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

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Abstract

The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1–42) 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 Aβ1–42 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 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 Aβ1–42; 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 Aβ1–42, 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 Aβ1–42 and for the ratio t-tau/Aβ1–42 were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau181 and Aβ1–42, together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the “gold standard” for the diagnosis of definite AD in the near future.

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Acknowledgments

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., as well as non-profit partners the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation., V. M-.Y. Lee is supported by the Marian S Ware Alzheimer Program, the John H Ware 3rd Professorship for Alzheimer’s Disease Research and JQT is supported by (AG10124) from the NIH (National Institute on Aging) and the William Maul Measy-Truman Schnabel Jr MD Professorship of Geriatric Medicine and Gerontology. We are grateful to Drs. H. Arai, K. Blennow, C. Clark, A. Fagan (provided by Wash U ADRC [through NIH grants P50AG005681, P01AG003991, P01AG026276, John Morris PI]), and H. Soares for providing aliquots of non-ADNI CSF samples to prepare the CSF quality control pools used in this investigation.

Conflict of interest

Leslie Shaw has served on technical advisory boards for Bristol Myers Squibb and Innogenetics; Piotr Lewczuk is a consultant to Innogenetics. Kaj Blennow has served on a technical advisory board for Innogenetics. No conflicts of interest declared by the other authors of this manuscript.

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Author notes

  1. Holly Soares

    Present address: Bristol-Myers Squibb, Wallingford, CT, 06492-1996, USA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 7 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Leslie M. Shaw, Malgorzata Knapik-Czajka, Michal Figurski, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Diagnostic Development, Innogenetics NV (Now Part of Fujirebio), Ghent, Belgium

    Hugo Vanderstichele & Els Coart

  3. Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at Göteborg University, Mölndal, Sweden

    Kaj Blennow

  4. Pfizer Global Research and Development, Groton, CT, USA

    Holly Soares

  5. Merck Research Laboratories, West Point, PA, USA

    Adam J. Simon & William Potter

  6. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    Piotr Lewczuk

  7. Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Robert A. Dean & Eric Siemers

  8. Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Virginia M.-Y. Lee & John Q. Trojanowski

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  1. Leslie M. Shaw
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the Alzheimer’s Disease Neuroimaging Initiative

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Correspondence to Leslie M. Shaw.

Additional information

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.

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Shaw, L.M., Vanderstichele, H., Knapik-Czajka, M. et al. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol 121, 597–609 (2011). https://doi.org/10.1007/s00401-011-0808-0

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