Amyloid beta-Peptides; Biomarkers; Peptide Fragments; amyloid beta-protein (1-42); tau Proteins; Alzheimer Disease/cerebrospinal fluid; Alzheimer Disease/diagnosis; Amyloid beta-Peptides/cerebrospinal fluid; Biological Assay/methods; Biomarkers/cerebrospinal fluid; Enzyme-Linked Immunosorbent Assay; Humans; Peptide Fragments/cerebrospinal fluid; Phosphorylation; Reproducibility of Results; Sweden; Time Factors; tau Proteins/cerebrospinal fluid; Quality Control; Alzheimer's disease; Cerebrospinal fluid; External assurance; External control; Proficiency testing; Epidemiology; Health Policy; Developmental Neuroscience; Neurology (clinical); Geriatrics and Gerontology; Cellular and Molecular Neuroscience; Psychiatry and Mental Health
Abstract :
[en] [en] 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.
Disciplines :
Neurology
Author, co-author :
Mattsson, Niklas; 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. niklas.mattsson@neuro.gu.se
Andreasson, Ulf; Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
Persson, Staffan; Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
Arai, Hiroyuki; Department of Geriatrics and Gerontology, Institute of Development, Tohoku University, Sendai, Japan
Batish, Sat Dev; Athena Diagnostics Inc., Worchester, MA, United States
Bernardini, Sergio; Department Biochimica Clinica, Policlinico, University of Tor Vergata, Rome, Italy
Bocchio-Chiavetto, Luisella; IRCCS Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy
Blankenstein, Marinus A; Department of Clinical Chemistry, VU University Medical Center, Amsterdam, Netherlands
Carrillo, Maria C; Alzheimer's Association, Chicago, IL, United States
Chalbot, Sonia; Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
Coart, Els; Innogenetics, Ghent, Belgium
Chiasserini, Davide; Laboratory of Clinical Neurochemistry, Centre for Memory Disturbances, University of Perugia, Perugia, Italy
Cutler, Neal; Worldwide Clinical Trials, King of Prussia, PA, United States
Dahlfors, Gunilla; Department of Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
Duller, Stefan; JSW Life Sciences GmbH, Grambach, Austria
Fagan, Anne M; Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
Forlenza, Orestes; Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil
Frisoni, Giovanni B; IRCCS Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy
Galasko, Douglas; Department of Neurosciences, UCSD School of Medicine, San Diego, CA, United States
Galimberti, Daniela; Department of Neurological Sciences, University of Milan, Milan, Italy
Hampel, Harald; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany
Handberg, Aase; Department of Clinical Biochemistry, Aarhus Hospital, Aarhus University Hospital, Aarhus, Denmark
HENEKA, Michael ; Klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, University of Bonn, Bonn, Germany
Herskovits, Adrianna Z; MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
Herukka, Sanna-Kaisa; Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
Holtzman, David M; Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
Humpel, Christian; Laboratory of Psychiatry and Experimental Alzheimers Research, Innsbruck Medical University, Innsbruck, Austria
Hyman, Bradley T; MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
Iqbal, Khalid; Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
Jucker, Mathias; Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Kaeser, Stephan A; Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Kaiser, Elmar; Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany
Kapaki, Elisabeth; 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
Kidd, Daniel; Janssen Alzheimer Immunotherapy Research and Development, South San Francisco, CA, United States
Klivenyi, Peter; Department of Neurology, University of Szeged, Szeged, Hungary
Knudsen, Cindy S; Department of Clinical Biochemistry, Aarhus Hospital, Aarhus University Hospital, Aarhus, Denmark
Kummer, Markus P; Klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, University of Bonn, Bonn, Germany
Lui, James; Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia
Lladó, Albert; Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigació Biomédica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Lewczuk, Piotr; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Erlangen, Germany
Li, Qiao-Xin; Neuropathology Research Group, Mental Health Research Institute, University of Melbourne, Melbourne, Australia
Martins, Ralph; Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia
Masters, Colin; Neuropathology Research Group, Mental Health Research Institute, University of Melbourne, Melbourne, Australia
McAuliffe, John; Athena Diagnostics Inc., Worchester, MA, United States
Mercken, Marc; Janssen Pharmaceutica, J and J, Beerse, Belgium
Moghekar, Abhay; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
Molinuevo, José Luis; Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigació Biomédica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Montine, Thomas J; Department of Pathology, University of Washington, Seattle, WA, United States
Nowatzke, William; Worldwide Clinical Trials, King of Prussia, PA, United States
O'Brien, Richard; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
Otto, Markus; Department of Neurology, University of Ulm, Ulm, Germany
Paraskevas, George P; 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
Parnetti, Lucilla; Laboratory of Clinical Neurochemistry, Centre for Memory Disturbances, University of Perugia, Perugia, Italy
Petersen, Ronald C; Alzheimer's Disease Research Center, Mayo Clinic, Rochester, MN, United States
Prvulovic, David; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany
de Reus, Herman P M; Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands ; Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
Rissman, Robert A; Department of Neurosciences, UCSD School of Medicine, San Diego, CA, United States
Scarpini, Elio; Department of Neurological Sciences, University of Milan, Milan, Italy
Stefani, Alessandro; IRCCS Fondazione S. Lucia, Rome, Italy
Soininen, Hilkka; Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
Schröder, Johannes; Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany
Shaw, Leslie M; Department of Pathology, Laboratory Medicine, University of Pennsylvania Medical Center (ADNI Biomarker Core), Philadelphia, PA, United States
Skinningsrud, Anders; Department of Clinical Biochemistry, Center of Laboratory Medicine, Akershus University Hospital, Oslo, Norway
Skrogstad, Brith; Department of Clinical Biochemistry, Center of Laboratory Medicine, Akershus University Hospital, Oslo, Norway
Spreer, Annette; Department of Neurology, University of Göttingen, Göttingen, Germany
Talib, Leda; Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil
Teunissen, Charlotte; Department of Clinical Chemistry, VU University Medical Center, Amsterdam, Netherlands
Trojanowski, John Q; Department of Pathology, Laboratory Medicine, University of Pennsylvania Medical Center (ADNI Biomarker Core), Philadelphia, PA, United States
Tumani, Hayrettin; Department of Neurology, University of Ulm, Ulm, Germany
Umek, Robert M; Meso Scale Discovery, Gaithersburg, MD, United States
Van Broeck, Bianca; Janssen Pharmaceutica, J and J, Beerse, Belgium
Vecsei, Laszlo; Department of Neurology, University of Szeged, Szeged, Hungary
Verbeek, Marcel M; Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands ; Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
Windisch, Manfred; JSW Life Sciences GmbH, Grambach, Austria
Zhang, Jing; Department of Pathology, University of Washington, Seattle, WA, United States
Zetterberg, Henrik; Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
Blennow, Kaj; Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
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