Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Patrick Oeckl¹, Claude Jardel², François Salachas³, Foudil Lamari², Peter M Andersen⁴, Robert Bowser^{5

6}, Mamede de Carvalho⁷, Júlia Costa⁸, Philip van Damme^{9

10}, Elizabeth Gray¹¹, Julian Grosskreutz¹², María Hernández-Barral¹³, Sanna-Kaisa Herukka¹⁴, André Huss¹, Andreas Jeromin⁵, Janine Kirby¹⁵, Magdalena Kuzma-Kozakiewicz¹⁶, Maria Del Mar Amador³, Jesús S Mora¹³, Claudia Morelli¹⁷, Petra Muckova¹⁸, Susanne Petri¹⁹, Koen Poesen²⁰, Heidrun Rhode¹⁸, Anna-Karin Rikardsson⁴, Wim Robberecht¹⁰, Ana I Rodríguez Mahillo¹³, Pamela Shaw¹⁵, Vincenzo Silani^{17

21}, Petra Steinacker¹, Martin R Turner¹¹, Erdem Tüzün²², Berrak Yetimler²², Albert C Ludolph¹, Markus Otto¹

Affiliations

¹ a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
² b Department of Metabolic Biochemistry , Hôpitaux universitaires Pitié Salpétrière-Charles Foix , 75651 Paris , France .
³ c Paris ALS Reference Center, Neurological Diseases Department , Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix , 75651 Paris , France .
⁴ d Department of Neurology , University of Umea , 90185 Umea , Sweden .
⁵ e Iron Horse Diagnostics, Inc. , 85255 Scottsdale , Arizona , USA .
⁶ f Divisions of Neurology and Neurobiology , Barrow Neurological Institute , 85013 Phoenix , Arizona , USA .
⁷ g Faculty of Medicine - Instituto de Medicina Molecular , University of Lisbon , 1649-028 Lisbon , Portugal .
⁸ h Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , 2780-157 Oeiras , Portugal .
⁹ i University Hospitals Leuven , Department of Neurology , 3000 Leuven , Belgium .
¹⁰ s KU Leuven - University of Leuven , Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology , Leuven , Belgium .
¹¹ j Nuffield Department of Clinical Neurosciences , University of Oxford , OX3 9DU Oxford , UK .
¹² k Department of Neurology , Jena University Hospital , 07747 Jena , Germany .
¹³ t ALS Unit, Hospital Carlos III, Madrid , 28029 Madrid , Spain .
¹⁴ l Department of Neurology , University of Eastern Finland and Kuopio University Hospital , 70211 Kuopio , Finland .
¹⁵ m Department of Neuroscience , Sheffield Institute for Translational Neuroscience, University of Sheffield , S10 2HQ Sheffield , UK .
¹⁶ n Department of Neurology , Medical University of Warsaw , 02-097 Warsaw , Poland .
¹⁷ o IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy .
¹⁸ p Institute of Biochemistry I, Jena University Hospital , 07743 Jena , Germany .
¹⁹ q Department of Neurology , Hannover Medical School , 30625 Hannover , Germany .
²⁰ r Laboratory of molecular neurobiomarker research , University of Leuven and Laboratory Medicine, University Hospitals of Leuven , 3000 Leuven , Belgium .
²¹ v Department "Dino Ferrari" Center, Department of Pathophysiology and Transplantation , Università degli Studi di Milano , 20122 Milano , Italy.
²² u Neuroscience Department , Institute of Experimental Medical Research, Istanbul University , 34393 Istanbul , Turkey , and.

PMID: 27415180
DOI: 10.3109/21678421.2016.1167913

Multicenter Study

Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS

Patrick Oeckl et al. Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug.

. 2016 Jul-Aug;17(5-6):404-13.

doi: 10.3109/21678421.2016.1167913. Epub 2016 Apr 11.

Authors

Affiliations

¹ a Department of Neurology , Ulm University Hospital , 89081 Ulm , Germany ;
² b Department of Metabolic Biochemistry , Hôpitaux universitaires Pitié Salpétrière-Charles Foix , 75651 Paris , France .
³ c Paris ALS Reference Center, Neurological Diseases Department , Hôpitaux universitaires La Pitié Salpêtrière-Charles Foix , 75651 Paris , France .
⁴ d Department of Neurology , University of Umea , 90185 Umea , Sweden .
⁵ e Iron Horse Diagnostics, Inc. , 85255 Scottsdale , Arizona , USA .
⁶ f Divisions of Neurology and Neurobiology , Barrow Neurological Institute , 85013 Phoenix , Arizona , USA .
⁷ g Faculty of Medicine - Instituto de Medicina Molecular , University of Lisbon , 1649-028 Lisbon , Portugal .
⁸ h Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , 2780-157 Oeiras , Portugal .
⁹ i University Hospitals Leuven , Department of Neurology , 3000 Leuven , Belgium .
¹⁰ s KU Leuven - University of Leuven , Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology , Leuven , Belgium .
¹¹ j Nuffield Department of Clinical Neurosciences , University of Oxford , OX3 9DU Oxford , UK .
¹² k Department of Neurology , Jena University Hospital , 07747 Jena , Germany .
¹³ t ALS Unit, Hospital Carlos III, Madrid , 28029 Madrid , Spain .
¹⁴ l Department of Neurology , University of Eastern Finland and Kuopio University Hospital , 70211 Kuopio , Finland .
¹⁵ m Department of Neuroscience , Sheffield Institute for Translational Neuroscience, University of Sheffield , S10 2HQ Sheffield , UK .
¹⁶ n Department of Neurology , Medical University of Warsaw , 02-097 Warsaw , Poland .
¹⁷ o IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, 20149 Milano, Italy .
¹⁸ p Institute of Biochemistry I, Jena University Hospital , 07743 Jena , Germany .
¹⁹ q Department of Neurology , Hannover Medical School , 30625 Hannover , Germany .
²⁰ r Laboratory of molecular neurobiomarker research , University of Leuven and Laboratory Medicine, University Hospitals of Leuven , 3000 Leuven , Belgium .
²¹ v Department "Dino Ferrari" Center, Department of Pathophysiology and Transplantation , Università degli Studi di Milano , 20122 Milano , Italy.
²² u Neuroscience Department , Institute of Experimental Medical Research, Istanbul University , 34393 Istanbul , Turkey , and.

PMID: 27415180
DOI: 10.3109/21678421.2016.1167913

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: Cerebrospinal fluid; amyotrophic lateral sclerosis; biomarker; neurofilament; round robin.

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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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