” says Iliff. “There is a particular depletion of slow wave activity as people age – so much so that many elderly don’t undergo much slow wave activity through the course of the night, even though they may be still sleeping six hours a night. In subjects with Alzheimer’s disease, sleep disruptions are even more severe.”
One of Iliff’s burning questions is why the slow wave activity of deep sleep would be the key to healthy glymphatic function. His hypothesis has to do with what makes slow wave sleep so unique. During waking and during REM sleep, the brain’s activity is desynchronized as neurons connecting different parts of the brain fire in a cacophony of activity. But during slow wave sleep, the brain switches back and forth between brief periods of synchronous activity (called ‘up-states’) and synchronous inactivity (called ‘down-states’) about once every second. “We think that these oscillating periods of activity and inactivity may be helping to move water and salt through brain tissue, like waves over the surface of a lake,” says Iliff. If glymphatic “brain rinsing” is slowed or is given less time to run, as with the reduced amounts of sleep seen in people as they age, particularly slow wave sleep, this alteration might set the stage for the development of neurodegeneration. If people get less sleep as they age, and less slow wave sleep in particular, the brain’s glymphatic wash cycle is given less time to run. This slowed or decreased clearance might set the stage for the development of neurodegeneration.
This slowing of the brain’s custodial service may give toxic proteins a leg up, allowing them to spread through the brain unchecked and accelerate the worsening of cognitive symptoms. “Diseases like Alzheimer’s and Parkinson’s have a stereotyped progression. Protein aggregates accumulate in different parts of the brain as the disease progresses,” Iliff says. “An emerging idea in the field is these protein aggregates actually spread from cell to cell over time, moving through the space between the brain’s cells to affect other brain regions.” Iliff believes that the slowing of the glymphatic system’s cleaning process may influence how this spreading happens. Ensuring the glymphatic system works optimally could help slow neurodegeneration by flushing out proteins or chemicals in the spaces around the cells before they’re taken up into neighboring neurons.
EMERGING TREATMENTS FOCUS IN ON SLEEP
Some scientists are working to develop new drugs to improve or restore glymphatic activity. Dr. Elaine Peskind, MD, Professor in the UW Department of Psychiatry and Behavioral Sciences and collaborator of UW ADRC, thinks that such a drug may already exist. She is studying prazosin, a drug used for treating PTSD, and its connection to sleep and glymphatic activity. “We think prazosin directly increases glymphatic function, and it may be independent of sleep,” says Peskind. Prazosin blocks the signaling of the alpha-1 adrenergic receptor, which mitigates a type of brain activity called noradrenergic tone. This activity, produced by norepinephrine (the brain’s adrenaline), is high when you’re awake but more subdued while you’re asleep. Iliff’s research has shown that treating awake mice with prazosin and similar drugs that block the brain’s noradrenergic system causes an up-tick in deep sleep associated delta waves and an increase in glymphatic function, effectively turning the glymphatic system on even while the animal is still awake.
Peskind and her collaborators are pursuing this possibility in a new study. PoND, Prevention of Neurodegeneration, is a study that seeks to investigate if prazosin can reduce spinal fluid biomarkers for toxic proteins implicated in Alzheimer’s, frontotemporal dementia, ALS, and Parkinson’s, while also measuring glymphatic activity with a new MRI technique developed by UW Medicine researchers Dr. Swati Rane, PhD and Dr. Jalal Andre, MD. They will also find out if the medication really does improve sleep quality by measuring study volunteers’ sleep and awake times over the course of a week, both before and after long-term prazosin treatment.
Prazosin is uniquely suited to the treatment of neurodegenerative disease because of its longstanding history and clinical safety. Prazosin was approved for hypertension in the early 1970s, and since then it has been tested in millions of people, primarily in men with hypertension and benign prostatic hyperplasia. Side effects are fairly trivial and are rarely reported.
But prazosin isn’t just safe – it’s practical for chronic, life-long use. “It’s dirt cheap,” says Peskind. “It’s been off patent since the 80s, it is taken orally, and it causes very few side-effects. It could be taken for the rest of somebody’s life as chronic management.” By contrast, if recently developed antibody-based anti-amyloid drug therapies were shown to be effective, they would need to be administered intravenously and would cost somewhere between $30,000 and $50,000 annually. And while other trials have been focused exclusively on preventing cognitive impairment and dementia in people who already have accumulated amyloid, PoND is also focusing on preventing neurodegenerative disease before toxic proteins begin to accumulate.
