Background: Several biomarkers have been proposed to discriminate sporadic Creutzfeldt-Jakob disease (sCJD) from other dementias and control cases. However, their clinical accuracy depends on the PRNP codon 129 genotype, leaving it unclear how well established markers behave in untested conditions. Methods: We analyzed 14-3-3, tau, p-tau levels, and the p-tau/tau ratio in a population sample collected from Polish hospitals including nondementia, dementia, and definite sCJD cases and validated their parameters according to previously established cutoffs. Additionally, the correlation between biomarkers and disease duration as well as the influence of the PRNP129 polymorphism are reported. Results: The tau levels and p-tau/tau ratios differed considerably between sCJD and clinically characterized non-CJD cases (p < 0.001). p-tau was only elevated in sCJD when compared to cases without dementia (p < 0.05). Tau and the p-tau/tau ratio showed a sensitivity of 95 and 100%, respectively, in detecting sCJD cases. A negative correlation between tau levels and disease duration, but not the timing of lumbar puncture was observed. Conclusion: The present findings confirmed the value of the p-tau/tau ratio as a robust sCJD biomarker and suggest a role for tau as prognostic marker.

Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P: Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol 2012;11:618-628.
Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J, Weber T, Kretzschmar HA, Poser S: Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997;225:210-212.
Zerr I, Bodemer M, Weber T: The 14-3-3 brain protein and transmissible spongiform encephalopathy. N Engl J Med 1997;336:874-875.
Hamlin C, Puoti G, Berri S, Sting E, Harris C, Cohen M, Spear C, Bizzi A, Debanne SM, Rowland DY: A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease. Neurology 2012;79:547-552.
Satoh K, Shirabe S, Tsujino A, Eguchi H, Motomura M, Honda H, Tomita I, Satoh A, Tsujihata M, Matsuo H, Nakagawa M, Eguchi K: Total tau protein in cerebrospinal fluid and diffusion-weighted MRI as an early diagnostic marker for Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 2007;24:207-212.
Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, Ciesielczyk B, Schulz-Schaeffer W, Kretzschmar HA, Poser S: Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2002;58:192-197.
Schmitz M, Ebert E, Stoeck K, Karch A, Collins S, Calero M, Sklaviadis T, Laplanche JL, Golanska E, Baldeiras I, Satoh K, Sanchez-Valle R, Ladogana A, Skinningsrud A, Hammarin AL, Mitrova E, Llorens F, Kim YS, Green A, Zerr I: Validation of 14-3-3 Protein as a marker in sporadic Creutzfeldt-Jakob disease diagnostic. Mol Neurobiol 2016;53:2189-2199.
Karch A, Koch A, Zapf A, Zerr I, Karch A: Partial verification bias and incorporation bias affected accuracy estimates of diagnostic studies for biomarkers that were part of an existing composite gold standard. J Clin Epidemiol 2016;78:73-82.
Llorens F, Schmitz M, Karch A, Cramm M, Lange P, Gherib K, Varges D, Schmidt C, Zerr I, Stoeck K: Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia. Alzheimers Dement 2016;12:577-589.
Schmidt C, Redyk K, Meissner B, Krack L, von Ahsen N, Roeber S, Kretzschmar H, Zerr I: Clinical features of rapidly progressive Alzheimer's disease. Dement Geriatr Cogn Disord 2010;29:371-378.
Skillback T, Rosen C, Asztely F, Mattsson N, Blennow K, Zetterberg H: Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol 2014;71:476-483.
Blennow K, Johansson A, Zetterberg H: Diagnostic value of 14-3-3beta immunoblot and T-tau/P-tau ratio in clinically suspected Creutzfeldt-Jakob disease. Int J Mol Med 2005;16:1147-1149.
Sanchez-Juan P, Green A, Ladogana A, Cuadrado-Corrales N, Saanchez-Valle R, Mitrovaa E, Stoeck K, Sklaviadis T, Kulczycki J, Hess K, Bodemer M, Slivarichova D, Saiz A, Calero M, Ingrosso L, Knight R, Janssens AC, van Duijn CM, Zerr I: CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2006;67:637-643.
Van Everbroeck B, Green AJ, Vanmechelen E, Vanderstichele H, Pals P, Sanchez-Valle R, Corrales NC, Martin JJ, Cras P: Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2002;73:79-81.
Skillback T, Farahmand BY, Rosen C, Mattsson N, Nagga K, Kilander L, Religa D, Wimo A, Winblad B, Schott JM, Blennow K, Eriksdotter M, Zetterberg H: Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia. Brain 2015;138:2716-2731.
