TY  - JOUR
AU  - Lang, Christina
AU  - Guillot, Simon J
AU  - Lule, Dorothee
AU  - Balz, Luisa T
AU  - Knehr, Antje
AU  - Weydt, Patrick
AU  - Dorst, Johannes
AU  - Kandler, Katharina
AU  - Muller, Hans-Peter
AU  - Kassubek, Jan
AU  - Wassermann, Laura
AU  - Da Cruz, Sandrine
AU  - Roselli, Francesco
AU  - Ludolph, Albert C
AU  - Bolborea, Matei
AU  - Dupuis, Luc
TI  - Early brain-wide disruption of sleep microarchitecture in amyotrophic lateral sclerosis.
JO  - The journal of clinical investigation
VL  - 136
IS  - 1
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2026-00019
SP  - e194555
PY  - 2026
N1  - FUNDING: 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).
AB  -  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).
KW  - Amyotrophic Lateral Sclerosis: physiopathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Humans
KW  - Animals
KW  - Male
KW  - Female
KW  - Mice
KW  - Middle Aged
KW  - Brain: physiopathology
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Aged
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase-1: metabolism
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - Sleep
KW  - Adult
KW  - Polysomnography
KW  - Mice, Transgenic
KW  - Disease Models, Animal
KW  - ALS (Other)
KW  - Genetics (Other)
KW  - Neuroscience (Other)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - SOD1 protein, human (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - Sod1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41196652
C2  - pmc:PMC12721911
DO  - DOI:10.1172/JCI194555
UR  - https://pub.dzne.de/record/283123
ER  -