Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI

The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-b1-42 (Ab1–42) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau181) and Ab1–42 as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were Data used in the preparation of this article were obtained through support from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the full data set is posted on the ADNI website (http://www.loni.ucla.edu\ADNI) in compliance with NIH governance rules for ADNI. Although no ADNI biosamples were used in this inter-laboratory performance study which was essential for studies of ADNI CSF samples, we also report on data here from studies that were performed using ADNI CSF samples with the methods defined here. As such, other ADNI investigators contributed to the design and implementation of ADNI and/or provided samples, but did not participate in analysis or writing of this report. These other ADNI investigators are listed at http://www.loni.ucla.edu\ADNI\ Collaboration\ADNI. L. M. Shaw (&)  M. Knapik-Czajka  M. Figurski  V. M.-Y. Lee  J. Q. Trojanowski Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 7 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, USA e-mail: les.shaw@uphs.upenn.edu H. Vanderstichele  E. Coart Department of Diagnostic Development, Innogenetics NV (Now Part of Fujirebio), Ghent, Belgium K. Blennow Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at Go¨teborg University, Mo¨lndal, Sweden H. Soares Pfizer Global Research and Development, Groton, CT, USA Present Address: H. Soares Bristol-Myers Squibb, Wallingford, CT 06492-1996, USA A. J. Simon  W. Potter Merck Research Laboratories, West Point, PA, USA P. Lewczuk Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany R. A. Dean  E. Siemers Eli Lilly and Company, Indianapolis, IN 46285, USA V. M.-Y. Lee  J. Q. Trojanowski Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA 123 Acta Neuropathol (2011) 121:597–609 DOI 10.1007/s00401-011-0808-0 analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0–6.0% (5.3%) for CSF Ab1–42; 6.4–6.8% (6.7%) for t-tau and 5.5–18.0% (10.8%) for p-tau181 and inter-center %CV 95% CI range of 15.9–19.8% (17.9%) for Ab1–42, 9.6–15.2% (13.1%) for t-tau and 11.3–18.2% (14.6%) for p-tau181. Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Ab1–42 and for the ra