Summary: A new potential treatment for rapid eye movement (REM) sleep behavior disorder has been identified.
The study established a new model detailing the disorder’s progression due to neurodegeneration linked with tau protein accumulation. Researchers found dual orexin receptor antagonists, used commonly for insomnia, significantly reduced symptoms of this disorder.
The discovery introduces a new treatment option that could potentially have fewer side effects.
Mount Sinai researchers discovered a new potential treatment for REM sleep behavior disorder, which impacts over 3 million Americans and involves acting out dreams during sleep.
The study presented a new model showing how the disorder develops due to neurodegeneration related to an accumulation of tau protein.
Sleep medications known as dual orexin receptor antagonists, usually used for insomnia, were found to significantly reduce the disorder, opening up a promising new treatment option.
Source: Mount Sinai Hospital
Mount Sinai researchers have published what they say is the first study to identify a new form of treatment for rapid eye movement (REM) sleep behavior disorder.
This condition affects more than 3 million Americans, mostly adults over the age of 50, who often unknowingly physically act out their dreams with vocal sounds or sudden, violent arm and leg movements during slumber, leading to significant injury to themselves or bed partners.
The new study, published in the Journal of Neuroscience, outlines a novel model to better characterize how REM sleep behavior disorder develops due to neurodegeneration—when brain cells lose function over time—which is associated with the accumulation of tau protein.
This model provides an early-life biomarker of impending deterioration of the brain, which could guide future prevention and treatment.
The paper also demonstrates for the first time that sleep medications known as dual orexin receptor antagonists—commonly used to treat insomnia, or difficulty falling and remaining asleep—can significantly reduce REM sleep behavior disorder.
Current therapeutic options for this disorder are primarily limited to melatonin and clonazepam, also known as Klonopin, so these findings suggest a promising new treatment with potentially fewer side effects.
“We were interested in understanding all of the ways in which sleep quality breaks down as neurodegeneration progresses and whether there were any ways to mitigate such changes,” said corresponding author Andrew W. Varga, MD, Ph.D., Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) at the Icahn School of Medicine at Mount Sinai.
“We identify a novel model in which REM sleep behavior disorder can develop, due to neurodegeneration associated with accumulation of tau protein, and a novel therapy that could minimize REM sleep behavior disorder.”
Mount Sinai researchers used a mouse model to study neurodegenerative disorders by examining the brain following abnormal deposits of tau, a protein that normally helps stabilize the internal skeleton of nerve cells in the brain.
They analyzed behavioral states including wakefulness, phases of REM (sleep with dreams), phases of non-REM (sleep without dreams), length of sleep, transitions from waking to sleep, and how some factors are related to age.
Nearly a third of the older subjects exhibited dream enactment behaviors reminiscent of REM sleep behavior disorder, including chewing and limb extension.
After administering a dual orexin receptor antagonist twice during a 24-hour period, to evaluate sleep in light and dark phases, the researchers observed that the medication not only reduced the time it took to fall asleep and increased both the quality and duration of sleep but also reduced levels of dream enactment.
Researchers hope their findings will encourage future trials of dual orexin receptor antagonists to treat REM sleep behavior disorder in humans, given that the medication is already FDA approved and available to treat people with insomnia.
“We anticipated finding breakdown of sleep quality with progressive neurodegeneration related to tau accumulation, but the observation of dream enactment was a surprise,” said lead author Korey Kam, Ph.D., Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) at Icahn Mount Sinai.
“It was even more surprising and exciting to observe that a dual orexin receptor antagonist could significantly minimize the dream enactment behaviors.”
Effect of aging and a dual orexin receptor antagonist on sleep architecture and NREM oscillations including a REM Behavior Disorder phenotype in the PS19 mouse model of tauopathy
The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling has been understudied, in spite of the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown.
In the PS19 mouse model of tauopathy (MAPT P301S, both male and female), young 2-3 month PS19 mice show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared to littermate controls, even though there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age.
With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macro-level, and reduced spindle density, SO density, and spindle-SO coupling at the micro-level. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and fore limb/hind limb extension, seemingly consistent with REM behavior disorder (RBD).
Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle-SO coupling, power in either the SO or spindle bands, or the arousal index.
We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment.