Repeated nocturnal awakenings, the feeling of never reaching deep sleep. For many, it’s another episode of stress. For some, these broken nights could herald early
Charcot diseasewell before the first hand that drops an object or the leg that gives way.
Amyotrophic lateral sclerosis (ALS), or Charcot diseaseis a rare neurodegenerative pathology which destroys motor neurons and leads to death on average 3 to 5 years after the first signs. In France, around 8,000 people live with this disease, for 2.7 new cases per year per 100,000 inhabitants. An Inserm – University of Strasbourg team reports, in the journal Science Translational Medicinethat
sleep disorders measurable symptoms appear to precede motor symptoms by several years.
Charcot disease: when sleep goes wrong before the muscles do
The progression of the disease affects respiratory functions, which indirectly leads to sleep disturbances as it develops. However, it was unclear whether these disturbances could precede motor symptoms, as observed in other neurodegenerative diseases such as Parkinson’s or Alzheimer’s. When do these problems appear? Are they a direct consequence of motor deficits? These questions were explored by the team of Luc Dupuis and Matei Bolborea, in close collaboration with the German Research Center for Neurodegenerative Diseases (DZNE) in Ulm.
The researchers recorded, by polysomnography, the sleep of patients with early-stage ALS, still without respiratory damage, and that of people carrying mutations such as C9ORF72 or SOD1 but without any motor symptoms. Their data was compared to that of volunteers of the same age without ALS or known mutations.
In these two risk groups, the recordings show increased waking time during the night and decreased deep non-REM sleep, compared to healthy controls. The more time patients spent awake, the more their performance on cognitive tests declined. The authors point out that “The results suggest that sleep disorders are present and observable, early on, several years before the manifestation of motor disorders.“, even though these anomalies often remain imperceptible to the people concerned.
Hypothalamus, orexin and MCH: the mechanism behind these nights
To trace the origin of these changes, the team looked at thehypothalamusthe conductor of the sleep-wake cycles. In three mouse models carrying mutations responsible for ALS, researchers found the same fragmented sleep profiles. They showed that the circuits of neurons orexinwhich maintain wakefulness, and those linked to melanin concentrating hormone (MCH), involved in sleep, were disrupted.
A single oral administration of an orexin receptor antagonist or an infusion of MCH for 15 days partially normalized the animals’ sleep and reduced the loss of lumbar motor neurons, even without clearly prolonging their survival.
Towards treatments that target sleep in ALS?
This work paved the way for a clinical trial which tests in people with ALS an orexin antagonist already used against insomnia, to check whether better restored sleep can slow down the disease. “The main aim of our study was to try to reconstruct what is happening in patients before they become ill. These discoveries on the chronology of symptoms allow us to rethink the role of the brain and particularly that of the hypothalamus in the onset of the pathology and to imagine new therapeutic targets.” said Matei Bolborea, co-senior author of the study.
“Our team’s discoveries are important on two levels. Firstly, they shed light on a new chronology of ALS symptoms, once again questioning the origins of the disease, and in particular the role of the brain in its genesis”, explains Luc Dupuis, co-last author of the study. “They also represent a slight hope for the sick, and those who report the disease, imagining that acting on the first manifestations of it could slow down its extremely rapid progression.
By targeting sleep and the hypothalamus, these discoveries open up a new therapeutic avenue for a disease that is still too often diagnosed too late.