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January 22, 2002; 58 (2) Articles

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt–Jakob disease

M. Otto, J. Wiltfang, L. Cepek, M. Neumann, B. Mollenhauer, P. Steinacker, B. Ciesielczyk, W. Schulz–Schaeffer, H. A. Kretzschmar, S. Poser
First published January 22, 2002, DOI: https://doi.org/10.1212/WNL.58.2.192
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Abstract

Background: Diagnosis of Creutzfeldt–Jakob disease (CJD) is made according to the typical clinical picture and can be supported by a positive 14-3-3 CSF immunoblot. Promising results for the diagnostic sensitivity and specificity of tau-protein measurement in CSF already have been described in a smaller group of patients. Both tests in a larger group of patients with the differential diagnosis of CJD were evaluated.

Methods: CSF of 297 patients under the differential diagnosis of CJD (109 definite, 55 probable, 39 possible; 85 others, 1 iatrogenic, 8 genetic), 23 nondemented control subjects, and 15 non-CJD patients with positive 14-3-3 immunoblots were analyzed. The 14-3-3 immunoblot bands were semiquantitatively rated as strong, medium, and weak. Tau-protein was analyzed using a commercially available ELISA. In addition, patients were neuropathologically classified according to prion protein type and polymorphism at codon 129.

Results: A diagnostic sensitivity of 94%, a diagnostic specificity of 90%, and a positive predictive value of 92% were achieved for tau-protein at a cut-off of 1,300 pg/mL. These results are comparable with those of the 14-3-3 immunoblot. For patients with type II prion protein and methionine/valine or valine/valine polymorphism at codon 129, tau-protein has a higher diagnostic sensitivity than 14-3-3 protein. Tau-protein levels were significantly higher in patients with higher-rated 14-3-3 immunoblot bands.

Conclusion: The differential diagnostic significance of the 14-3-3 immunoblot is similar to that of the tau-protein ELISA. The advantage of the tau-protein ELISA is that it is easy to use in routine laboratories. Patients with a negative 14-3-3 immunoblot already have measurable tau-protein levels. This increases information on 14-3-3—negative patients with CJD and especially on patients with other diseases.

A definite diagnosis of Creutzfeldt–Jakob disease (CJD) can be made only by neuropathologic or immunochemical demonstration of the pathologic isoform of the prion protein (PrPSc) in human brain tissue.1 Routine detection of PrPSc outside the brain for an early in vivo diagnosis of sporadic CJD has yet to be established. First attempts to detect PrP aggregates were made using fluorescence-correlated spectroscopy.2 Unfortunately, the sensitivity of this test in the CSF is low (20%). In patients with new-variant CJD (vCJD), a pathologic isoform also was detected in tonsils.3

Recently, six different subtypes of sporadic CJD were described.4 These subtypes were classified according to the prion protein type (type I, type II) and the polymorphism at codon 129 (methionine/methionine, methionine/valine, valine/valine).4,5⇓ These subtypes may correlate with the clinical picture of the patients.4

Up to now, the intra vitam diagnosis has been made according to clinical6,7⇓ and EEG criteria.8 The clinical diagnosis of CJD can be supported by biochemical analysis of CSF for neuron-specific enolase (NSE),9 S100 protein,10,11⇓ or 14-3-3 protein.12-14⇓⇓ Elevated levels of S100 also were described in serum of patients with CJD.11 However, only the 14-3-3 immunoblot is included in the diagnostic criteria,15,16⇓ despite the fact that the other surrogate markers also have a high differential diagnostic potential.17,18⇓

Promising results for the diagnostic sensitivity and specificity of tau-protein measurement in CSF have been reported in a smaller group of patients.19 In the meantime, measurement of tau-protein has gained acceptance as a standard diagnostic procedure in the differential diagnostic evaluation of patients under the differential diagnosis of AD.20-23⇓⇓⇓

We now have evaluated both tests on a larger group of patients under the differential diagnosis of CJD and especially looked at the different subtypes of sporadic CJD. We also evaluated patients with other forms of dementia with positive 14-3-3 immunoblots for their tau-protein levels.

Patients and methods.

We analyzed CSF of 297 patients under the differential diagnosis of CJD. All patients were seen by a member of the national CJD surveillance team. Since June 1993, suspected cases of CJD in Germany have been reported to the CJD surveillance unit at the Department of Neurology at Georg-August-University in Göttingen. Each patient was visited by a research physician and examined using a standardized protocol. According to the clinical criteria, all suspected cases of CJD were classified as “probable,” “possible,” or “other” cases.6,7⇓ Before clinical staging into “probable” or “possible,” all patients underwent at least one cranial CT or MRI, or both, to exclude ischemic stroke, hemorrhage, or space-occupying lesions as a cause of the illness.