Riemenschneider M, Wagenpfeil S, Vanderstichele H, Otto M, Wiltfang J, Kretzschmar H, Vanmechelen E, Forstl H, Kurz A: Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Mol Psychiatry 2003;8:343-347.
Cramm M, Schmitz M, Karch A, Mitrova E, Kuhn F, Schroeder B, Raeber A, Varges D, Kim YS, Satoh K, Collins S, Zerr I: Stability and reproducibility underscore utility of RT-QuIC for diagnosis of Creutzfeldt-Jakob disease. Mol Neurobiol 2016;53:1896-1904.
Cramm M, Schmitz M, Karch A, Zafar S, Varges D, Mitrova E, Schroeder B, Raeber A, Kuhn F, Zerr I: Characteristic CSF prion seeding efficiency in humans with prion diseases. Mol Neurobiol 2015;51:396-405.
Karch A, Hermann P, Ponto C, Schmitz M, Arora A, Zafar S, Llorens F, Muller-Heine A, Zerr I: Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease. Neurobiol Aging 2015;36:1964-1968.
Karch A, Llorens F, Schmitz M, Arora A, Zafar S, Lange P, Schmidt C, Zerr I: Stratification by genetic and demographic characteristics improves diagnostic accuracy of cerebrospinal fluid biomarkers in rapidly progressive dementia. J Alzheimers Dis 2016;54:1385-1393.
Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Hoftberger R, Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean D, Tagliavini F, Giese A, Kretzschmar HA: Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 2012;124:517-529.
Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, Windl O, Kretzschmar HA, Weber T: Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 1998;43:32-40.
Golanska E, Hulas-Bigoszewska K, Rutkiewicz E, Styczynska M, Peplonska B, Barcikowska M, Bratosiewicz-Wasik J, Liberski PP: Polymorphisms within the prion (PrP) and prion-like protein (Doppel) genes in AD. Neurology 2004;62:313-315.
Hyeon JW, Kim SY, Lee J, Park JS, Hwang KJ, Lee SM, An SA, Lee MK, Ju YR: Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: improvement for weakly positive 14-3-3 protein in the laboratory. Sci Rep 2015;5:15283.
Andreasen N, Vanmechelen E, Van de Voorde A, Davidsson P, Hesse C, Tarvonen S, Raiha I, Sourander L, Winblad B, Blennow K: Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease: a community based follow up study. J Neurol Neurosurg Psychiatry 1998;64:298-305.
Vandermeeren M, Mercken M, Vanmechelen E, Six J, Van de Voorde A, Martin JJ, Cras P: Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 1993;61:1828-1834.
Sjogren M, Davidsson P, Tullberg M, Minthon L, Wallin A, Wikkelso C, Granerus AK, Vanderstichele H, Vanmechelen E, Blennow K: Both total and phosphorylated tau are increased in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2001;70:624-630.
Cohen OS, Chapman J, Korczyn AD, Warman-Alaluf N, Nitsan Z, Appel S, Kahana E, Rosenmann H: CSF tau correlates with CJD disease severity and cognitive decline. Acta Neurol Scand 2015, Epub ahead of print.
Li X, Li TQ, Andreasen N, Wiberg MK, Westman E, Wahlund LO: The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer's disease. J Intern Med 2014;275:418-427.
Tapiola T, Overmyer M, Lehtovirta M, Helisalmi S, Ramberg J, Alafuzoff I, Riekkinen P Sr, Soininen H: The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease. Neuroreport 1997;8:3961-3963.
Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T: Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 2009;66:382-389.
Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E: Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 1995;26:231-245.
Van Everbroeck B, Quoilin S, Boons J, Martin JJ, Cras P: A prospective study of CSF markers in 250 patients with possible Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2003;74:1210-1214.
Sanchez-Juan P, Sanchez-Valle R, Green A, Ladogana A, Cuadrado-Corrales N, Mitrova E, Stoeck K, Sklaviadis T, Kulczycki J, Hess K, Krasnianski A, Equestre M, Slivarichova D, Saiz A, Calero M, Pocchiari M, Knight R, van Duijn CM, Zerr I: Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis. J Neurol 2007;254:901-906.
Cepek L, Steinacker P, Mollenhauer B, Wiese B, Ciesielczyk B, Bibl M, Wiltfang J, Zerr I, Schulz-Schaeffer W, Kretzschmar HA, Poser S, Otto M: Follow-up investigations of tau protein and S-100B levels in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 2005;19:376-382.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.