A comparison of tau and 14-3-3 protein in
the diagnosis of Creutzfeldt-Jakob disease
Clive Hamlin, PhD
Gianfranco Puoti, MD
Sally Berri, MS
Elliott Sting, BSc
Carrie Harris, BSc
Mark Cohen, MD
Charles Spear, BSc
Alberto Bizzi, MD
Sara M. Debanne, PhD
Douglas Y. Rowland,
Objective: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein
(qualitative) in the diagnosis of prion disease.
Methods: We made measurements on 420 live subjects, who subsequently underwent a postmor-
tem neuropathology examination, including protein chemistry, immunohistochemistry, and histol-
ogy. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were
optimized for maximum efficiency (accuracy).
Results: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better
well as when both assays’ results are combined in a variety of ways. Importantly, the area under the
receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3
protein (0.68) (p ? 0.001). Diagnostic test statistics are provided for the study subjects with 58.3%
prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center.
Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein.
AUC ? area under the curve; CJD ? Creutzfeldt-Jakob disease; NPDPSC ? National Prion Disease Pathology Surveillance
Center; PPV ? positive predictive value; ROC ? receiver operating characteristic.
Accurate and possibly early markers are increasingly important in prion diseases which often
present a rapid course and, because of their infectivity, require special biosafety precautions
during clinical management and tissue examinations.1,2The CSF 14-3-3 protein is widely used
as a surrogate marker in the premortem diagnosis of Creutzfeldt-Jakob disease (CJD) and
related prion illnesses.3–7The test is usually performed by immunoblot, but is not quantitative.
This leads to a significant percentage of the 14-3-3 tests being excluded as ambiguous. ELISA
has been proposed for the quantitative determination of the 14-3-3,7although the lack of a
commercial kit has limited this approach.
Most recent studies report 14-3-3 protein sensitivity in the range of 43%–100%.7–11The
specificity is stated to range from 47% to 97%.7,12,13
Other CSF markers have been proposed along with 14-3-3 protein, including S-100 protein,
ity or specificity.14–16In contrast, total tau protein is reported to be clinically useful.12,17
The purpose of this study was to establish the diagnostic test statistics for tau, including the
Bayesian concept of diagnosticity given by the likelihood ratio for comparison with 14-3-3,
with a defined patient population and sized to be statistically valid. Also, we intended to
establish the most efficient combination of tau and 14-3-3 protein for the diagnosis of prion
From the Departments of Pathology (National Prion Disease Pathology Surveillance Center) (C.H., G.P., S.B., E.S., C.H., M.C., C.S.) and Epidemiology
and Biostatistics (S.D., D.Y.R.), Case Western Reserve University, Cleveland, OH; and Istituto Neurologico Carlo Besta (A.B.), Milan, Italy.
Study funding: Supported by CDC (CCU515004) and NIH NIA (AG14359).
Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Correspondence & reprint
requests to Dr. Hamlin:
Copyright © 2012 by AAN Enterprises, Inc.
METHODS CSF specimens were referred to the National
Prion Disease Pathology Surveillance Center (NPDPSC) from
US medical institutions for patients with CJD or other prion
diseases in the differential diagnosis. Over a 27-month time pe-
riod, tau and 14-3-3 protein were measured on 5,496 samples
(tau: 812 positive, 4,684 negative; protein 14-3-3: 1,157 posi-
tive, 2,048 negative, 2,291 ambiguous), but tau values were not
reported. Both assays were optimized for maximum accuracy
(efficiency). During an additional 21 months, deaths followed
by neuropathology completed our study population. Genetic
analysis was performed to assess the polymorphism at codon 129
the prion protein gene (PRNP).18,19The decision to request an au-
by the decedent’s clinican and was usually preceded by an extensive
neurologic evaluation that included 14-3-3 protein.
We measured 14-3-3 protein by Western blot with a detec-
tion polyclonal antibody (sc-629, Santa Cruz Biotechnology,
CA). We judged blots negative, ambiguous (weakly positive), or
positive according to the density of the 14-3-3 immunoblot
bands. We measured total tau by ELISA following an initial 1:10
dilution (Biosource; now Invitrogen, CA).
The prevalence of prion diseases in our population of 420
autopsy-verified patients was 58.3%. We estimated the preva-
lence of confirmed prion disease among all patients tested during
the same time period to be 7.5%.
More details of the methods, statistical analyses, and results
are presented in appendices e-1 to e-3 on the Neurology®Web
site at www.neurology.org.
