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Multicenter Study
. 2024 Sep;31(9):e16379.
doi: 10.1111/ene.16379. Epub 2024 Jun 10.

Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study

Thomas Meyer  1   2 , Marie Dreger  1 , Torsten Grehl  3 , Ute Weyen  4 , Dagmar Kettemann  1 , Patrick Weydt  5   6 , René Günther  7   8 , Paul Lingor  9   10 , Susanne Petri  11 , Jan Christoph Koch  12 , Julian Großkreutz  13 , Annekathrin Rödiger  14   15 , Petra Baum  16 , Andreas Hermann  17   18 , Johannes Prudlo  17   18 , Matthias Boentert  19 , Jochen H Weishaupt  20 , Wolfgang N Löscher  21 , Johannes Dorst  22   23 , Yasemin Koc  1 , Sarah Bernsen  1   5   6 , Isabell Cordts  9 , Maximilian Vidovic  7 , Robert Steinbach  14 , Moritz Metelmann  16 , Vera E Kleinveld  21 , Jenny Norden  1 , Albert Ludolph  22   23 , Bertram Walter  1 , Peggy Schumann  1   2 , Christoph Münch  1   2 , Péter Körtvélyessy  1 , André Maier  1
Affiliations
Multicenter Study

Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study

Thomas Meyer et al. Eur J Neurol. 2024 Sep.

Abstract

Objective: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS).

Methods: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival.

Results: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001).

Conclusions: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.

Keywords: NfL; amyotrophic lateral sclerosis; biomarker; phenotype; serum neurofilament light chain.

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Conflict of interest statement