This focus on glymphatic-based interventions for the prevention of dementia ushers in a welcome direction in a rapidly shifting field of medical research. The recent failure of aducanumab, an amyloid-clearing drug that made it to phase III clinical trials, has seeded the field with doubts over the hypothesis that removing amyloid will be enough to treat or prevent Alzheimer’s disease symptoms. Many scientists wonder if the Alzheimer’s research community needs to undergo a shift away from amyloid. “Up to this point, the field has been very amyloid focused, because that’s where a lot of the early evidence in Alzheimer’s disease pointed,” says Iliff. “But people are starting to think much more broadly now.” Prazosin’s non-specific approach of enhancing glymphatic clearance hopes to cast a broader net in the prevention of neurodegenerative disease, potentially supporting the clearance of other toxic proteins, such as tau, alpha synuclein, and TDP-43.
While research at the UW may someday lead to new therapeutic approaches to preventing and treating diseases such as Alzheimer’s disease, these newly emerging insights into the connection between sleep, aging, and neurodegenerative disease also provide an immediately relevant take-home message: How you are sleeping now matters to your brain health for decades to come. “If people know that how they sleep when they are in their 30s, 40s, and 50s is going to influence the way their brain functions in their 60s, 70s, and 80s, they might pay more attention to getting the recommended 7 - 9 hours per night,” Iliff notes. “Many of us are starting to view sleep as a potentially modifiable risk factor, like high blood pressure or smoking, for the development of dementia later in life.” Tasked with keeping neurons freshly stocked and clean, the glymphatic system’s biology has far reaching implications for a wide range of neurodegenerative disorders. Given the recent history and disappointments in Alzheimer’s clinical trials, the study of something as broad-based as the glymphatic system carries hope for greater progress in how we treat cognitive impairment and dementia. No matter what advancements emerge in the next 2,000 years, a good night’s sleep can only help.
♦ TIPS FOR HEALTHY SLEEP ♦
...from Dr. Michael Persenaire, M.D, Neurologist at the UW Memory and Brain Wellness Center.
►“Manage your circadian rhythms and keep your brain informed of where you are in the 24-hour cycle. Light exposure and having your body in an upright posture are both powerful signals to your brain that it’s time to be awake, so limiting nighttime light exposure and exercising in the day can help you fall asleep at night.”
►“Make sure that any environmental or medical conditions affecting sleep are being addressed. We like to remind patients that the consistent use of CPAP machines has been shown to make a significant difference in cognitive outcomes for people diagnosed with sleep apnea. Cognitive behavioral therapy has been shown to be particularly effective in treating insomnia.”
►“Avoid or decrease substances that are clearly harmful for sleep, such as stimulants, caffeine, tobacco, and alcohol.”
Eide PK et al. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study. J Cereb Blood Flow Metab. 2019 Jul;39(7):1355-1368.
Iliff JJ et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147ra111.
Iliff JJ et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014 Dec 3;34(49):16180-93.
Kress BT et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014 Dec;76(6):845-61.
Li J et al. Assessment of the Mid-Life Demographic and Lifestyle Risk Factors of Dementia: Using Data from the Framingham Heart Study Offspring Cohort. J Alzheimers Dis. 2018;63(3):1119-1127.
Lutsey PL et al. Sleep characteristics and risk of dementia and Alzheimer's disease: The Atherosclerosis Risk in Communities Study. Alzheimers Dement. 2018 Feb;14(2):157-166.
Mawuenyega KG et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774.
Patterson BW et al. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol. 2015 Sep;78(3):439-53.
Potter R et al. Increased in Vivo Amyloid-β42 Production, Exchange, and Loss in Presenilin Mutation Carriers. Science Translational Medicine. 12 Jun 2013: Vol. 5, Issue 189, pp. 189ra77.
Wang M et al. Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts. J Neurosci. 2017 Mar 15;37(11):2870-2877.
Xie L et al. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18; 342(6156): 373-7.