title: Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients.
abstract: OBJECTIVE
  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.
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Petra
authors: P
authors: Steinacker
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Emily
authors: E
authors: Feneberg
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Jochen
authors: J
authors: Weishaupt
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Johannes
authors: J
authors: Brettschneider
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Hayrettin
authors: H
authors: Tumani
authors: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors: Peter M
authors: PM
authors: Andersen
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Christine A F
authors: CA
authors: von Arnim
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Sarah
authors: S
authors: Böhm
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Jan
authors: J
authors: Kassubek
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christian
authors: C
authors: Kubisch
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Dorothée
authors: D
authors: Lulé
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Hans-Peter
authors: HP
authors: Müller
authors: Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
authors: Rainer
authors: R
authors: Muche
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Elmar
authors: E
authors: Pinkhardt
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Patrick
authors: P
authors: Oeckl
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Angela
authors: A
authors: Rosenbohm
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Sarah
authors: S
authors: Anderl-Straub
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Alexander E
authors: AE
authors: Volk
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Patrick
authors: P
authors: Weydt
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Albert C
authors: AC
authors: Ludolph
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Markus
authors: M
authors: Otto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid / Q000175:diagnosis; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004247:DNA / Q000235:genetics; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D007382:Intermediate Filaments / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid; D009460:Neurologic Examination; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D015203:Reproducibility of Results; D055815:Young Adult; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D015415:Biomarkers; C054369:MAPT protein, human; D016900:Neurofilament Proteins; D016875:tau Proteins; D004247:DNA