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. 2024 Dec;96(6):1040-1057.
doi: 10.1002/ana.27054. Epub 2024 Aug 23.

Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis

Simon Witzel  1 , André Huss  1 , Gabriele Nagel  2 , Angela Rosenbohm  1 , Dietrich Rothenbacher  2 , Raphael S Peter  2 , Hansjörg Bäzner  3 , Axel Börtlein  3 , Silke Dempewolf  4 , Martin Schabet  4 , Martin Hecht  5 , Andreas Kohler  6 , Christian Opherk  6 , Andrea Naegele  7 , Norbert Sommer  7 , Alfred Lindner  8 , Christoforos Alexudis  1 , Franziska Bachhuber  1 , Steffen Halbgebauer  1   9 , David Brenner  1 , Wolfgang Ruf  1 , Ulrike Weiland  1 , Benjamin Mayer  2 , Joachim Schuster  1   9 , Johannes Dorst  1 , Hayrettin Tumani  1   9 , Albert C Ludolph  1   9 ; and the ALS Registry Swabia Study Group
Collaborators, Affiliations

Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis

Simon Witzel et al. Ann Neurol. 2024 Dec.

Abstract

Objective: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.

Methods: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.

Results: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.

Interpretation: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.

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References

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