A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease

Abstract

Objective: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease.

Methods: We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy).

Results: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center.

Conclusion: In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation.

Figure 1. Receiver operating characteristic curves for tau and 14-3-3 protein

Four categories (negative, ambiguous negative, ambiguous positive, and positive) are used for 14-3-3 protein. The area under the curve ± SE for tau was 0.819 ± 0.020 vs 0.672 ± 0.022 for the 14-3-3 test. The thin green line represents a test that does not change predictive ability.

Figure 2. Histogram of distribution of tau values (log) per 0.1 log unit

Positive Creutzfeldt-Jakob disease (CJD) cases (blue triangles) and negative cases (red squares) are shown. The log scale is used for clarity with tau values from 10 to 140,800 pg/mL. The most accurate cutoff of tau between cases positive and negative for CJD is 1,150 pg/mL. The prion disease-positive subjects were distributed as follows: 247 with tau at or above 1,150 pg/mL, 24 between 1,149 and 800 pg/mL, and 149 below 800 pg/mL. BN represents the level below which 10% of positive cases fall. BP represents the level above which 10% of negative cases fall.

Figure 3. Diagnostic reliability of tau for “typical” and “atypical” cases

The 2 receiver operating characteristic curves (typical and atypical) show greater area under the curve (AUC) for typical (0.886) vs atypical (0.750) cases (95% confidence interval for AUC for atypical is 0.667 to 0.833, which is lower than, and has no overlap with, the 95% confidence interval for typical, which is 0.840 to 0.932).