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000257342 1001_ $$0P:(DE-2719)9001951$$aDorst, Johannes$$b0$$udzne
000257342 245__ $$aMetabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers.
000257342 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2023
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000257342 520__ $$aThe 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.
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000257342 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000257342 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000257342 650_7 $$2Other$$aMetabolic
000257342 650_7 $$2Other$$aMetabolism
000257342 650_7 $$2Other$$aMutations carriers
000257342 650_7 $$2Other$$aPresymptomatic
000257342 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSuperoxide Dismutase-1
000257342 650_7 $$2NLM Chemicals$$aBiomarkers
000257342 650_2 $$2MeSH$$aHumans
000257342 650_2 $$2MeSH$$aMale
000257342 650_2 $$2MeSH$$aAdult
000257342 650_2 $$2MeSH$$aMiddle Aged
000257342 650_2 $$2MeSH$$aFemale
000257342 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: diagnosis
000257342 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000257342 650_2 $$2MeSH$$aIntermediate Filaments
000257342 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000257342 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000257342 650_2 $$2MeSH$$aBiomarkers
000257342 7001_ $$0P:(DE-2719)9001116$$aWeydt, Patrick$$b1$$udzne
000257342 7001_ $$0P:(DE-2719)9002137$$aBrenner, David$$b2$$udzne
000257342 7001_ $$0P:(DE-2719)9001976$$aWitzel, Simon$$b3$$udzne
000257342 7001_ $$aKandler, Katharina$$b4
000257342 7001_ $$0P:(DE-2719)9002029$$aHuss-Malejko, Andre$$b5$$udzne
000257342 7001_ $$aHerrmann, Christine$$b6
000257342 7001_ $$aWiesenfarth, Maximilian$$b7
000257342 7001_ $$aKnehr, Antje$$b8
000257342 7001_ $$aGünther, Kornelia$$b9
000257342 7001_ $$0P:(DE-HGF)0$$aMüller, Kathrin$$b10
000257342 7001_ $$0P:(DE-HGF)0$$aWeishaupt, Jochen H$$b11
000257342 7001_ $$0P:(DE-2719)2380559$$aPrudlo, Johannes$$b12$$udzne
000257342 7001_ $$aForsberg, Karin$$b13
000257342 7001_ $$aAndersen, Peter M$$b14
000257342 7001_ $$0P:(DE-HGF)0$$aRosenbohm, Angela$$b15
000257342 7001_ $$0P:(DE-2719)9002279$$aSchuster, Joachim$$b16$$udzne
000257342 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b17$$udzne
000257342 7001_ $$aDupuis, Luc$$b18
000257342 7001_ $$aMayer, Benjamin$$b19
000257342 7001_ $$0P:(DE-2719)9002007$$aTumani, Hayrettin$$b20$$udzne
000257342 7001_ $$0P:(DE-2719)9001967$$aKassubek, Jan$$b21$$udzne
000257342 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert C$$b22$$eLast author$$udzne
000257342 773__ $$0PERI:(DE-600)2799017-5$$a10.1016/j.ebiom.2023.104521$$gVol. 90, p. 104521 -$$p104521$$tEBioMedicine$$v90$$x2352-3964$$y2023
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