Sleep problems may develop years before ALS motor symptoms: Study
Researchers studying potential therapies for sleep changes in early ALS
Sleep problems may become evident in people with amyotrophic lateral sclerosis (ALS) several years before the characteristic motor symptoms of the disease develop, a new study shows.
The study suggests alterations in a brain region called the hypothalamus, which are seen in early disease stages and sometimes even in patients who haven’t developed any symptom, are responsible for those early sleep problems.
Experiments done in mouse models indicate treatments to normalize those hypothalamic alterations can improve sleep and may help stave off the loss of nerve cells and the progression of ALS.
Findings shed light on new timeline of ALS symptoms
“Our team’s findings are significant on two levels,” Luc Dupuis, PhD, co-senior author of the study at the French public research organization Inserm, said in a press release. “First, they shed light on a new timeline of ALS symptoms, prompting us to reevaluate the origins of the disease and the brain’s role in its development. Second, they offer a glimmer of hope for patients, as addressing the early manifestations of the disease might slow its otherwise extremely rapid progression.”
The study, “Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models,” was published in Science Translational Medicine.
ALS is characterized by the progressive sickening and death of motor neurons, the specialized nerve cells that are responsible for controlling movement. The loss of motor neurons ultimately leads to ALS symptoms, such has weakness and paralysis.
It’s been known that people with ALS may experience sleep problems. In theory, this could be a byproduct of motor symptoms, such as respiratory issues, that impair sleep, but it could also be a direct result of changes in parts of the brain responsible for controlling sleep. The new study suggests that the latter is more likely.
For the study, researchers evaluated sleep patterns in people who had ALS and those who didn’t, as well as people who carried an ALS-causing mutation but had not yet developed any motor symptoms of the disease.
Results showed people with ALS experienced more nighttime wakefulness and less deep sleep. These sleep problems also were seen in carriers of mutations who didn’t have motor symptoms, which implies that the changes in sleep patterns develop before motor symptoms. Notably, these problems were often subtle and detected only via tests that monitored sleep.
“Our main objective was to unveil what happens in patients before they show any motor symptoms,” said Matei Bolborea, PhD, co-senior author of the study at Inserm. “These discoveries about the timeline of symptoms allow us to reconsider the brain’s role … in the onset of ALS and to explore new therapeutic targets.”
Experiments in mouse models of ALS caused by different mutations
Seeking to understand the neurological underpinnings of disrupted sleep in ALS, the researchers then conducted a series of experiments in mouse models of ALS caused by different mutations. They found mice in these models show similar sleep problems as people with the disease.
The ALS mice also showed abnormalities in the activity of neurons that produce orexin, which is a signaling molecule that promotes wakefulness. Orexin normally works in concert with a signaling molecule that promotes sleepiness, called melanin-concentrating hormone (MCH), to regulate sleeping and waking up.
Because the data indicated orexin activity was abnormally increased in the ALS hypothalamus, a central hub for regulating sleep-wake patterns, the researchers tried treating the mice with a pump that delivered extra MCH continuously to the brain for 15 days. This helped normalize the mice’s sleep.
MCH treatment also led to less loss of motor neurons, but it did not affect the long-term survival of the mice, possibly due to the limited treatment time, the researchers noted.
Treatment with suvorexant, an orexin-blocking drug sold under the brand name Belsomra as a treatment for insomnia, yielded comparable results.
“These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of [ALS],” the researchers wrote.
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