Some people literally act out their dreams. Their bodies fail to undergo the normal paralysis that accompanies REM sleep, the stage most associated with dreaming. Their bodies may quake violently, pantomiming the scenes unfolding in their heads. This dream state often is a sign of larger health problems to come.
More than 80 percent of people with rapid eye movement sleep behavior disorder (RBD), as the condition is known, go on to develop certain neurodegenerative maladies such as Parkinson’s disease, multiple system atrophy or dementia with Lewy bodies, studies have found. Autopsies of RBD patients have revealed that clumps of proteins deep in the brain, known asalpha-synuclein aggregates, congregate in the regions that regulate rapid eye movement sleep.
Even when the underlying diagnosis is not RBD, people with neurodegenerative diseases suffer from a wide range of sleep-related problems, including insomnia, interrupted sleep and excessive daytime sleepiness. Researchers have long thought such disturbances were consequences rather than causes of brain pathology—either a direct result of degeneration of sleep regions in the brain, side effects of a particular drug regimen or other triggers. But many now suspect the relationship may be more complex. Sleep disturbances often occur early, sometimes decades before the symptoms that characterize various neurodegenerative diseases. In fact, several studies have found that the extent of sleep disruption predicts subsequent cognitive decline or disease.
In a review published in Science last month, Erik Musiek and David Holtzman of Washington University School of Medicine in Saint Louis, discussed the evidence for a link between sleep and neurodegeneration and the mechanisms by which disruption of the bodily clocks (circadian rhythms) may influence diseases of later life.
“Circadian” comes from Latin, meaning “about a day.” In humans the average cycle is about 24.2 hours. Two genes, CLOCK and BMAL1, produce proteins that join to form a structure that binds to DNA to control the activity of other genes. This internal clock regulates about 10 percent of the 20,000 or so human genes, orchestrating rhythms of sleep, eating, body temperature, hormone levels and other processes. Among the genes targeted are three in the Period family (PER1, PER2 and PER3) and two in the Cryptochrome family (CRY1 and CRY2), which produce proteins that block the activity of CLOCK and BMAL1.This feedback loop causes the oscillation in gene activity that drives circadian rhythms.
Almost every cell in the body carries this machinery, and outside the brain cellular clocks control local circadian processes, notably in the heart and lungs. But the core of the circadian system is the suprachiasmatic nucleus (SCN), a pinhead-size region within a larger structure deep in the brain called the hypothalamus. The SCN acts as a central pacemaker, sending signals that keep all the other clocks synchronized. It also controls levels of melatonin and cortisol, two hormones important for the sleepwake cycle. The SCN receives signals from its surroundings—the most important of which is daylight, received by the retinas, that keeps it synchronized with the 24-hour cycle.
In a study published in 2011, Kristine Yaffe of the University of California, San Francisco, and colleagues collected circadian data from 1,282 healthy elderly women using actigraphy, which involves wearing a watchlike sensor that records physical activity. They assessed participants’ cognitive functions five years later, and found that various measures of impaired circadian rhythms conferred significantly higher risks for mild cognitive impairment (which often presages Alzheimer’s) or actual dementia.
That study and the research on RBD are not enough to prove that sleep disturbances cause neurodegeneration. The proteins linked to that condition start accumulating many years prior to clinical symptoms, and the timing of their buildup relative to the onset of sleep disturbances is still undetermined. “The overall question is one of cause and effect,” says Michel Goedert, a leading neurodegenerative disease researcher at the University of Cambridge in England.
More Cellular Junk
The best evidence for a causal relationship comes from Alzheimer's research. Holtzman’s group published a study in 2009 that found levels of amyloid beta, the peptide that forms plaques in Alzheimer’s, are higher during waking hours—both in mouse brains and in human cerebrospinal fluid. The group also showed that depriving mice of sleep increased amyloid levels. Infusing the animals with orexin, a peptide produced in the hypothalamus that promotes wakefulness, also increased amyloid whereas injecting a drug that blocks orexin decreased amyloid levels. Holtzman’s team then used mice engineered to produce a human form of a protein that is processed chemically to make amyloidbeta to study the effects on plaque formation. It found sleep deprivation increased plaque formation whereas blocking orexin decreased plaques. “That’s the first evidence showing that if you manipulate the sleep/wake cycle, that could potentially play a role in the cause of a neurodegenerative disease,” Holtzman says.
Studies have also shown that when amyloid deposits build up in both animals and humans, sleep disturbances occur. It may, in fact, be a two-way street: Neurodegeneration may disrupt sleep and disrupted sleep may exacerbate neurodegeneration in a vicious cycle. “In other words, if you have too little sleep, it favors protein aggregation. Then once you get the aggregation, it makes sleep worse,” Holtzman says.
Others in the field are more guarded. “I can’t see any evidence [thatsleep deprivation] is going to cause aggregation, but it could influence the rate,” Goedert says.
Amyloid production increases with neural activity. And because the brain is less active during slow-wave sleep, researchers assumed fluctuations of the peptide were due to changes in brain activity. A 2013 study presented another mechanism by which sleep may influence amyloid levels. Maiken Nedergaard and colleagues at the University of Rochester described what they called the “glymphatic system,” which channels cerebrospinal fluid into the brain and flushes interstitial fluid—as well as amyloid beta—out of the brain. They found a striking increase in interstitial fluid volume during sleep, resulting in a substantial increase in “glymphatic flow.” They proposed “that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer’s disease progression.” They also found that amyloid betainjected into mouse brains was cleared faster from the brains of sleeping mice.
It is not news that sleep disturbances affect health, but sleep/wake cycles and the circadian clock, although tightly linked, are different things—and relatively little is known about the effects of circadian clock disruption on brain health. To investigate this question, Musiek and Holtzman, working with Garret Fitzgerald at the University of Pennsylvania, engineered mice lacking key clock genes. They deleted BMAL1 in mice brains, but only in the cortex and hippocampus, sparing the SCN. This left sleep/wake cycles intact while completely disrupting the rise and fall of the activity of clock genes in most of the brain.
The mice gradually developed signs of pathology, including loss of synapses (the connection points among neurons), free radical damage and signs of inflammation. “The mouse gets a kind of neuroinflammatory syndrome that’s pretty striking,” Musiek says. “Circadian clock genes clearly play some important role in maintaining the brain.”
The team also saw reduced activity of genes that defend against free radicals, suggesting lack of this protection was a major cause of damage, according to the study, which was published in 2013. Processes likefree radical damage, inflammation and others have all been implicated in neurodegeneration. They can also influence, and be influenced by, the circadian clock, providing potential paths by which circadian disturbances and neurodegeneration could affect each other. “Sorting out the mechanisms of this is probably the most important next step in this field,” Holtzman says.
A few small genetic studies have found clock-gene mutations that increase risk for Alzheimer’s and Parkinson’s, but these findings need to be replicated in bigger studies. “The problem with clock genes is they’re going to influence susceptibility to a lot of diseases, and maybe you never get Alzheimer’s because you get some other illness,” Musiek says. “The influence on risk might be relatively small, just because there's a lot of other factors, so it may be more difficult to find.”
The impact of circadian rhythms on neurodegenerative disease also extends to Huntington’s disease, which is caused by a mutation in a single gene. Because inheritance of one copy of the gene ensures that a person will develop Huntington’s, researchers are able to study people they know will develop the disorder before those people show symptoms, and then track them through onset and progression. In a study published last year neuroscientist Alpar Lazar of Cambridge and colleagues found that presymptomatic carriers of the Huntington’s mutation had more fragmented sleep than healthy controls, and the degree of disturbance related to age and genetic burden. “The closer someone is to the onset of disease, the more likely they are to have a more severe sleep problem,” Lazar says.
Another group at Cambridge, led by Jennifer Morton, has shown that Huntington’s mice exhibit disrupted circadian rhythms, including disrupted clock-gene activity that gets worse as the disease progresses. They have also shown that enforcing regular sleep on these mice, by giving them sedatives at bedtime and stimulants to wake them, slowed cognitive decline and restored normal clock-gene activity. Whether this holds true for humans remains to be seen, but these findings suggest that merely altering sleep/wake cycles might slow disease progression. Possible treatment strategies include a set of simple measures: exposure to bright light and enforced daytime activity such as exercise along with evening melatonin supplements. Combinations of these options have already been tested with mixed results, and more research is needed. “Every clinic should consider these nonpharmaceutical interventions as a first step and secondly evaluate their efficacy,” Lazar says, “then consider existing pharmaceutical methods like orexin [blockers] or other sedatives.”
None of this research hinges on circadian factors being the underlying cause of neurodegeneration. “Sleep and circadian disruptions may be considered a modifiable risk factor, like cholesterol in heart disease,” Musiek says. “If we could lower that risk and stave off disease by a few years, millions fewer people every year would be affected.”
It may also be possible to develop drugs that directly target the circadian clock. “Rather than giving people sleeping pills, something that synchronizes their clocks at the molecular level—that’s what we think would be a good idea. Or could we turn on protective aspects of the clock machinery so they were protecting our brain all the time, not just at certain times of day?” Musiek says. “Targeting these pathways would be the next generation of therapy, beyond just getting a good night’s sleep.”
An ideal drug would have to balance any beneficial effects against the possibility that a multitude of other biological processes might veer out of whack. “It will take awhile to sort out how to selectively enhance or suppress clock-gene functions, and how to translate that into favorable outcomes while not affecting other physiological outcomes,” says neurologist Aleksandar Videnovic, a movement disorder specialist at Massachusetts General Hospital. “One has to be very careful when manipulating the circadian system.”
To move forward, large epidemiological studies are needed to determine the actual risk for neurodegenerative diseases associated with sleep disturbances. This might help to identify people early in the disease process for testing new therapies. RBD is likely to be important because it seems to reliably lead to a specific disease. “It will undoubtedly be the population to study, because it’s probably very late to act after the disease is diagnosed,” Videnovic says. “Disease-modifying therapies are rapidly starting to emerge, and once they’re developed it’s important we’re positioned to study them in a population with the most likelihood of success.”
The field also needs to determine whether treating sleep disorders in early-stage patients can slow disease progression. “We don’t have the intervention data, and that’s where this needs to be,” says Allan Pack, an expert on the genetics of sleep at the University of Pennsylvania. Besides gaining more time, he says, targeting sleep or the circadian clock might even enhance the effects of other drugs under development that are targeted at clearing cellular junk.
“The vision in the field now is it’s going to take a multipronged approach,” Musiek says. “We haven’t gotten to the point where one works at all. But once one works we can start looking at combination therapies.” A drug that keeps molecular clocks synchronized could be added to a cocktail of other therapies to finally provide treatments for diseases that have stubbornly resisted most pharmaceutical interventions.