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Open Access Research article

Diagnostic accuracy of cerebrospinal fluid protein markers for sporadic Creutzfeldt-Jakob disease in Canada: a 6-year prospective study

Michael B Coulthart1*, Gerard H Jansen23, Elina Olsen2, Deborah L Godal1, Tim Connolly2, Bernard CK Choi456, Zheng Wang2 and Neil R Cashman7

Author affiliations

1 Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg MB R3E 3R2, Canada

2 Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, 200 Églantine Driveway AL 1910B, Ottawa ON K1A 0K9, Canada

3 Department of Pathology and Laboratory Medicine, Eastern Ontario Regional Laboratory, CCW 4240B, The Ottawa Hospital - General Campus, 501 Smyth Rd, Ottawa ON K1H 8L6, Canada

4 Chronic Disease Surveillance and Monitoring Division, CCDPC, HPCDPB, Public Health Agency of Canada, Room 622A3, 785 Carling Avenue, PL# 6806A, Ottawa ON K1A 0K9, Canada

5 Department of Epidemiology and Community Medicine, University of Ottawa, ON, Canada

6 Shantou University Medical College, Shantou, China

7 Brain Research Centre and PrioNet Canada, University of British Columbia, 2011 Wesbrook Mall, Vancouver BC V6T 2B5, Canada

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Citation and License

BMC Neurology 2011, 11:133  doi:10.1186/1471-2377-11-133

Published: 27 October 2011

Abstract

Background

To better characterize the value of cerebrospinal fluid (CSF) proteins as diagnostic markers in a clinical population of subacute encephalopathy patients with relatively low prevalence of sporadic Creutzfeldt-Jakob disease (sCJD), we studied the diagnostic accuracies of several such markers (14-3-3, tau and S100B) in 1000 prospectively and sequentially recruited Canadian patients with clinically suspected sCJD.

Methods

The study included 127 patients with autopsy-confirmed sCJD (prevalence = 12.7%) and 873 with probable non-CJD diagnoses. Standard statistical measures of diagnostic accuracy were employed, including sensitivity (Se), specificity (Sp), predictive values (PVs), likelihood ratios (LRs), and Receiver Operating Characteristic (ROC) analysis.

Results

At optimal cutoff thresholds (empirically selected for 14-3-3, assayed by immunoblot; 976 pg/mL for tau and 2.5 ng/mL for S100B, both assayed by ELISA), Se and Sp respectively were 0.88 (95% CI, 0.81-0.93) and 0.72 (0.69-0.75) for 14-3-3; 0.91 (0.84-0.95) and 0.88 (0.85-0.90) for tau; and 0.87 (0.80-0.92) and 0.87 (0.84-0.89) for S100B. The observed differences in Sp between 14-3-3 and either of the other 2 markers were statistically significant. Positive LRs were 3.1 (2.8-3.6) for 14-3-3; 7.4 (6.9-7.8) for tau; and 6.6 (6.1-7.1) for S100B. Negative LRs were 0.16 (0.10-0.26) for 14-3-3; 0.10 (0.06-0.20) for tau; and 0.15 (0.09-0.20) for S100B. Estimates of areas under ROC curves were 0.947 (0.931-0.961) for tau and 0.908 (0.888-0.926) for S100B. Use of interval LRs (iLRs) significantly enhanced accuracy for patient subsets [e.g., 41/120 (34.2%) of tested sCJD patients displayed tau levels > 10,000 pg/mL, with an iLR of 56.4 (22.8-140.0)], as did combining tau and S100B [e.g., for tau > 976 pg/mL and S100B > 2.5 ng/mL, positive LR = 18.0 (12.9-25.0) and negative LR = 0.02 (0.01-0.09)].

Conclusions

CSF 14-3-3, tau and S100B proteins are useful diagnostic markers of sCJD even in a low-prevalence clinical population. CSF tau showed better overall diagnostic accuracy than 14-3-3 or S100B. Reporting of quantitative assay results and combining tau with S100B could enhance case definitions used in diagnosis and surveillance of sCJD.