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CSF biomarker variability in the Alzheimer's Association quality control program

2013; Wiley; Volume: 9; Issue: 3 Linguagem: Inglês

10.1016/j.jalz.2013.01.010

1552-5279

Niklas Mattsson, Ulf Andréasson, Staffan Persson, María C. Carrillo, Steven Collins, Sonia Chalbot, Neal E. Cutler, Diane Dufour‐Rainfray, Anne M. Fagan, Niels H. H. Heegaard, Ging‐Yuek Robin Hsiung, Bradley T. Hyman, Khalid Iqbal, D. Richard Lachno, Alberto Lleó, Piotr Lewczuk, José Luís Molinuevo, Piero Parchi, Axel Regeniter, Robert A. Rissman, Hanna Rosenmann, Giuseppe Sancesario, Johannes Schröder, Leslie M. Shaw, Charlotte E. Teunissen, John Q. Trojanowski, Hugo Vanderstichele, Manu Vandijck, Marcel M. Verbeek, Henrik Zetterberg, Kaj Blennow, Stephan A. Käser, Aladro José A. Rojo, Marilyn Albert, Daniel Alcolea, Ulf Andréasson, Anna Antonell, Hiroyuki Arai, Silvana Archetti, Eva Lagberg Arkblad, Inês Baldeiras, Aleš Bartoš, Dev Batish, Aurélie Bedel, Danièle Bentué‐Ferrer, Flora Berisha, Sergio Bernardini, Marinus A. Blankenstein, Kaj Blennow, Olivier Bousiges, Michael C. Camuso, Maria Carrillo, Tiziana Casoli, Sebastiano Cavallaro, Sonia Chalbot, Steven Collins, Odete Cruz e Silva, Neal E. Cutler, I. Cuvelier, Odile Delaroche, Diane Dufour‐Rainfray, Roy B. Dyer, Sebastiaan Engelborghs, Anne M. Fagan, Anne Fogli, Orestes Vicente Forlenza, Nick C. Fox, Giovanni B. Frisoni, Daniela Galimberti, Elisabetta Galloni, Silvana Maria Gritti, Karen H. Gylys, Harald Hampel, Sabine Haustein, Theresa Heath, Niels H. H. Heegaard, Michael T. Heneka, Sanna‐Kaisa Herukka, David M. Holtzman, Ging‐Yuek Robin Hsiung, Christian Humpel, Bradley T. Hyman, Takeshi Iwatsubo, Khalid Iqbal, Claude Jardel, Mathias Jucker, Elisabeth Kapaki, Stephan A. Käser, Daniel Kidd, Péter Klivényi, Ryozo Kuwano, D. Richard Lachno, Foudil Lamari, Jean Laplanche, Jordan Laser, Sylvian Lehmann, Piotr Lewczuk, Qiao‐Xin Li, Alberto Lleó, Walter Maetzler, Catherine Malaplate‐Armand, Ralph Martin, Robert Martone, Colin L. Masters, Niklas Mattsson, Marc Mercken, José Luís Molinuevo, Tom Montine, William Nowatzke, Markus Otto, Piero Parchi, Xavier Parent, Lucilla Parnetti, Staffan Persson, Ronald C. Petersen, Koen Poesen, Isabelle Quadrio, Muriel Quillard, Axel Regeniter, Luis Rello, Robert A. Rissman, Zdeněk Rohan, Hanna Rosenmann, Giuseppe Sancesario, Johannes Schröder, Leslie M. Shaw, Christin Sisowath, Anders Skinningsrud, Holly Soares, Hilkka Soininen, Knudsen Cindy Søndersø, Annette Spreer, Silvia Suardi, Charlotte E. Teunissen, John Q. Trojanowski, Robert M. Umek, Bianca Van Broeck, Rik Vandenberghe, Hugo Vanderstichele, Manu Vandijck, László Vécsei, Marcel M. Verbeek, Igor Voštiar, Manfred Windisch, Henrik Zetterberg,

Health Systems, Economic Evaluations, Quality of Life

Abstract Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single‐analyte enzyme‐linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within‐run CVs, less than 5% to 10%; and longitudinal within‐laboratory CVs, 5% to 19%. Interestingly, longitudinal within‐laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between‐kit lot effects were much less than between‐laboratory effects. Despite the measurement variability, the between‐laboratory consistency in classification of samples (using prehoc‐derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.