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Neurodegeneration
Original research
Comparison of CSF and serum neurofilament light and heavy chain as differential diagnostic biomarkers for ALS
  1. Steffen Halbgebauer1,
  2. Petra Steinacker1,
  3. Federico Verde2,3,
  4. Jochen Weishaupt4,
  5. Patrick Oeckl1,5,
  6. Christine von Arnim6,
  7. Johannes Dorst1,
  8. Emily Feneberg7,
  9. Benjamin Mayer8,
  10. Angela Rosenbohm1,
  11. Vincenzo Silani2,3,
  12. Albert C Ludolph1,
  13. Markus Otto1,9
  1. 1Neurology, University of Ulm, Ulm, Germany
  2. 2Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy
  3. 3Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milano, Italy
  4. 4Department of Neurology, Institute for Neurodegeneration, Universitätsmedizin Mannheim, Mannheim, Germany
  5. 5Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE e.V.), Ulm, Germany
  6. 6Department of Geriatrics, University Medical Center, Göttingen, Germany
  7. 7Department of Neurology, University Hospital Rechts der Isar, Munich, Bayern, Germany
  8. 8Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
  9. 9Department of Neurology, University clinic, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
  1. Correspondence to Professor Markus Otto, Neurology, University of Ulm, Ulm, Germany and Department of Neurology, University clinic, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; markus.otto{at}uk-halle.de

Abstract

Objective Elevated levels of neurofilament light (NfL) and heavy (NfH) chain in amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) and serum reflect neuro-axonal degeneration and are used as diagnostic biomarkers. However, studies comparing the differential diagnostic potential for ALS of all four parameters are missing. Here, we measured serum NfL/NfH and CSF NfL/NfH in a large cohort of ALS and other neurological disorders and analysed the differential diagnostic potential.

Methods In total CSF and serum of 294 patients were analysed. The diagnostic groups comprised: ALS (n=75), frontotemporal lobar degeneration (FTLD) (n=33), Alzheimer’s disease (n=20), Parkinson’s disease (dementia) (n=18), Creutzfeldt-Jakob disease (n=11), non-neurodegenerative controls (n=77) (Con) and 60 patients who were seen under the direct differential diagnosis of a patient with ALS (Con.DD).

Results CSF and serum NfL and NfH showed significantly increased levels in ALS (p<0.0001) compared with Con and Con.DD. The difference between ALS and FTLD was markedly stronger for NfH than for NfL. CSF and serum NfL demonstrated a stronger correlation (r=0.84 (95% CI 0.80 to 0.87), p<0.001) than CSF and serum NfH (r=0.68 (95% CI 0.61 to 0.75), p<0.0001). Comparing ALS and Con.DD, receiver operating characteristic analysis revealed the best area under the curve (AUC) value for CSF NfL (AUC=0.94, 95% CI 0.91 to 0.98), followed by CSF NfH (0.93, 95% CI 0.88 to 0.98), serum NfL (0.93, 95% CI 0.89 to 0.97) and serum NfH (0.88, 95% CI 0.82 to 0.94).

Conclusion Our results demonstrate that CSF NfL and NfH as well as serum NfL are equally suited for the differential diagnosis of ALS, whereas serum NfH appears to be slightly less potent.

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study are included in the article and the supplementary information.

https://doi.org/10.1136/jnnp-2021-327129

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study are included in the article and the supplementary information.

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    Footnotes

    • Contributors All authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data. All authors gave final approval of the version to be submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Conception and design of the study: SH, PS and MO; Sample collection and data management: SH, PS, FV, JW, PO, CVA, JD, EF, BM, AR, VS, ACL and MO; Study management and coordination: SH, MO; Statistical methods and analysis: SH, PS, BM and MO; Interpretation of results: SH, PS, FV, JW, PO, CVA, JD, EF, BM, AR, VS, ACL and MO; Manuscript writing (first draft): SH and MO; Critical revision of the manuscript: SH, PS, FV, JW, PO, CVA, JD, EF, BM, AR, VS, ACL and MO.

    • Funding This study was supported by the EU Joint Programme-Neurodegenerative Diseases networks Genfi-Prox (01ED2008A), the German Federal Ministry of Education and Research (FTLDc 01GI1007A), the EU (Moodmarker) programme (01EW2008), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009), the Thierry Latran Foundation (D.2468) and the ALS association (D.5809).

    • Competing interests SH, PS, FV, JW, PO, JD, EF, BM, AR, VS and ACL report no competing interests. CVA received honoraria from serving on the scientific advisory board of Biogen, Roche, and Willmar Schwabe & Co. KG and has received funding for travel and speaker honoraria from Lilly GmbH, Daiichi Sankyo, Biogen, Roche diagnostics AG and Willmar Schwabe GmbH &Co. KG and has received research support from Roche diagnostics AG. MO gave scientific advice for Fujirebio, Roche, Biogen and Axon.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.