Standard protocol approvals, registrations, and patient
consents. Case Western Reserve University institutional review
board approved the use of human subjects and discarded tissues
for this study via protocol 01-95-01.
RESULTS Tissue-verified prion positive cases. A to-
tal of 420 of the 5,496 patients underwent autopsy,
which definitely confirmed the diagnosis of prion dis-
ease in 245 (58.3%). None of the prion-positive cases
treatments, making the possibility of iatrogenic prion dis-
Individual CSF examinations: 14-3-3 protein. We
conducted 14-3-3 tests according to our standard
procedure, which identifies the 3 diagnostic catego-
ries of positive, negative, and ambiguous. Semiquan-
tification was extended by splitting the ambiguous
category based on the median density (?300 ng/
mL), thereby providing 4 categories.
Individual CSF examinations: tau protein. The
amount of tau (pg/mL) determined in the 420 cases,
which varied from 0 to 140,000 pg/mL, required the
choice of an appropriate decision point. Plotting the
diagnostic capabilities of each test as receiver operat-
ing characteristic (ROC) curves indicated that 900–
1,200 pg/mL was an optimal range to separate
negative from positive cases for tau, determined by
the region of maximum change of curve slope (figure
1). We also analyzed the tau test with the histogram
of the distribution of positive and negative prion dis-
ease cases as a function of the amounts of tau de-
tected in the individual CSF samples (figure 2). This
histogram pointed to a maximally efficient decision
point at 1,150 pg/mL. The suitability of the 1,150
pg/mL decision point was further confirmed by com-
paring the tau test predictive values at this decision
point with those at 900 pg/mL, 1,000 pg/mL, and
1,400 pg/mL (table 1). The ROC curve of the tau
tests was also compared with that of the 14-3-3 tests.
The area under the curve (AUC) ? SE of the ROC
curve for tau was 0.819 ? 0.020 vs 0.672 ? 0.022
for the 14-3-3 test (p ? 0.001) when the 4 categories
(ambiguous tests assigned to the negative or positive
category) were adopted (figure 1). At 7.5% preva-
lence and a 1,150 cutoff, the diagnosticity given by
the likelihood ratio equal to sensitivity/(1 ? specific-
ity) for tau is 2.67, while for 14-3-3 protein, with
ambiguous considered negative, it is 1.78.
Effect of disease progression on tau test. The mean
amount of tau detected decreased progressively at in-
creasing time intervals between CSF withdrawal and
disease onset spanning from over 14,600 pg/mL, at
an interval of less than 43 days from clinical onset
(highest quintile), to 2,030 pg/mL at more than 200
days (lowest quintile).
Neuropathology of the false-positive and false-
negative cases with the tau test. Conditions among
the 57 false-positive cases with adequate neuropatho-
logic examination included neurodegenerative dis-
eases such as Alzheimer disease, which was the most
Figure 1 Receiver operating characteristic curves for tau and 14-3-3 protein
Four categories (negative, ambiguous negative, ambiguous positive, and positive) are used
for 14-3-3 protein. The area under the curve ? SE for tau was 0.819 ? 0.020 vs 0.672 ?
0.022 for the 14-3-3 test. The thin green line represents a test that does not change pre-
Neurology 79August 7, 2012
common diagnosis, multiple infarcts in 11 cases,
and brain neoplasms in 4 cases (table 2). More-
over, in 5 of these cases the CSF was contaminated
by blood, which in itself is likely to lead to a false-
No special cause for the 32 false-negative cases
emerged except for the prion disease being familial
(3 cases) and blood contamination (1 case). Technical
reasons such as long storage before testing could not be
verified because collection date of specimen was not al-
ways provided by the sender. However, both tau and
14-3-3 protein tend to increase with disease progres-
sion. Of the 32 false-negative cases, 9 were associated
with a second specimen. Had the last specimen been
Effect of blood presence in CSF. Blood is a contami-
nant sometimes found in received CSF samples. Blood
was detected in the CSF from 13 confirmed CJD and
20 non prion cases. Incorrect results were 19 for 14-3-3
protein (18 FP/1 FN) and 12 for tau (11 FP/1 FN).
samples is small, the presence of blood in the CSF in-
creases the number of false-positive cases in both tests.