The diagnostic criteria for the clinical CJD staging are as follows:

  • Probable: patients with a rapidly progressive dementia of less than 2 years’ duration, periodic sharp-wave complexes in the EEG, and two of the following:

  • Myoclonus

  • Visual or cerebellar symptoms

  • Pyramidal or extrapyramidal signs

  • Akinetic mutism

  • Possible: patients fulfilling the preceding criteria but without typical EEG abnormalities.

  • Other: patients not fulfilling the criteria for possible or probable CJD.

  • Definite: cases with immunohistochemical detection of the PrPSC in brain tissue.1

A total of 109 patients were later neuropathologically verified as definite CJD patients1; 55 were classified as probable CJD, 39 as possible, and 85 as others. We also analyzed one iatrogenic and eight genetic cases. In addition, 23 nondemented control subjects were seen, as were 15 patients without CJD but with a positive 14-3-3 immunoblot.

Neuropathology.

Patients were neuropathologically verified according to standard methods.1 In addition, prion protein typing was performed and polymorphism at codon 129 was determined.4

Prion protein gene analysis.

In eight patients, a mutation was detected in the prion protein gene.24

14-3-3 immunoblot.

The 14-3-3 immunoblot was performed on all samples according to the previously published standard method.12,13⇓ The 14-3-3 immunoblots were semiquantitatively scored according to the following algorithm: no detectable signal, faint signal (+), moderate signal (++), strong signal (+++).25

Tau-protein measurement.

Tau-protein was measured with a commercially available assay (Innogenetics, Ghent, Belgium).19,22⇓ In 30 patients (15 CJD and 15 other diseases), tau-protein also was analyzed in serum samples.26

Statistical analysis.

The comparison of the tau-protein level distribution between subgroups in the study population was based on nonparametric rank tests (for two groups, Wilcoxon–Mann–Whitney U test; for more than two groups, Kruskal–Wallis test). Standard measures of diagnostic test validity such as sensitivity, specificity, and predictive values were calculated. For this calculation, all definite CJD cases (n = 109) and the group of others (n = 85) were used. The optimal cut-off level for dichotomizing tau-protein values was selected as the situation maximizing the Youden index.27

Results.

Tau-protein levels were determined from 335 patients. Of these 335 patients, 297 were initially seen under the differential diagnosis of CJD. In addition, tau-protein levels were measured on 15 patients with a positive 14-3-3 immunoblot (other diseases/14-3-3+). In these 15 patients, the diagnosis of CJD was easily excluded, but nevertheless the 14-3-3 immunoblot was conducted. CSF from 23 patients (nondemented control subjects) without any sign of dementia also was analyzed for tau-protein and 14-3-3 protein.

The group of 297 patients comprised 109 definite, 55 probable, 39 possible, 85 other, 8 genetic cases, and 1 iatrogenic case. For grouping of the patients, the latest available data were taken, if possible the neuropathologic examination. Age and sex distribution of these study groups is given in table 1.

View this table:
Table 1.

Age and sex distribution of investigated patients

The genetic cases comprised three cases of fatal familiar insomnia (FFI; D178N), three patients with E200K mutation, one patient with V210I mutation, and one patient with an insert mutation (9*24). Only two of the E200K patients and the V210I patient were clinically staged as probable CJD. One patient with FFI was staged as other than CJD. The other genetic cases were clinically staged as possible CJD.

The iatrogenic case was initially staged as other than CJD.

Tau-protein levels in CSF.

There was a difference in tau-protein levels within the groups (p < 0.0001). Levels of tau-protein in the group of definite cases ranged between 150 pg/mL and 35,360 pg/mL (median, 5,024 pg/mL; mean, 8,699 pg/mL). In the group of probable cases, levels ranged between 190 pg/mL and 121,022 pg/mL (median, 4,743 pg/mL; mean, 10,008 pg/mL). Levels in possible cases ranged between 94 pg/mL and 17,231 pg/mL (median, 1,772 pg/mL; mean, 3,476 pg/mL). The group of “other” patients had levels between 50 pg/mL and 3,296 pg/mL (median, 355 pg/mL; mean, 593 pg/mL). This result is illustrated by the box plot in figure 1.

Figure

Figure 1. Box plot: level of tau-protein in CSF. Plots show 10th, 25th, 50th, 75th, and 90th percentiles and outliers.

