TY - JOUR
T1 - Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis
AU - the ALS Registry Swabia Study Group
AU - Witzel, Simon
AU - Huss, André
AU - Nagel, Gabriele
AU - Rosenbohm, Angela
AU - Rothenbacher, Dietrich
AU - Peter, Raphael S.
AU - Bäzner, Hansjörg
AU - Börtlein, Axel
AU - Dempewolf, Silke
AU - Schabet, Martin
AU - Hecht, Martin
AU - Kohler, Andreas
AU - Opherk, Christian
AU - Naegele, Andrea
AU - Sommer, Norbert
AU - Lindner, Alfred
AU - Alexudis, Christoforos
AU - Bachhuber, Franziska
AU - Halbgebauer, Steffen
AU - Brenner, David
AU - Ruf, Wolfgang
AU - Weiland, Ulrike
AU - Mayer, Benjamin
AU - Schuster, Joachim
AU - Dorst, Johannes
AU - Tumani, Hayrettin
AU - Ludolph, Albert C.
AU - Alber, B.
AU - Andres, F.
AU - Arnold, G.
AU - Asshauer, I.
AU - Baezner, H.
AU - Baier, H.
AU - Baumgärtner, J.
AU - Beattie, J.
AU - Becker, T.
AU - Behne, F.
AU - Bengel, D.
AU - Bergmeier, C.
AU - Boertlein, A.
AU - Born, Ch
AU - Bracknies, V.
AU - Broer, R.
AU - Bürgy, M.
AU - Buttmann, M.
AU - Clauer-Bredt, M.
AU - Connemann, B.
AU - Dempewolf, S.
AU - Hemmer, B.
AU - Lingor, P.
N1 - Publisher Copyright:
© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85202071751&partnerID=8YFLogxK
U2 - 10.1002/ana.27054
DO - 10.1002/ana.27054
M3 - Article
C2 - 39177232
AN - SCOPUS:85202071751
SN - 0364-5134
JO - Annals of Neurology
JF - Annals of Neurology
ER -