T.M. has received grants, personal fees, non‐financial support, and research support from AL‐S Pharma, Amylyx, Cytokinetics, Ferrer, Mitsubishi Tanabe, Sanofi, Orphazyme, and served on the advisory boards of Amylyx, Biogen, and ITF Pharma outside of the submitted work. T.M. and C.M. are founders and shareholders of the Ambulanzpartner Soziotechnologie APST GmbH, which makes the mobile application “ALS‐App.” T.G. has received personal fees from ITF Pharma and served on the advisory boards of Amylyx and ITF Pharma outside of the submitted work. P.W. has served on advisory boards of Biogen, ITF Pharma, and Novartis outside of the submitted work. R.G. has received grants, personal fees, non‐financial support, and research support from Biogen and served on the advisory boards of Biogen, Roche, and ITF Pharma outside of the submitted work. P.L. has received consulting fees from AbbVie, Alexion, BIAL, Desitin, ITF Pharma, STADA Pharm, Woolsey Pharmaceuticals, and Zambon outside of the submitted work. He is co‐inventor on patents EP 2825175 B1, US 9.980,972 B2 for the use of Fasudil in ALS. J.C.K. has received consulting fees and compensations for talks from Biogen, Roche, and AbbVie and has served on advisory boards for Biogen and Roche. S.P. has received speaker fees, non‐financial support, and research support from Biogen, Roche, ALS Pharma, Amylyx, Cytokinetics, Ferrer, ITF Pharma, and Sanofi and served on advisory boards of Amylyx, Biogen, Roche, Zambon, and ITF Pharma outside of the submitted work. A.H. has received funding from the European Social Fonds, the Federal Ministry of Education and Research, and the “Hermann und Lilly Schilling‐Stiftung für medizinische Forschung im Stifterverband”, honoraria for presentations/advisory boards from Amylyx, Desitin, and ITF Pharma, and royalties from Elsevier Press and Kohlhammer. J.P. has received consulting fees from Hormosan Pharma. M.B. has served on advisory boards for Sanofi, Amicus, and Biogen and has received speaker honoraria from Sanofi, Amicus, ITF Pharma, and Biogen, and financial research support from Sanofi and Löwenstein Medical, all outside of the submitted work. J.D. has received speaker honoraria from Biogen, ITF Pharma, and Zambon. I.C. received personal fees from Biogen and Roche (speaker honoraria and/or participation in advisory boards) outside the submitted work. A.L. has served on advisory boards of Roche, Biogen, Alector, and Amylyx and received compensation from Biologix, German Society of Neurology, Biogen, Springer Medicine, Amylyx, and Streamed Up!, and financial research support from Amylyx, Biogen, Ferrer International, Novartis, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, Orphazyme, the European Union, and BMBF. P.K. received consulting fees from Biogen. R.S. has received honoraria for presentations from ITF Pharma outside of the submitted work. A.M. has received personal fees, non‐financial support, and research support from ITF Pharma and Zambon outside the submitted work. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Studied amyotrophic lateral sclerosis cohort and patient stratification. For phenotyping, two anatomic determinants were distinguished: the variable dysfunction of upper and lower motor neurons (motor neuron phenotypes) and onset and propagation of motor neuron dysfunction throughout the body regions (onset and propagation phenotypes).
FIGURE 2
FIGURE 2
Serum neurofilament light chain in correlation to phenotypes. For phenotyping, two anatomical determinants of motor neuron dysfunction were distinguished: (1) motor neuron involvement phenotypes with variable involvement of upper and lower motor neuron dysfunction and (2) onset and propagation phenotypes with distinct onset and propagation of motor neuron dysfunction throughout the body regions. LMNp, lower motor neuron predominant phenotype; PLS, primary lateral sclerosis; sNfL, serum neurofilament light chain; UMNp, upper motor neuron predominant phenotype. The bar indicates the median, hinges extend from the 25th to the 75th percentile. Significance levels are indicated as: **p ≤ 0.05, ***p ≤ 0.01, ****p ≤ 0.001; non‐significant differences are not shown.
FIGURE 3
FIGURE 3
Amyotrophic lateral sclerosis progression rate in correlation to phenotypes. For phenotyping, two anatomical determinants of motor neuron dysfunction were distinguished: (1) motor neuron phenotypes with variable involvement of upper and lower motor neurons and (2) onset and propagation phenotypes with distinct onset and propagation of motor neuron dysfunction throughout the body regions. ALS, amyotrophic lateral sclerosis; ALS‐PR, ALS progression rate; LMNp, lower motor neuron predominant phenotype; MN, motor neuron, UMNp, upper motor neuron predominant phenotype; PLS, primary lateral sclerosis; typical, upper and lower motor neuron involvement. The bar indicates the median, hinges extend from the 25th to the 75th percentile. Significance levels are indicated as: **p ≤ 0.05, ****p ≤ 0.0001.
FIGURE 4
FIGURE 4
Correlation of phenotypes with survival probability. For phenotyping, two anatomical determinants of motor neuron dysfunction were distinguished: (a) motor neuron phenotypes with variable involvement of upper and lower motor neurons and (b) onset and propagation phenotypes with distinct onset and propagation of motor neuron dysfunction throughout the body regions. LMNp, lower motor neuron predominant phenotype; PLS, primary lateral sclerosis; UMNp, upper motor neuron predominant phenotype.
FIGURE 5
FIGURE 5
Contribution of phenotypes to elevation of neurofilament light chain (NfL). Results of binomial logistic regression analysis to determine the concurrent effect of phenotypes, age, and amyotrophic lateral sclerosis progression rate on serum neurofilament light chain (sNfL) concentrations. For motor neuron involvement phenotypes, the typical phenotype served as reference category whereas for onset/propagation phenotypes, the limb onset phenotype served as reference. Odds ratios determine the likelihood of reaching high sNfL concentrations (>93.5 pg/mL, highest third in the cohort). ALS‐PR, amyotrophic lateral sclerosis progression rate; CI, confidence interval; LMNp, lower motor neuron predominant phenotype; OR, odds ratio; PLS, primary lateral sclerosis; UMNp, upper motor neuron predominant phenotype.
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