title: Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS.
abstract: Neurofilaments are leading neurochemical biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigated the effect of preanalytical factors on neurofilament concentrations in cerebrospinal fluid (CSF) in a "reverse" round-robin with 15 centers across Europe/U.S.
  
  
  
  Samples from ALS and control patients (5/5 each center, n = 150) were analyzed for phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at two laboratories.
  
  
  
  CSF pNfH was increased (p < 0.05) in ALS in 10 out of 15 centers and NfL in 5 out of 12 centers. The coefficient of variation (CV%) of pNfH measurements between laboratories was 18.7 ± 19.1%. We calculated a diagnostic cut-off of >568.5 pg/mL for pNfH (sensitivity 78.7%, specificity 93.3%) and >1,431pg/mL for NfL (sensitivity 79.0%, specificity 86.4%).
  
  
  
  Values in ALS patients are already comparable between most centers, supporting eventual implementation into clinical routine. However, continuous quality control programs will be necessary for inclusion in the diagnostic work-up.
authors.affiliation: a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
authors.forename: Patrick
authors.initials: P
authors.lastname: Oeckl
authors.affiliation: b Department of Metabolic Biochemistry , Hôpitaux universitaires Pitié Salpétrière-Charles Foix , 75651 Paris , France .
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.affiliation: c Paris ALS Reference Center, Neurological Diseases Department , Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix , 75651 Paris , France .
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.affiliation: b Department of Metabolic Biochemistry , Hôpitaux universitaires Pitié Salpétrière-Charles Foix , 75651 Paris , France .
authors.forename: Foudil
authors.initials: F
authors.lastname: Lamari
authors.affiliation: d Department of Neurology , University of Umea , 90185 Umea , Sweden .
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: e Iron Horse Diagnostics, Inc. , 85255 Scottsdale , Arizona , USA .|f Divisions of Neurology and Neurobiology , Barrow Neurological Institute , 85013 Phoenix , Arizona , USA .
authors.forename: Robert
authors.initials: R
authors.lastname: Bowser
authors.affiliation: g Faculty of Medicine - Instituto de Medicina Molecular , University of Lisbon , 1649-028 Lisbon , Portugal .
authors.forename: Mamede
authors.initials: M
authors.lastname: de Carvalho
authors.affiliation: h Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , 2780-157 Oeiras , Portugal .
authors.forename: Júlia
authors.initials: J
authors.lastname: Costa
authors.affiliation: i University Hospitals Leuven , Department of Neurology , 3000 Leuven , Belgium .|s KU Leuven - University of Leuven , Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology , Leuven , Belgium .
authors.forename: Philip
authors.initials: P
authors.lastname: van Damme
authors.affiliation: j Nuffield Department of Clinical Neurosciences , University of Oxford , OX3 9DU Oxford , UK .
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.affiliation: k Department of Neurology , Jena University Hospital , 07747 Jena , Germany .
authors.forename: Julian
authors.initials: J
authors.lastname: Grosskreutz
authors.affiliation: t ALS Unit, Hospital Carlos III, Madrid , 28029 Madrid , Spain .
authors.forename: María
authors.initials: M
authors.lastname: Hernández-Barral
authors.affiliation: l Department of Neurology , University of Eastern Finland and Kuopio University Hospital , 70211 Kuopio , Finland .
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
authors.forename: André
authors.initials: A
authors.lastname: Huss
authors.affiliation: e Iron Horse Diagnostics, Inc. , 85255 Scottsdale , Arizona , USA .
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeromin
authors.affiliation: m Department of Neuroscience , Sheffield Institute for Translational Neuroscience, University of Sheffield , S10 2HQ Sheffield , UK .
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.affiliation: n Department of Neurology , Medical University of Warsaw , 02-097 Warsaw , Poland .
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kuzma-Kozakiewicz
authors.affiliation: c Paris ALS Reference Center, Neurological Diseases Department , Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix , 75651 Paris , France .
authors.forename: Maria Del Mar
authors.initials: Mdel M
authors.lastname: Amador
authors.affiliation: t ALS Unit, Hospital Carlos III, Madrid , 28029 Madrid , Spain .
authors.forename: Jesús S
authors.initials: JS
authors.lastname: Mora
authors.affiliation: o IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy .
authors.forename: Claudia
authors.initials: C
authors.lastname: Morelli
authors.affiliation: p Institute of Biochemistry I, Jena University Hospital , 07743 Jena , Germany .
authors.forename: Petra
authors.initials: P
authors.lastname: Muckova
authors.affiliation: q Department of Neurology , Hannover Medical School , 30625 Hannover , Germany .
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.affiliation: r Laboratory of molecular neurobiomarker research , University of Leuven and Laboratory Medicine, University Hospitals of Leuven , 3000 Leuven , Belgium .
authors.forename: Koen
authors.initials: K
authors.lastname: Poesen
authors.affiliation: p Institute of Biochemistry I, Jena University Hospital , 07743 Jena , Germany .
authors.forename: Heidrun
authors.initials: H
authors.lastname: Rhode
authors.affiliation: d Department of Neurology , University of Umea , 90185 Umea , Sweden .
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Rikardsson
authors.affiliation: s KU Leuven - University of Leuven , Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology , Leuven , Belgium .
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: t ALS Unit, Hospital Carlos III, Madrid , 28029 Madrid , Spain .
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodríguez Mahillo
authors.affiliation: m Department of Neuroscience , Sheffield Institute for Translational Neuroscience, University of Sheffield , S10 2HQ Sheffield , UK .
authors.forename: Pamela
authors.initials: P
authors.lastname: Shaw
authors.affiliation: o IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy .|v Department "Dino Ferrari" Center, Department of Pathophysiology and Transplantation , Università degli Studi di Milano , 20122 Milano , Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
authors.forename: Petra
authors.initials: P
authors.lastname: Steinacker
authors.affiliation: j Nuffield Department of Clinical Neurosciences , University of Oxford , OX3 9DU Oxford , UK .
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
authors.affiliation: u Neuroscience Department , Institute of Experimental Medical Research, Istanbul University , 34393 Istanbul , Turkey , and.
authors.forename: Erdem
authors.initials: E
authors.lastname: Tüzün
authors.affiliation: u Neuroscience Department , Institute of Experimental Medical Research, Istanbul University , 34393 Istanbul , Turkey , and.
authors.forename: Berrak
authors.initials: B
authors.lastname: Yetimler
authors.affiliation: a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005060:Europe; D005260:Female; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D015203:Reproducibility of Results; D018709:Statistics, Nonparametric; D014481:United States
chemical_list: D015415:Biomarkers
keywords: Cerebrospinal fluid; amyotrophic lateral sclerosis; biomarker; neurofilament; round robin