Challenging the Clinical Utility of the 14-3-3 Protein for the Diagnosis of Sporadic Creutzfeldt-Jakob Disease

Geschwind, Michael D.; Martindale, Jennifer L.; Miller, Deborah; DeArmond, Stephen J.; Uyehara-Lock, Jane; Gaskin, David A.; Kramer, Joe I.H.; Barbaro, Nicholas M.; Miller, Bruce L.

doi:10.1001/archneur.60.6.813

Cited by 140 publications

(73 citation statements)

References 15 publications

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“…Immunodetection of protein 14-3-3 in CSF was originally demonstrated to have a high sensitivity and specificity for sCJD [19,42] and has, therefore, been included by the World Health Organization (WHO) in the diagnostic criteria for probable disease [41]. However, this view has been challenged by findings of poor specificity [6,7] and low sensitivity in autopsy-proven sCJD cases [11]. One of the major limitations of this assay is that the 14-3-3 immunoblot is usually analysed in a qualitative manner, by visual inspection, leading to a subjective interpretation of borderline results.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

et al. 2009

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The clinical diagnosis of sporadic CreutzfeldtJakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and b amyloid (Ab42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Ab42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Ab42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.

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Section: Introductionmentioning

confidence: 99%

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

et al. 2009

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“…4,5 This sensitivity has been disputed, however. 6 Variation in sensitivity has also been demonstrated on the basis of the duration of illness, 7 Creutzfeldt-Jakob disease (CJD) subtype, 8 and laboratory techniques. 9,10,11 False-positive results occur in numerous disorders in which there is rapid neuronal loss, including acute stroke, encephalitis, and other dementing disorders.…”

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confidence: 99%

Evidence-based guideline: Diagnostic accuracy of CSF 14-3-3 protein in sporadic Creutzfeldt-Jakob disease

2012

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Objective: To assess the available evidence for the diagnostic accuracy of CSF testing for protein 14-3-3 in patients with suspected sporadic Creutzfeldt-Jakob disease (sCJD). Methods:The authors performed a systematic review of the available literature from 1995 to January 1, 2011, to identify articles involving patients who were suspected of having sCJD and who had CSF analysis for protein 14-3-3. Studies were rated according to the American Academy of Neurology classification of evidence scheme for diagnostic studies, and recommendations were linked to the strength of the evidence. A pooled estimate of sensitivity and specificity was obtained for all studies rated Class II or higher. The question asked is "Does CSF 14-3-3 protein accurately identify Creutzfeldt-Jakob disease (CJD) in patients with sCJD?" Results:The analysis was conducted on the basis of samples of 1,849 patients with suspected sCJD from 9 Class II studies. Assays for CSF 14-3-3 protein are probably moderately accurate in diagnosing sCJD: sensitivity 92% (95% confidence interval [CI] 89.8-93.6), specificity 80% (95% CI 77.4-83.0), likelihood ratio of 4.7, and negative likelihood ratio of 0.10. Recommendation:For patients who have rapidly progressive dementia and are strongly suspected of having sCJD and for whom diagnosis remains uncertain (pretest probability ϳ20%-90%), clinicians should order CSF 14-3-3 assays to reduce the uncertainty of the diagnosis (Level B). Neurology ® 2012;79:1499-1506 GLOSSARY CI ϭ confidence interval; CJD ϭ Creutzfeldt-Jakob disease; DWI ϭ diffusion-weighted imaging; FLAIR ϭ fluid-attenuated inversion recovery; NSE ϭ neuron-specific enolase; PSWC ϭ periodic sharp and slow wave complexes; ROC ϭ receiver operator characteristic; sCJD ϭ sporadic Creutzfeldt-Jakob disease; WB ϭ Western blot.

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“…This practice avoids the exclusion of other potentially treatable diseases, since a 14-3-3 positive result might be interpreted by the clinician as a confirmation of the clinical suspicion of this so far untreatable disease. On the other hand, this strategy increases the number of falsenegative results that according to other authors pose an important risk due to the transmissibility of the disease and the potential hazards derived from patient care and sample manipulation [14]. However, as we have presently discussed, a negative result in a patient with high clinical suspicion does not exclude the diagnosis of sCJD.…”

Section: Discussionmentioning

confidence: 86%

Hemidystonia Associated With Focal Status Epilepticus as Incipient Manifestations in Probable Creutzfeldt-Jakob Disease

Lee¹,

Song²,

Lee³

et al. 2008

JMD

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Background: The 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series.

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Challenging the Clinical Utility of the 14-3-3 Protein for the Diagnosis of Sporadic Creutzfeldt-Jakob Disease

Abstract: Testing for the 14-3-3 protein is only modestly sensitive to sporadic CJD, and we caution against ruling out a diagnosis of the disease on the basis of a negative 14-3-3 result.

Cited by 140 publications

References 15 publications

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Evidence-based guideline: Diagnostic accuracy of CSF 14-3-3 protein in sporadic Creutzfeldt-Jakob disease

Hemidystonia Associated With Focal Status Epilepticus as Incipient Manifestations in Probable Creutzfeldt-Jakob Disease

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