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000283123 037__ $$aDZNE-2026-00019
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000283123 1001_ $$0P:(DE-2719)9002237$$aLang, Christina$$b0$$eFirst author$$udzne
000283123 245__ $$aEarly brain-wide disruption of sleep microarchitecture in amyotrophic lateral sclerosis.
000283123 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2026
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000283123 500__ $$aFUNDING: Agence Nationale de la Recherche (ANR); Fondation Thierry Latran; Association Francaise de Recherche sur la sclérose latérale amyotrophique; Association Française contre les myopathies; TargetALS; and Joint Program on Neurodegenerative Diseases Research (JPND).
000283123 520__ $$a 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).
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000283123 650_7 $$2Other$$aALS
000283123 650_7 $$2Other$$aGenetics
000283123 650_7 $$2Other$$aNeuroscience
000283123 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSuperoxide Dismutase-1
000283123 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000283123 650_7 $$2NLM Chemicals$$aSOD1 protein, human
000283123 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000283123 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSod1 protein, mouse
000283123 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: physiopathology
000283123 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000283123 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000283123 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000283123 650_2 $$2MeSH$$aHumans
000283123 650_2 $$2MeSH$$aAnimals
000283123 650_2 $$2MeSH$$aMale
000283123 650_2 $$2MeSH$$aFemale
000283123 650_2 $$2MeSH$$aMice
000283123 650_2 $$2MeSH$$aMiddle Aged
000283123 650_2 $$2MeSH$$aBrain: physiopathology
000283123 650_2 $$2MeSH$$aBrain: pathology
000283123 650_2 $$2MeSH$$aBrain: metabolism
000283123 650_2 $$2MeSH$$aAged
000283123 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000283123 650_2 $$2MeSH$$aSuperoxide Dismutase-1: metabolism
000283123 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000283123 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000283123 650_2 $$2MeSH$$aSleep
000283123 650_2 $$2MeSH$$aAdult
000283123 650_2 $$2MeSH$$aPolysomnography
000283123 650_2 $$2MeSH$$aMice, Transgenic
000283123 650_2 $$2MeSH$$aDisease Models, Animal
000283123 7001_ $$0P:(DE-HGF)0$$aGuillot, Simon J$$b1
000283123 7001_ $$0P:(DE-2719)9002172$$aLule, Dorothee$$b2$$udzne
000283123 7001_ $$0P:(DE-HGF)0$$aBalz, Luisa T$$b3
000283123 7001_ $$0P:(DE-HGF)0$$aKnehr, Antje$$b4
000283123 7001_ $$0P:(DE-2719)9001116$$aWeydt, Patrick$$b5$$udzne
000283123 7001_ $$0P:(DE-2719)9001951$$aDorst, Johannes$$b6$$udzne
000283123 7001_ $$0P:(DE-HGF)0$$aKandler, Katharina$$b7
000283123 7001_ $$0P:(DE-HGF)0$$aMuller, Hans-Peter$$b8
000283123 7001_ $$0P:(DE-2719)9001967$$aKassubek, Jan$$b9$$udzne
000283123 7001_ $$0P:(DE-HGF)0$$aWassermann, Laura$$b10
000283123 7001_ $$0P:(DE-HGF)0$$aDa Cruz, Sandrine$$b11
000283123 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b12$$udzne
000283123 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert C$$b13$$udzne
000283123 7001_ $$0P:(DE-HGF)0$$aBolborea, Matei$$b14
000283123 7001_ $$0P:(DE-HGF)0$$aDupuis, Luc$$b15
000283123 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI194555$$gVol. 136, no. 1, p. e194555$$n1$$pe194555$$tThe journal of clinical investigation$$v136$$x0021-9738$$y2026
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