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@ARTICLE{Dorst:257342,
      author       = {Dorst, Johannes and Weydt, Patrick and Brenner, David and
                      Witzel, Simon and Kandler, Katharina and Huss-Malejko, Andre
                      and Herrmann, Christine and Wiesenfarth, Maximilian and
                      Knehr, Antje and Günther, Kornelia and Müller, Kathrin and
                      Weishaupt, Jochen H and Prudlo, Johannes and Forsberg, Karin
                      and Andersen, Peter M and Rosenbohm, Angela and Schuster,
                      Joachim and Roselli, Francesco and Dupuis, Luc and Mayer,
                      Benjamin and Tumani, Hayrettin and Kassubek, Jan and
                      Ludolph, Albert C},
      title        = {{M}etabolic alterations precede neurofilament changes in
                      presymptomatic {ALS} gene carriers.},
      journal      = {EBioMedicine},
      volume       = {90},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2023-00411},
      pages        = {104521},
      year         = {2023},
      note         = {CC BY-NC-ND},
      abstract     = {The emergence of potentially effective new therapies for
                      genetic forms of amyotrophic lateral sclerosis (ALS)
                      necessitates the identification of biomarkers to facilitate
                      early treatment, prior to the onset of motor symptoms. Here,
                      we sought to investigate whether metabolic alterations are
                      detectable in presymptomatic ALS gene mutation carriers, and
                      whether such alterations precede neurofilament light chain
                      (NfL) changes in serum.Between 02/2014 and 11/2021, we
                      prospectively studied 60 presymptomatic ALS gene mutation
                      carriers $(40\%$ male, age 48.7 ± 14.9; 28 C9orf72, 22
                      SOD1, 10 other) compared to 73 individuals from the same
                      families $(47\%$ male, age 47.4 ± 12.9) without pathogenic
                      mutations as controls. Bioimpedance analysis (BIA) and
                      indirect calorimetry were performed, and Body Mass Index
                      (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW),
                      Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell
                      Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle,
                      Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL
                      were measured. Participants and evaluators were blinded
                      regarding gene carrier status.Presymptomatic ALS gene
                      carriers showed reduced LBM (p = 0.02), BCM (p = 0.004),
                      Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p =
                      0.04), and increased ECM/BCM ratio (p = 0.04), consistently
                      indicating a loss of metabolically active body cells. While
                      in C9orf72 mutation carriers all tissue masses were reduced,
                      only metabolically active tissue was affected in SOD1
                      mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p =
                      0.01) were lower in presymptomatic ALS gene carriers
                      compared to non-carriers. NfL serum levels were similar in
                      mutation carriers and non-carriers (p = 0.60).The observed
                      metabolic phenomena might reflect reduced physical activity
                      and/or preemptive, insufficient compensatory mechanisms to
                      prepare for the later hypermetabolic state. As
                      pre-symptomatic biomarkers we propose ECM/BCM ratio and
                      Phase Angle for SOD1, and a 4-compartment affection in BIA
                      for C9orf72 mutation carriers.This work was an
                      investigator-initiated trial. On the German side, there was
                      no institutional or industrial funding. On the Swedish side,
                      this work was supported by grants from the Swedish Brain
                      Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310,
                      2020-0353), the Swedish Research Council (grants nr.
                      2012-3167, 2017-03100), the Knut and Alice Wallenberg
                      Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the
                      Ulla-Carin Lindquist Foundation, Umeå University
                      (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the
                      Västerbotten County Council (grants nr 56103-7002829), King
                      Gustaf V:s and Queen Victoria's Freemason's Foundation.},
      keywords     = {Humans / Male / Adult / Middle Aged / Female / Amyotrophic
                      Lateral Sclerosis: diagnosis / Amyotrophic Lateral
                      Sclerosis: genetics / Intermediate Filaments / C9orf72
                      Protein: genetics / Superoxide Dismutase-1: genetics /
                      Biomarkers / C9orf72 Protein (NLM Chemicals) / Amyotrophic
                      lateral sclerosis (Other) / Metabolic (Other) / Metabolism
                      (Other) / Mutations carriers (Other) / Presymptomatic
                      (Other) / Superoxide Dismutase-1 (NLM Chemicals) /
                      Biomarkers (NLM Chemicals)},
      cin          = {Clinical Study Center Ulm / AG Teipel / AG Roselli},
      ddc          = {610},
      cid          = {I:(DE-2719)5000077 / I:(DE-2719)1510100 /
                      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:36917918},
      pmc          = {pmc:PMC10024076},
      doi          = {10.1016/j.ebiom.2023.104521},
      url          = {https://pub.dzne.de/record/257342},
}