• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jnnpsycJournal of Neurology, Neurosurgery and PsychiatryVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Neurol Neurosurg Psychiatry. Sep 2003; 74(9): 1210–1214.
PMCID: PMC1738637

A prospective study of CSF markers in 250 patients with possible Creutzfeldt–Jakob disease


Objective: To investigate various cerebrospinal fluid (CSF) markers that could assist in the clinical diagnosis of Creutzfeldt–Jakob disease (CJD).

Methods: CSF samples were analysed for the presence of 14-3-3 protein, microtubule associated protein tau, and ß amyloid in 250 patients with possible CJD. Densitometric analysis was used to quantify the level of 14-3-3 in all patients.

Results: Analysis of the clinical data showed that cerebellar signs or myoclonus combined with progressive dementia were the main features leading to a clinical suspicion of CJD. While 14-3-3 detection had a sensitivity of 100% and a specificity of 92%, tau determination using a threshold of 1300 pg/ml had a sensitivity of 87% and a specificity of 97%. If the protocol for the analysis of 14-3-3 was modified (using densitometric analysis) a higher specificity (97%) could be obtained, but with a lower sensitivity (96%). Maximum sensitivity, specificity, and positive predictive value were obtained with a combination of 14-3-3 and ß amyloid determinations. The concentrations of 14-3-3 and tau in the CSF were reduced in CJD patients with a long duration of disease (more than one year; p < 0.05). The concentrations of 14-3-3 or tau were lowest at the onset or at the end stage of the disease, while the ß amyloid concentration remained low throughout the course of the disease.

Conclusions: Both 14-3-3 and tau protein are sensitive and specific biomarkers for CJD. The combination of 14-3-3 and ß amyloid analysis resulted in the maximum sensitivity, specificity, and positive predictive value. When these biomarkers are used in the diagnosis of CJD, the phase of the disease in which the CSF sample was obtained should be taken into account. Disease duration, dependent on the PrP genotype, also has a significant influence on the level of 14-3-3 and tau in the CSF.

Full Text

The Full Text of this article is available as a PDF (128K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Prusiner SB, Hsiao KK. Human prion diseases. Ann Neurol. 1994 Apr;35(4):385–395. [PubMed]
  • Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani O, Gullotta F, Haltia M, Hauw JJ, Ironside JW, Jellinger K, et al. Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol. 1995 Oct;5(4):459–466. [PubMed]
  • Masters CL, Harris JO, Gajdusek DC, Gibbs CJ, Jr, Bernoulli C, Asher DM. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol. 1979 Feb;5(2):177–188. [PubMed]
  • Poser S, Mollenhauer B, Kraubeta A, Zerr I, Steinhoff BJ, Schroeter A, Finkenstaedt M, Schulz-Schaeffer WJ, Kretzschmar HA, Felgenhauer K. How to improve the clinical diagnosis of Creutzfeldt-Jakob disease. Brain. 1999 Dec;122(Pt 12):2345–2351. [PubMed]
  • Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996 Sep 26;335(13):924–930. [PubMed]
  • 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 Apr 11;225(3):210–212. [PubMed]
  • Zerr I, Bodemer M, Räcker S, Grosche S, Poser S, Kretzschmar HA, Weber T. Cerebrospinal fluid concentration of neuron-specific enolase in diagnosis of Creutzfeldt-Jakob disease. Lancet. 1995 Jun 24;345(8965):1609–1610. [PubMed]
  • Otto M, Stein H, Szudra A, Zerr I, Bodemer M, Gefeller O, Poser S, Kretzschmar HA, Mäder M, Weber T. S-100 protein concentration in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurol. 1997 Sep;244(9):566–570. [PubMed]
  • Beaudry P, Cohen P, Brandel JP, Delasnerie-Lauprêtre N, Richard S, Launay JM, Laplanche JL. 14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord. 1999 Jan-Feb;10(1):40–46. [PubMed]
  • Otto M, Esselmann H, Schulz-Shaeffer W, Neumann M, Schröter A, Ratzka P, Cepek L, Zerr I, Steinacker P, Windl O, et al. Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology. 2000 Mar 14;54(5):1099–1102. [PubMed]
  • Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996 Apr 6;347(9006):921–925. [PubMed]
  • Vanmechelen E, Vanderstichele H, Hulstaert F, Andreasen N, Minthon L, Winblad B, Davidsson P, Blennow K. Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders. Mech Ageing Dev. 2001 Nov;122(16):2005–2011. [PubMed]
  • Weber T. Clinical and laboratory diagnosis of Creutzfeldt-Jakob disease. Clin Neuropathol. 2000 Sep-Oct;19(5):249–250. [PubMed]
  • Van Everbroeck B, Pals P, Dziedzic T, Dom R, Godfraind C, Sciot R, Brucher JM, Martin JJ, Cras P. Retrospective study of Creutzfeldt-Jakob disease in Belgium: neuropathological findings. Acta Neuropathol. 2000 Apr;99(4):358–364. [PubMed]
  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. [PubMed]
  • Zerr I, Bodemer M, Weber T. The 14-3-3 brain protein and transmissible spongiform encephalopathy. N Engl J Med. 1997 Mar 20;336(12):874–875. [PubMed]
  • 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 Jan;43(1):32–40. [PubMed]
  • 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 Dec;26(3):231–245. [PubMed]
  • Van Everbroeck B, Croes EA, Pals P, Dermaut B, Jansen G, van Duijn CM, Cruts M, Van Broeckhoven C, Martin JJ, Cras P. Influence of the prion protein and the apolipoprotein E genotype on the Creutzfeldt-Jakob Disease phenotype. Neurosci Lett. 2001 Nov 2;313(1-2):69–72. [PubMed]
  • Green AJ, Thompson EJ, Stewart GE, Zeidler M, McKenzie JM, MacLeod MA, Ironside JW, Will RG, Knight RS. Use of 14-3-3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. 2001 Jun;70(6):744–748. [PMC free article] [PubMed]
  • Kapaki E, Kilidireas K, Paraskevas GP, Michalopoulou M, Patsouris E. Highly increased CSF tau protein and decreased beta-amyloid (1-42) in sporadic CJD: a discrimination from Alzheimer's disease? J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):401–403. [PMC free article] [PubMed]
  • 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 Jan 22;58(2):192–197. [PubMed]
  • Brandel JP, Peoc'h K, Beaudry P, Welaratne A, Bottos C, Agid Y, Laplanche JL. 14-3-3 protein cerebrospinal fluid detection in human growth hormone-treated Creutzfeldt-Jakob disease patients. Ann Neurol. 2001 Feb;49(2):257–260. [PubMed]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...