Early brain-wide disruption of sleep microarchitecture in amyotrophic lateral sclerosis

BACKGROUNDAmyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to motor symptoms, including altered sleep, with increased wakefulness and decreased deep nonrapid eye movement (NREM). Whether these alterations in sleep macroarchitecture are associated with - or even precede - abnormalities in sleep-related EEG features remains unknown.METHODSHere, we characterize sleep microarchitecture using polysomnography for patients with ALS (n = 33) and controls (n = 32) as well as for asymptomatic carriers of superoxide dismutase 1 (SOD1) or C9ORF72 mutations (n = 57) and noncarrier controls (n = 30). Patients and controls with factors that could confound sleep structure, including respiratory insufficiency, were prospectively excluded. The results were complemented in 3 ALS mouse models (Sod1G86R, FusΔNLS/+, and TDP-43Q331K).RESULTSWe observed a brain-wide reduction in the density of sleep spindles, slow oscillations, and K-complexes in patients with early-stage ALS and in presymptomatic gene carriers. These defects in sleep spindles and slow oscillations correlated with cognitive performance in both cohorts, particularly with scores on memory, verbal fluency, and language function. Alterations in sleep microarchitecture were replicated in 3 mouse models, and decreases in sleep spindles were rescued following intracerebroventricular supplementation of melanin-concentrating hormone (MCH) or by oral administration of a dual orexin receptor antagonist.CONCLUSIONSleep microarchitecture was associated with cognitive deficits and causally linked to aberrant MCH and orexin signaling in ALS.FUNDINGAgence Nationale de la Recherche (ANR); Fondation Thierry Latran; Association Francaise de Recherche sur la sclérose latérale amyotrophique; Association Française contre les myopathies; TargetALS; and Joint Program on Neurodegenerative Diseases Research (JPND).