Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.

Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non–rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1^G86R, Fus^ΔNLS/+, and TDP43^Q331K). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1^G86R mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease. Editor's summary: Patients with amyotrophic lateral sclerosis (ALS) often experience poor sleep, but whether these disturbances are caused by alterations in sleep regulating brain circuits or triggered by motor symptoms remains unclear. Guillot et al. found that patients with ALS and presymptomatic carriers of ALS risk genes show increased wakefulness and reduced non–rapid eye movement sleep. Disruptions in sleep architecture were also found in three mouse models of ALS and partially normalized by intraventricular injection of melanin-concentrating hormone or oral administration of an orexin antagonist. These results suggest that sleep disturbances occur before symptom onset and can be ameliorated by targeting neuropeptides involved in sleep/wake regulation. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]