Original Contributions |

Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of β-Amyloid 1-42, Total tau, and P-tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology

Anne M. Fagan, PhD; Leslie M. Shaw, PhD; Chengjie Xiong, PhD; Hugo Vanderstichele, PhD; Mark A. Mintun, MD; John Q. Trojanowski, MD, PhD; Els Coart, PhD; John C. Morris, MD; David M. Holtzman, MD
Arch Neurol. 2011;68(9):1137-1144. doi:10.1001/archneurol.2011.105.
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Background Cerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of antemortem diagnosis.

Objective To test whether CSF biomarker assays differ in their ability to identify true markers of underlying AD pathology (eg, amyloid plaques and/or neurofibrillary tangles) in living individuals.

Design We compared the performances of the 2 most commonly used platforms, INNOTEST enzyme-linked immunosorbent assay and INNO-BIA AlzBio3, for measurement of CSF β-amyloid (Aβ) and tau proteins to identify the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau, and phosphorylated tau 181 (p-tau181) using the 2 assay platforms were compared with brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent Pittsburgh compound B.

Setting The Knight Alzheimer's Disease Research Center at Washington University in St Louis, Missouri.

Subjects Research volunteers who were cognitively normal or had mild to moderate AD dementia.

Results The 2 assay platforms yielded different (approximately 2- to 6-fold) absolute values for the various analytes, but relative values were highly correlated. The CSF Aβ1-42 correlated inversely and tau and p-tau181 correlated positively with the amount of cortical Pittsburgh compound B binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau to Aβ1-42 and p-tau181 to Aβ1-42 outperformed any single analyte, including Aβ1-42, in discriminating individuals with vs without cortical amyloid.

Conclusions The INNOTEST and INNO-BIA CSF platforms perform equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cutoff values.

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Figure 1. Relationship between the assay platforms for the various cerebrospinal fluid (CSF) analytes. Analytes include β-amyloid 1-42 (Aβ1-42) (A); total tau protein (B); tau phosphorylated at tyrosine 181 (p-tau181) (C); the ratio of total tau to Aβ1-42 (D); and the ratio of p-tau181 to Aβ1-42 (E).

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Figure 2. Relationship between cerebrospinal fluid (CSF) analytes and cortical amyloid load. Analytes include β-amyloid 1-42 (Aβ1-42) (A and B), total tau protein (C and D), tau phosphorylated at tyrosine 181(p-tau181) (E and F), the ratio of total tau to Aβ1-42 (G and H), and the ratio of p-tau181 to Aβ1-42 (I and J). PiB indicates Pittsburgh compound B.

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Figure 3. Receiver operating characteristic curves and area under the curve (AUC) describing cerebrospinal fluid biomarker sensitivity and specificity for discriminating amyloid-positive (mean cortical Pittsburgh compound B binding potential [MCBP] ≥0.18) from amyloid-negative (MCBP < 0.18) participants. The values were obtained with the INNOTEST (A) or INNO-BIA (B) assay. Aβ1-42 indicates β-amyloid 1-42; p-tau181, tau phosphorylated at tyrosine 181.





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