Accuracy of tau and 14-3-3 tests (ambiguous cases
excluded) according to prion disease molecular charac-
teristics and prion disease form and subtype. When
the positive cases were examined according to the
PrP genotype at codon 129 and the PrPSctype, va-
line homozygosity (VV) and PrPSctype 1 had the
highest sensitivity with the tau test (100% and
95.5%) while methionine/valine (MV) heterozygos-
ity and the presence of both PrPSctypes (type 1–2)
had the lowest with 82% and 72%, respectively. Fur-
thermore, VV homozygosity and presence of PrPSc
type 1 were associated with the highest amounts of
CSF tau (10,431 pg/mL and 14,515 pg/mL). Sensi-
tivity of the 14-3-3 test was consistently higher than
that of the tau test (see appendix e-2).
The diagnostic accuracy of tau was greater for
“typical” than “atypical” cases (figure 3).
Combined use of the tau and 14-3-3 tests. Ourseparate
analysis of the 2 tests indicates that although both are
tried to combine the 2 tests in different ways to assess
whether the combinations resulted in better predictive
values than the tau test alone. Various ways, described
in brief below, of combining tau protein and 14-3-3
protein were statically performed. A complete descrip-
tive analysis is provided in appendix e-3.
An ambiguous 14-3-3 protein was linked to ambig-
uous tau (between 307 pg/mL and various higher deci-
dominant and additive to ambiguous tau, or replaced
by numeric or ambiguous tau. Tau was next taken as
the single decision point for 14-3-3 protein was used.
with ambiguous 14-3-3 protein taken as positive, nega-
tive, or substituted by tau. Next, both tests were re-
quired to be positive, with ambiguous 14-3-3 protein
taken as positive, negative, or substituted by tau.
None of the combinations is clearly superior to
the tau protein test alone.
Figure 2Histogram of distribution of tau values (log) per 0.1 log unit
Positive Creutzfeldt-Jakob disease (CJD) cases (blue triangles) and negative cases (red
squares) are shown. The log scale is used for clarity with tau values from 10 to 140,800
pg/mL. The most accurate cutoff of tau between cases positive and negative for CJD is
1,150 pg/mL. The prion disease-positive subjects were distributed as follows: 247 with tau
at or above 1,150 pg/mL, 24 between 1,149 and 800 pg/mL, and 149 below 800 pg/mL.
BN represents the level below which 10% of positive cases fall. BP represents the level
above which 10% of negative cases fall.
Table 1 Tau test statistics at different decision points
Decision points900 1,0001,150 1,400
24 2732 42
221218 213 203
No. of cases
76.74 77.58 78.8979.30
The following are for when
the true prevalence is 7.5%
16.04 16.6917.79 18.16
63.85 65.87 68.8970.70
Abbreviations: NPV ? negative predictive value; PPV ? positive predictive value.
Neurology 79 August 7, 2012
DISCUSSION In 1998, the CSF 14-3-3 diagnostic
test for prion diseases was adopted by the WHO.4
This led to increased scrutiny of the CSF 14-3-3 pro-
tein test with widely reported Bayesian statistics, and
studies suggesting use of other CSF surrogate mark-
ers.4–17Many of these studies were conducted with
relatively small numbers, because prion diseases are
uncommon. Additionally, a substantial proportion
of the cases were not subject to neuropathology. Our
experience has shown that some cases meeting WHO
criteria are shown not to have prion disease following
neuropathologic examination.21Conversely, others
believed not to have prion disease are found to have
it upon tissue examination.
A large multicenter study, considered to be one of
the more useful, compared 14-3-3, tau, and other
brain-derived proteins.22The findings of this study
differ from ours, perhaps for the following reasons: in
our study case selection was based solely on 14-3-3
and tau tests having been performed during a 27-
month period, followed by neuropathology on all
study subjects during the same time period plus an
additional 21 months. No cases were excluded and
none were rejected provided the stated criteria were
met. Only a single set of CSF tests were included,
and were always performed on the first CSF speci-
men received. Some selection bias may exist in our
study owing to 14-3-3 protein, but not tau, having
been reported and available for inclusion in the deci-
sion process leading to neuropathology. This could
have led to an overestimation of 14-3-3 sensitivity.
As in the multicenter study, it is noted that a second
lumbar test in negative cases would be of value.
The tested population for tau and 14-3-3 tests
was representative of the general tissue-confirmed
population examined at the NPDPSC judged by the
percentage of prion positive and negative cases, fa-
milial and sporadic cases of prion disease, and the 6
subtypes of the sCJD.
40%), and overall offered better accuracy with less am-
biguous reports. The superiority of tau is supported by
comparing the ROC curves and the diagnosticity, i.e.,
the likelihood ratios of the 2 tests. Although the sensi-
ture.12,13,23–25The lower specificity values of our 14-3-3
and tau may be due to the relative representation in our
patient population of the sCJD 1–2 cases (20.3%)
which are associated with lower sensitivities, the relative
high number of negative cases (41.7%), and the fre-
quent lack of advanced diagnostic selection of our pa-
tient population which included many subjects often
examined in nonspecialized centers where prion disease
was one of several possible clinical diagnoses.
