Volume 7, Issue 4 p. 386-395.e6
Featured Article

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Niklas Mattsson

Corresponding Author

Niklas Mattsson

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

Corresponding author. Tel.: +46-706-393-851; Fax: +46-313-432-426.

E-mail address: [email protected]

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Ulf Andreasson

Ulf Andreasson

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

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Staffan Persson

Staffan Persson

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

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Hiroyuki Arai

Hiroyuki Arai

Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

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Sat Dev Batish

Sat Dev Batish

Athena Diagnostics Inc., Worchester, MA, USA

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Sergio Bernardini

Sergio Bernardini

Department Biochimica Clinica, Policlinico, University of Tor Vergata, Rome, Italy

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Luisella Bocchio-Chiavetto

Luisella Bocchio-Chiavetto

IRCCS Centro S. Giovanni di Dio—Fatebenefratelli, Brescia, Italy

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Marinus A. Blankenstein

Marinus A. Blankenstein

Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

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Maria C. Carrillo

Maria C. Carrillo

The Alzheimer's Association, Chicago, IL, USA

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Sonia Chalbot

Sonia Chalbot

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

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Els Coart

Els Coart

Innogenetics, Ghent, Belgium

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Davide Chiasserini

Davide Chiasserini

Section of Neurology, Laboratory of Clinical Neurochemistry, Centre for Memory Disturbances, University of Perugia, Perugia, Italy

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Neal Cutler

Neal Cutler

Worldwide Clinical Trials, King of Prussia, PA, USA

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Gunilla Dahlfors

Gunilla Dahlfors

Department of Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden

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Stefan Duller

Stefan Duller

JSW Life Sciences GmbH, Grambach, Austria

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Anne M. Fagan

Anne M. Fagan

Department of Neurology, Alzheimer's Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

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Orestes Forlenza

Orestes Forlenza

Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil

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Giovanni B. Frisoni

Giovanni B. Frisoni

IRCCS Centro S. Giovanni di Dio—Fatebenefratelli, Brescia, Italy

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Douglas Galasko

Douglas Galasko

Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA

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Daniela Galimberti

Daniela Galimberti

Department of Neurological Sciences, University of Milan, Milan, Italy

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Harald Hampel

Harald Hampel

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany

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Aase Handberg

Aase Handberg

Department of Clinical Biochemistry, Aarhus Hospital, Aarhus University Hospital, Aarhus, Denmark

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Michael T. Heneka

Michael T. Heneka

Klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, University of Bonn, Bonn, Germany

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Adrianna Z. Herskovits

Adrianna Z. Herskovits

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Massachusetts Alzheimer Disease Research Center, Harvard Medical School, Charlestown, MA, USA

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Sanna-Kaisa Herukka

Sanna-Kaisa Herukka

Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland

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David M. Holtzman

David M. Holtzman

Department of Neurology, Alzheimer's Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

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Christian Humpel

Christian Humpel

Laboratory of Psychiatry and Experimental Alzheimers Research, Innsbruck Medical University, Innsbruck, Austria

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Bradley T. Hyman

Bradley T. Hyman

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Massachusetts Alzheimer Disease Research Center, Harvard Medical School, Charlestown, MA, USA

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Khalid Iqbal

Khalid Iqbal

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

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Mathias Jucker

Mathias Jucker

Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen and DZNE—German Center for Neurodegenerative Diseases, Tübingen, Germany

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Stephan A. Kaeser

Stephan A. Kaeser

Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen and DZNE—German Center for Neurodegenerative Diseases, Tübingen, Germany

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Elmar Kaiser

Elmar Kaiser

Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany

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Elisabeth Kapaki

Elisabeth Kapaki

1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Daniel Kidd

Daniel Kidd

Janssen Alzheimer Immunotherapy Research and Development, South San Francisco, CA, USA

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Peter Klivenyi

Peter Klivenyi

Department of Neurology, University of Szeged, Szeged, Hungary

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Cindy S. Knudsen

Cindy S. Knudsen

Department of Clinical Biochemistry, Aarhus Hospital, Aarhus University Hospital, Aarhus, Denmark

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Markus P. Kummer

Markus P. Kummer

Klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, University of Bonn, Bonn, Germany

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James Lui

James Lui

Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia

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Albert LladÓ

Albert LladÓ

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'InvestigaciÓ BiomÉdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain

