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Research paper
Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients
  1. Petra Steinacker1,
  2. Emily Feneberg1,
  3. Jochen Weishaupt1,
  4. Johannes Brettschneider1,
  5. Hayrettin Tumani1,
  6. Peter M Andersen2,
  7. Christine A F von Arnim1,
  8. Sarah Böhm1,
  9. Jan Kassubek1,
  10. Christian Kubisch3,4,
  11. Dorothée Lulé1,
  12. Hans-Peter Müller1,
  13. Rainer Muche5,
  14. Elmar Pinkhardt1,
  15. Patrick Oeckl1,
  16. Angela Rosenbohm1,
  17. Sarah Anderl-Straub1,
  18. Alexander E Volk3,4,
  19. Patrick Weydt1,
  20. Albert C Ludolph1,
  21. Markus Otto1
  1. 1Department of Neurology, University of Ulm, Ulm, Germany
  2. 2Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
  3. 3Institute of Human Genetics, University of Ulm, Ulm, Germany
  4. 4Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  5. 5Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  1. Correspondence to Dr Markus Otto, Department of Neurology, Ulm University Hospital, Oberer Eselsberg 45, Ulm D-89081, Germany; markus.otto{at}uni-ulm.de

Abstract

Objectives Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics).

Methods In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed.

Results Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration.

Conclusions Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

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