The best results for sensitivity and specificity were obtained at a cut-off of 1,300 pg/mL (Youden index, 0.84). The sensitivity is 94%, specificity, 90%, and positive predictive value, 92%. The sensitivity of the 14-3-3 immunoblot in this study population is 90% and the specificity is 88%.

In all genetic cases, the 14-3-3 immunoblot was negative. In a follow-up CSF sample of one patient with E200K mutation, the 14-3-3 immunoblot became positive.

Tau-protein levels in the E200K mutation ranged between 2,172 pg/mL and 16,220 pg/mL (median, 3,512 pg/mL). The FFI cases (D178N) ranged between 385 pg/mL and 648 pg/mL (median, 411 pg/mL). The patient with V210I mutation had a tau-protein level of 3,579 pg/mL, and the patient with an insert mutation (9*24) a level of 1,578 pg/mL.

The 14-3-3 immunoblot was negative for the iatrogenic case. The tau-protein level in CSF was 1,983 pg/mL for this patient.

Follow-up.

Follow-up data were available for 10 definite cases and 8 “other” cases. In all except two definite cases, levels of tau-protein were rising or above the cut-off level (figure 2). The two cases that were below the cut-off level were patients with type II prion protein and a methionine/valine or valine/valine polymorphism at codon 129. The interval between the lumbar punctures ranged from 1 to 14 weeks.

Figure

Figure 2. Follow-up of 10 patients with definite Creutzfeldt–Jakob disease (CJD) and 8 patients classified as “other.” Solid line indicates definite CJD; dashed line, others; solid squares, 14-3-3 positive; diamonds, 14-3-3 negative.

Comparison of clinical diagnosis and CJD subtype with 14-3-3 immunoblot and tau-protein ELISA.

Of the 109 definite cases, 77 were clinically diagnosed as probable cases, 26 as possible cases, and 6 as other cases. Tau-protein levels and the 14-3-3 immunoblot distribution are given in table 2.

View this table:
Table 2.

Clinical diagnoses of patients neuropathologically verified to have Creutzfeldt–Jakob disease (n = 109)

Typing of the 109 definite sporadic cases according to Parchi was available on 69 cases (table 3). Methionine/valine type II prion protein and valine/valine type II prion protein cases were better detected by measurement of tau-protein than by immunoblot of 14-3-3 protein.

View this table:
Table 3.

CSF findings in subtypes of sporadic Creutzfeldt–Jakob disease

Comparison of the thickness of immunoblot and tau-protein level.

Comparison of the thickness of 14-3-3 bands with the level of tau-protein revealed higher levels of tau-protein in CSF of patients with thicker bands (p < 0.0001). However, this is not predictable for a single case. Comparison of the tau-protein level in patients whose bands were scored with + and ++ were below a significance level of p < 0.05.

Tau-protein level in serum.

In 6 of 15 patients with definite CJD, tau-protein levels were above the detection limit of the assay, and in 3 of 15 patients classified as other than CJD, the detection limit was crossed.

Patients with other forms of dementia than CJD.

Patients with AD comprised the largest group within the group of other diseases (table 4). Only 2 of 28 patients had tau-protein levels above 1,300 pg/mL. Noteworthy is the low level of CSF tau-protein of the patient with Hashimoto’s disease.

View this table:
Table 4.

Median CSF concentrations of tau-protein and results of 14-3-3 immunoblot in patients classified as having other diseases (n = 85)

In the other diseases/14-3-3+ group, patients with AD and vascular dementia comprised the largest part (table 5). Levels of tau-protein lay within previously described ranges for the differential diagnosis of AD and other non-CJD dementias. Also in this group, patients with glioma showed a prominent 14-3-3 band with comparable low tau-protein levels.

View this table:
Table 5.

CSF concentrations of tau-protein of patients with a dementia as the leading symptom and a positive 14-3-3 immunoblot (n = 15)

Discussion.

We conclude from our results that the differential diagnostic significance of the tau-protein ELISA is at least similar to that of the 14-3-3 immunoblot. CSF of patients with genetic, iatrogenic, and rare subtypes of sporadic CJD can be negative for the 14-3-3 immunoblot, whereas tau-protein already can be measured. Even if the diagnostic cut-off for CJD (>1,300 pg/mL) is not reached, tau-protein levels usually are elevated on a high level (>800 pg/mL). This holds especially true for patients with type II prion protein and methionine/valine or valine/valine polymorphism at codon 129. This finding also gives hope that patients with vCJD will present with elevated levels of tau-protein in CSF, because the 14-3-3 immunoblot is positive only in approximately 50% of vCJD cases.3,28⇓ Especially because patients with vCJD often present with psychiatric symptoms, even slightly elevated levels might be useful in this differential diagnosis because patients with true psychiatric disorders (e.g., depression or psychosis) have normal values of CSF tau-protein.29

Six patients who were later neuropathologically verified as having CJD were clinically grouped as having other disease. All six patients had tau-protein levels above 1,300 pg/mL, so that measurement of tau-protein also may serve as a marker for early diagnosis.

