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Research Article

Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Patrick OecklDepartment of Neurology, Ulm University Hospital, 89081Ulm, Germany;

, PHD,

Claude JardelDepartment of Metabolic Biochemistry, Hôpitaux universitaires Pitié Salpétrière-Charles Foix, 75651Paris, France,

, PharmD, PhD,

François SalachasParis ALS Reference Center, Neurological Diseases Department, Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix, 75651Paris, France,

, MD,

Foudil LamariDepartment of Metabolic Biochemistry, Hôpitaux universitaires Pitié Salpétrière-Charles Foix, 75651Paris, France,

, MD,

Peter M. AndersenDepartment of Neurology, University of Umea, 90185Umea, Sweden,

, MD, PhD,

Robert BowserIron Horse Diagnostics, Inc., 85255Scottsdale, Arizona, USA, ;Divisions of Neurology and Neurobiology, Barrow Neurological Institute, 85013Phoenix, Arizona, USA,

, PhD,

Mamede de CarvalhoFaculty of Medicine - Instituto de Medicina Molecular, University of Lisbon, 1649-028Lisbon, Portugal,

, PhD,

Júlia CostaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157Oeiras, Portugal,

, PhD,

Philip van DammeUniversity Hospitals Leuven, Department of Neurology, 3000Leuven, Belgium, ;KU Leuven - University of Leuven, Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium,

, MD, PhD,

Elizabeth GrayNuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DUOxford, UK,

, PhD,

Julian GrosskreutzDepartment of Neurology, Jena University Hospital, 07747Jena, Germany,

, MD,

María Hernández-BarralALS Unit, Hospital Carlos III, Madrid, 28029Madrid, Spain,

, MD,

Sanna-Kaisa HerukkaDepartment of Neurology, University of Eastern Finland and Kuopio University Hospital, 70211Kuopio, Finland,

, PhD, MD,

André HussDepartment of Neurology, Ulm University Hospital, 89081Ulm, Germany;

, MSc,

Andreas JerominIron Horse Diagnostics, Inc., 85255Scottsdale, Arizona, USA,

, PhD,

Janine KirbyDepartment of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, S10 2HQSheffield, UK,

, PhD,

Magdalena Kuzma-KozakiewiczDepartment of Neurology, Medical University of Warsaw, 02-097Warsaw, Poland,

, MD, PhD,

Maria del Mar AmadorParis ALS Reference Center, Neurological Diseases Department, Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix, 75651Paris, France,

, MD,

Jesús S. MoraALS Unit, Hospital Carlos III, Madrid, 28029Madrid, Spain,

, MD,

Claudia MorelliIRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy,

, MD,

Petra MuckovaInstitute of Biochemistry I, Jena University Hospital, 07743Jena, Germany,

, PhD,

Susanne PetriDepartment of Neurology, Hannover Medical School, 30625Hannover, Germany,

, MD,

Koen PoesenLaboratory of molecular neurobiomarker research, University of Leuven and Laboratory Medicine, University Hospitals of Leuven, 3000Leuven, Belgium,

, PharmD, PhD,

Heidrun RhodeInstitute of Biochemistry I, Jena University Hospital, 07743Jena, Germany,

, MD,

Anna-Karin RikardssonDepartment of Neurology, University of Umea, 90185Umea, Sweden,

Wim RobberechtKU Leuven - University of Leuven, Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium,

, MD, PhD,

Ana I. Rodríguez MahilloALS Unit, Hospital Carlos III, Madrid, 28029Madrid, Spain,

, PhD,

Pamela ShawDepartment of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, S10 2HQSheffield, UK,

, MD,

Vincenzo SilaniIRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy, ;Department “Dino Ferrari” Center, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122Milano, Italy

, MD,

Petra SteinackerDepartment of Neurology, Ulm University Hospital, 89081Ulm, Germany;

, PhD,

Martin R. TurnerNuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DUOxford, UK,

, PhD,

Erdem TüzünNeuroscience Department, Institute of Experimental Medical Research, Istanbul University, 34393Istanbul, Turkey, and

, MD, PhD,

Berrak YetimlerNeuroscience Department, Institute of Experimental Medical Research, Istanbul University, 34393Istanbul, Turkey, and

, MSc,

Albert C. LudolphDepartment of Neurology, Ulm University Hospital, 89081Ulm, Germany;

, MD &

Markus OttoDepartment of Neurology, Ulm University Hospital, 89081Ulm, Germany; Correspondence[email protected]

, MD show all

Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Keywords:

Acknowledgement

We are grateful to the excellent technical assistance of Imen Ben Younes, Dagmar Schattauer, Sandra Hübsch and Mehtap Bulut-Karac.

This study was supported by the JPND networks SOPHIA (01ED1202A) and BiomarkAPD (01ED1203F), the German Federal Ministry of Education and Research (FTLDc O1GI1007A, KKMS, MND-Net 01GM1103A, PYRAMID 01GM1304), the EU (NADINE 246513, FAIR-PARK II 633190), the foundation of the state Baden-Württemberg (D.3830), BIU (D.5009), the Scientific and Technological Research Council of Turkey (TUBITAK 112S362) and the E-rare grant PYRAMID (E-rare 12-093). MRT is funded by a Medical Research Council & Motor Neurone Disease Association Lady Edith Wolfson Senior Clinical Fellowship (MR/K01014X/1)

Declaration of interest

PVD holds a senior clinical investigatorship of FWO-Vlaanderen. The other authors report no conflicts of interest.

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Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

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Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

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