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Piotr Lewczuk

Piotr Lewczuk

Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Erlangen, Germany

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Qiao-Xin Li

Qiao-Xin Li

Neuropathology Research Group, The Mental Health Research Institute, University of Melbourne, Melbourne, Australia

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Ralph Martins

Ralph Martins

Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia

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Colin Masters

Colin Masters

Neuropathology Research Group, The Mental Health Research Institute, University of Melbourne, Melbourne, Australia

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John McAuliffe

John McAuliffe

Athena Diagnostics Inc., Worchester, MA, USA

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Marc Mercken

Marc Mercken

Janssen Pharmaceutica, J&J, Beerse, Belgium

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Abhay Moghekar

Abhay Moghekar

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

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JosÉ Luis Molinuevo

JosÉ Luis Molinuevo

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'InvestigaciÓ BiomÉdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain

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Thomas J. Montine

Thomas J. Montine

Department of Pathology, University of Washington, Seattle, WA, USA

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William Nowatzke

William Nowatzke

Worldwide Clinical Trials, King of Prussia, PA, USA

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Richard O'Brien

Richard O'Brien

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

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Markus Otto

Markus Otto

Department of Neurology, University of Ulm, Ulm, Germany

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George P. Paraskevas

George P. Paraskevas

1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Lucilla Parnetti

Lucilla Parnetti

Section of Neurology, Laboratory of Clinical Neurochemistry, Centre for Memory Disturbances, University of Perugia, Perugia, Italy

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Ronald C. Petersen

Ronald C. Petersen

Alzheimer's Disease Research Center, Mayo Clinic, Rochester, MN, USA

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David Prvulovic

David Prvulovic

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany

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Herman P.M. de Reus

Herman P.M. de Reus

Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Nijmegen, The Netherlands

Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Nijmegen, The Netherlands

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Robert A. Rissman

Robert A. Rissman

Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA

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Elio Scarpini

Elio Scarpini

Department of Neurological Sciences, University of Milan, Milan, Italy

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Alessandro Stefani

Alessandro Stefani

IRCCS Fondazione S. Lucia, Rome, Italy

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Hilkka Soininen

Hilkka Soininen

Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland

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Johannes Schröder

Johannes Schröder

Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany

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Leslie M. Shaw

Leslie M. Shaw

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center (ADNI Biomarker Core), Philadelphia, PA, USA

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Anders Skinningsrud

Anders Skinningsrud

Department of Clinical Biochemistry, Center of Laboratory Medicine, Akershus University Hospital, Oslo, Norway

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Brith Skrogstad

Brith Skrogstad

Department of Clinical Biochemistry, Center of Laboratory Medicine, Akershus University Hospital, Oslo, Norway

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Annette Spreer

Annette Spreer

Department of Neurology, University of Göttingen, Göttingen, Germany

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Leda Talib

Leda Talib

Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil

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Charlotte Teunissen

Charlotte Teunissen

Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

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John Q. Trojanowski

John Q. Trojanowski

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center (ADNI Biomarker Core), Philadelphia, PA, USA

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Hayrettin Tumani

Hayrettin Tumani

Department of Neurology, University of Ulm, Ulm, Germany

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Robert M. Umek

Robert M. Umek

Meso Scale Discovery, Gaithersburg, MD, USA

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Bianca Van Broeck

Bianca Van Broeck

Janssen Pharmaceutica, J&J, Beerse, Belgium

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Hugo Vanderstichele

Hugo Vanderstichele

Innogenetics, Ghent, Belgium

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Laszlo Vecsei

Laszlo Vecsei

Department of Neurology, University of Szeged, Szeged, Hungary

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Marcel M. Verbeek

Marcel M. Verbeek

Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Nijmegen, The Netherlands

Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Nijmegen, The Netherlands

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Manfred Windisch

Manfred Windisch

JSW Life Sciences GmbH, Grambach, Austria

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Jing Zhang

Jing Zhang

Department of Pathology, University of Washington, Seattle, WA, USA

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Henrik Zetterberg

Henrik Zetterberg

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

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Kaj Blennow

Kaj Blennow

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

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First published: 01 July 2011
Citations: 298

Abstract

Background

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

Methods

The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.

Results

Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories.

Conclusions

Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.