The lower diagnostic sensitivity of the 14-3-3 immunoblot compared with our earlier studies12 might be explained by the fact that we used only definite cases for calculation of cut-off values, whereas in earlier studies definite and probable CJD cases were grouped together.11,12⇓ However, levels of sensitivity and specificity are still within the previously calculated confidence intervals.

The high diagnostic sensitivity and specificity for both tests hold true only if the patient is seen under the differential diagnosis of CJD, as was done in our study. Screening with both tests is not useful and leads to a high rate of false-positive results. In table 5, some examples are given of the use of the 14-3-3 immunoblot as a screening parameter.

Tau-protein in serum seems not to be of differential diagnostic relevance. Even though more patients with CJD had detectable levels in serum compared with patients with other dementias, sensitivity and specificity are low. This finding is consistent with an earlier study in which no significant difference in the serum tau-protein level between demented and nondemented patients was found.26

Certainly, the advantage of the tau-protein ELISA is that it is easy to use in routine laboratories. In the meantime, measurement of tau-protein and Abeta(1-42) in CSF have gained acceptance in the differential diagnosis of dementias.20-22,30-34⇓⇓⇓⇓⇓⇓⇓ Unlike Abeta(1-42), which can be normal or decreased in CSF of patients with CJD,35 very high tau-protein levels can lead the diagnosis toward CJD. Patients with a negative 14-3-3 immunoblot already have measurable tau-protein levels. This increases the information on 14-3-3—negative patients with CJD, especially on patients with other diseases like AD or depression. Tau-protein levels in CSF of patients with other forms of dementia lay within previously described limits. Because of the great overlap, we do not think that the level of tau-protein will help to distinguish between the other forms of dementias within these limits (300 to 800 pg/mL), apart from the fact that elevated levels may exclude depression as the single cause of a dementia syndrome. Of diagnostic and pathophysiologic relevance is the fact that glioma patients can have normal tau-protein levels, whereas the 14-3-3 immunoblot shows a marked signal.

Whether the recently described 14-3-3 ELISA14,36⇓ will have the same diagnostic accuracy as the tau-protein ELISA needs to be investigated.

Tau-protein is found in neurofibrillary tangles in brains of patients with AD. These tangles are composed mainly of paired helical filaments that are formed by the aggregation of abnormally phosphorylated microtubule-associated tau-protein.37 The 14-3-3 proteins, which also were found in neurofibrillary tangles,38 are a highly conserved protein family that exists as seven isoforms and regulates diverse cellular processes.39,40⇓ Up to now, it has not been known which role 14-3-3 isoforms play in CJD or AD. A recent report has speculated that the beta and zeta 14-3-3 isoforms are involved in the pathologic phosphorylation of tau-protein.41 Such specifically phosphorylated tau-protein isoforms can be found in brains of patients with AD, corticobasal degeneration, and Pick’s disease.42 Neurofibrillary tangles and a specific phosphorylation are not described in patients with CJD. Therefore, we suspect that the very high levels of tau-protein in CSF of patients with CJD may be the result of alterated neurons and enhanced release into the CSF space.

Some assays measuring phospho-tau-protein isoforms were described recently.43,44⇓ In the future, the measurement of phospho-tau-protein in combination with 14-3-3 isoforms and total tau-protein may help in the differential diagnosis of diseases that have dementia as their leading symptom.45

Acknowledgments

Supported in part by a grant from the Bundesministerium für Gesundheit (M.O., S.P., K. Felgenhauer) and the European Community (M.O., J.W., and A. Aitken).

Acknowledgment

The authors thank the physicians who provided data on suspect cases to the German CJD surveillance unit; and Drs. Maria Seipelt, Kati Weidehaas, Andreas Schröter, Anke Otto, Sönke Arlt, Karsten Henkel, Henriette Tschampa, Christian Jakobi, Inga Zerr, and Monika Bodemer.

  • Received April 4, 2001.
  • Accepted October 7, 2001.

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