Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers.

BACKGROUND

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.

METHODS

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.

FINDINGS

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).

INTERPRETATION

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.

FUNDING

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.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests JD reports honoraria for presentations from Biogen and ITF Pharma. PW reports grants or contracts from Alle Lieben Schmidt e.V., Boris Canessa Stiftung, and EHDN; consulting fees from Biogen, ITF Pharma, and Novartis. DB reports stocks from Ionis pharmaceuticals. PMA reports consultancies or advisory boards for Biogen, Roche, Avrion, Regeneron, uniQure and Orphazyme; clinical trial site investigator for Biogen, Alexion, Sanofi, Lilly AL-S Pharma, Amylyx, PTC Pharmaceuticals, Orion Pharma and Orphazyme; since 1993 Director of the ALS-genetic laboratory at Umeå University Hospital that performs clinical and research genetic testing; member of the ClinGen ALS Gene Curation Expert panel. LD reports grants from Cytokinetics and Lecture Fees from Cytokinetics. ACL reports grants or contracts from European Union (Horizon), BMBF, Deutsche Forschungsgemeinschaft (DFG), and Deutscher Akademischer Austauschdienst (DAAD) as well as sponsored trials by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, Biogen, and Orphazyme; payment for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx, and Streamed Up! GmbH; support for attending meetings and/or travel from Biogen; participation on advisory boards from Roche Pharme, Biogen, Alextor, and Amylyx; President of Deutsche Neurowissenschaftliche Gesellschaft (NWG). All other authors report no conflicts of interests.