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@ARTICLE{Lang:283123,
      author       = {Lang, Christina and Guillot, Simon J and Lule, Dorothee and
                      Balz, Luisa T and Knehr, Antje and Weydt, Patrick and Dorst,
                      Johannes and Kandler, Katharina and Muller, Hans-Peter and
                      Kassubek, Jan and Wassermann, Laura and Da Cruz, Sandrine
                      and Roselli, Francesco and Ludolph, Albert C and Bolborea,
                      Matei and Dupuis, Luc},
      title        = {{E}arly brain-wide disruption of sleep microarchitecture in
                      amyotrophic lateral sclerosis.},
      journal      = {The journal of clinical investigation},
      volume       = {136},
      number       = {1},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DZNE-2026-00019},
      pages        = {e194555},
      year         = {2026},
      note         = {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).},
      abstract     = {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).},
      keywords     = {Amyotrophic Lateral Sclerosis: physiopathology /
                      Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: pathology / Amyotrophic Lateral
                      Sclerosis: metabolism / Humans / Animals / Male / Female /
                      Mice / Middle Aged / Brain: physiopathology / Brain:
                      pathology / Brain: metabolism / Aged / Superoxide
                      Dismutase-1: genetics / Superoxide Dismutase-1: metabolism /
                      C9orf72 Protein: genetics / C9orf72 Protein: metabolism /
                      Sleep / Adult / Polysomnography / Mice, Transgenic / Disease
                      Models, Animal / ALS (Other) / Genetics (Other) /
                      Neuroscience (Other) / Superoxide Dismutase-1 (NLM
                      Chemicals) / C9orf72 Protein (NLM Chemicals) / SOD1 protein,
                      human (NLM Chemicals) / C9orf72 protein, human (NLM
                      Chemicals) / Sod1 protein, mouse (NLM Chemicals)},
      cin          = {Clinical Study Center (Ulm) / Clinical Research (Bonn) / AG
                      Roselli},
      ddc          = {610},
      cid          = {I:(DE-2719)5000077 / I:(DE-2719)1011001 /
                      I:(DE-2719)1910001},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41196652},
      pmc          = {pmc:PMC12721911},
      doi          = {10.1172/JCI194555},
      url          = {https://pub.dzne.de/record/283123},
}