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


Shaw, Leslie M., Vanderstichele, Hugo, Knapik-Czajka, Malgorzata, Figurski, Michal, Coart, Els, Blennow, Kaj, Soares, Holly, Simon, Adam J., Lewczuk, Piotr, Dean, Robert A., Siemers, Eric, Potter, William, Lee, Virginia M.-Y., Trojanowski, John Q.


Acta Neuropathologica, Volume: 121, No.: 5, Pages.: 597-609

Year of Publication



The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) 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-tau(181)) and Aβ(1-42) 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 Aβ(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aβ(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ(1-42) and for the ratio t-tau/Aβ(1-42) 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-tau(181) and Aβ(1-42), 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.;

Bibtex Citation

@article{Shaw_2011, doi = {10.1007/s00401-011-0808-0}, url = {}, year = 2011, month = {feb}, publisher = {Springer Science $mathplus$ Business Media}, volume = {121}, number = {5}, pages = {597--609}, author = {Leslie M. Shaw and Hugo Vanderstichele and Malgorzata Knapik-Czajka and Michal Figurski and Els Coart and Kaj Blennow and Holly Soares and Adam J. Simon and Piotr Lewczuk and Robert A. Dean and Eric Siemers and William Potter and Virginia M.-Y. Lee and John Q. Trojanowski}, title = {Qualification of the analytical and clinical performance of {CSF} biomarker analyses in {ADNI}}, journal = {Acta Neuropathologica} }


aged, aged, 80 and over, alzheimer disease, biological markers, cerebrospinal fluid, diagnosis, humans, middle aged, mild cognitive impairment, mortality, peptide fragments, predictive value of tests, prognosis, reproducibility of results, sensitivity and specificity, tau proteins

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Non randomised controlled trial

Type of Outcomes


Type of Interventions

Diagnostic Target Identification

Diagnostic Targets

Biological Testing