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Original Contribution |

Comparison of Cerebrospinal Fluid Levels of Tau and Aβ 1-42 in Alzheimer Disease and Frontotemporal Degeneration Using 2 Analytical Platforms

David J. Irwin, MD; Corey T. McMillan, PhD; Jon B. Toledo, MD; Steven E. Arnold, MD; Leslie M. Shaw, PhD; Li-San Wang, PhD; Vivianna Van Deerlin, MD, PhD; Virginia M.-Y. Lee, PhD, MBA; John Q. Trojanowski, MD, PhD; Murray Grossman, MD
Arch Neurol. 2012;69(8):1018-1025. doi:10.1001/archneurol.2012.26.
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Objective  To use values of cerebrospinal fluid tau and β-amyloid obtained from 2 different analytical immunoassays to differentiate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD).

Design  Cerebrospinal fluid values of total tau (T-tau) and β-amyloid 1-42 (Aβ 1-42) obtained using the Innotest enzyme-linked immunosorbent assay were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross validated in another series of autopsy-confirmed samples using transformed enzyme-linked immunosorbent assay values to assess sensitivity and specificity for differentiating AD from FTLD.

Setting  Tertiary memory disorder clinics and neuropathologic and biomarker core centers.

Participants  Seventy-five samples from patients with cerebrospinal fluid data obtained from both assays were used for transformation of enzyme-linked immunosorbent assay values. Forty autopsy-confirmed cases (30 with AD and 10 with FTLD) were used to establish diagnostic cutoff values and then cross validated in a second sample set of 21 autopsy-confirmed cases (11 with AD and 10 with FTLD) with transformed enzyme-linked immunosorbent assay values.

Main Outcome Measure  Diagnostic accuracy using transformed biomarker values.

Results  Data obtained from both assays were highly correlated. The T-tau to Aβ 1-42 ratio had the highest correlation between measures (r = 0.928, P < .001) and high reliability of transformation (intraclass correlation coefficient= 0.89). A cutoff of 0.34 for the T-tau to Aβ 1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross-validation samples, respectively.

Conclusions  Values from 2 analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis.

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Figure 1. Flowchart of the transformation (A) and validation and cross-validation (B) steps. ELISA indicates enzyme-linked immunosorbent assay; ROC, receiver operating characteristic.

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Figure 2. Transformation of cerebrospinal fluid analytes into equivalent values between platforms. Shown are plots of raw and natural log transformed values of Aβ 1-42 (A), total tau (T-tau) (B), phosphorylated tau181 (p-tau181) (C), T-tau to Aβ 1-42 ratio (D), and p-tau181 to Aβ 1-42 ratio (E) obtained with enzyme-linked immunosorbent assay (ELISA) and xMAP. T-ELISA = transformed data. ICC indicates intraclass correlation coefficient.

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Figure 3. Receiver operating characteristic curve analysis of xMAP analyte values in an autopsy-confirmed sample (neuropathologic sample 1). The T-tau to Aβ 1-42 ratio had the highest area under the curve at the optimal diagnostic cutpoint of 0.34.

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Figure 4. Diagnostic accuracy of total tau (T-tau) to Aβ 1-42 ratio cutoff in the validation and cross-validation data sets. A, A box-plot of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) values from both samples. B, The T-tau to Aβ 1-42 ratio was highly sensitive and specific for identifying AD and FTLD, with improved diagnostic accuracy compared with antemortem clinical diagnosis. CSF indicates cerebrospinal fluid and ELISA, enzyme-linked immunosorbent assay. * Four genetically determined cases of FTLD were omitted from clinical diagnosis analysis.

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