Early brain-wide disruption of sleep microarchitecture in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to the motor system, including altered sleep, with increased wake and decreased NREM sleep phases. Whether these alterations in sleep macroarchitecture are associated, or even preceded by abnormalities in sleep-related EEG hallmarks is unknown. Here we used polysomnography to characterize sleep microarchitecture in the early phases of ALS. We observed a brain-wide decrease in density of sleep spindles, slow oscillations and k-complexes, three sleep-related EEG signals, in both early-stage ALS patients and presymptomatic gene carriers. These alterations in sleep spindles were correlated with cognitive performance, particularly of scores in memory, verbal fluency and speech, in both cohorts. Importantly, alterations in sleep microarchitecture were replicated in 3 mouse models and decreases in sleep spindles were rescued by MCH intracerebroventricular supplementation or oral administration of a dual orexin receptor antagonist. Thus, sleep microarchitecture is associated with cognitive deficits and causally related to aberrant MCH and orexin signaling in ALS.