Unexpectedly, we found none of the combinations
protein test alone. However, equivalent performance
was obtained with the combination requiring both tests
to be positive and with tau replacing ambiguous 14-3-3
protein. The combination with 14-3-3 protein domi-
nant and ambiguous replaced by tau or ambiguous tau
became statistically superior at higher upper limits for
ably large number of excluded ambiguous tau cases.
ments, the ability of the 2 assays to predict disease sta-
Figure 3Diagnostic reliability of tau for “typical” and “atypical” cases
The 2 receiver operating characteristic curves (typical and atypical) show greater area un-
der the curve (AUC) for typical (0.886) vs atypical (0.750) cases (95% confidence interval
for AUC for atypical is 0.667 to 0.833, which is lower than, and has no overlap with, the
95% confidence interval for typical, which is 0.840 to 0.932).
Table 2Neuropathologic diagnoses of tau false-positive cases
DiagnosisNo.Tau amount (pg/mL) mean (range)
Multi-infarcts and vascular diseasesa
3 8,369 (4,104–14,211)
4 3,988 (1,277–8,970)
4 4,392 (2,599–7,204)
Focal severe astrogliosis
2 4,411 (2,721–6,101)
No or not distinct pathology
4 7,461 (2,386–17,966)
Tissue inadequate or unavailable
Total false-positive cases
aAll cases with multiple ischemic lesions more than1
degeneration with mild cortical involvement, and 1 case of frontotemporal dementia.
cOne case of granulomatous encephalitis, one case of Cryptococcus meningoencephalitis
(both with multiple areas of necrosis), one case with large and destructive perivascular lym-
phocyte infiltrates, and one case of unspecified encephalitis with infarcts.
2cm except for 2 with diffuse ischemia.
Neurology 79August 7, 2012
tus, individually and jointly, was examined statistically
protein alone has significantly better ability to predict
disease status than the 14-3-3 protein alone. Further
details can be found in appendix e-3.
The sensitivity associated with each of the 3 129
genotypes, PrPSctypes 1, 2, or both types together
(1–2), as well as in the individual subtypes of sCJD,
consistently shows higher values for the 14-3-3 test
(ambiguous values excluded) than tau. However, the
variation of the values from one subtype to the other
is similar with the exception of the 129 MV cases in
which the 14-3-3 sensitivity is higher than in 129
MM cases, while the opposite is true for tau. Overall,
the present findings are similar to those of previous
European studies.5,7,22A study on the correlation be-
tween type and topography of brain pathology and
predictability of CSF surrogate markers in sCJD has
reported that 14-3-3 and tau tests correlate nega-
tively with the severity of the spongiform degenera-
tion and other lesions present in the cerebral cortex,
severity of histologic lesions in the cerebellum and the
degree of glial reaction in the basal ganglia.26
Histopathologic examination led to a definitive di-
agnosis in 41 out of the 57 cases which received a false-
positive diagnosis by the tau test (table 2). In at least 23
of these cases, including cases with multiple infarcts,
leukodystrophy, cerebellar degeneration, encephalitis,
and brain neoplasms, the brain lesions were detectable
by MRI study. Were these 23 cases reassigned from
false-positive to true-negative on the basis of MRI, the
test alone would have improved from 67.43% and
78.89% to, with combined tau and MRI examination,
80.57% and 86.23%, respectively. Similar findings
were found with 14-3-3 protein. This suggests that the
MRI examination might be carried out before or after
ability and relative cost.
Tau and 14-3-3 protein testing and other surro-
gate tests are included along with clinical evaluation,
EEG evaluation, and MRI testing during disease pro-
gression. None of these tests or procedures perfectly
separate prion disease from other neurologic diseases.
Only carefully performed neuropathology is believed
capable of this segregation. However, each test or
procedure should increase the clinical impression
that prion disease is present when it is, and seem less
likely when not present. The diagnosticity evaluates
the ability of a test and is calculated as the likelihood
ratio. In this study, the likelihood ratios for the tau
test are better than those for the 14-3-3 protein test.
Although diagnosticity values would change with
prevalence and disease progression, the superiority of
tau would not. Similar to the likelihood ratio is the
ratio of the post-test PPV to the pretest PPV. After
performing the 14-3-3 protein test, a positive test
increases the probability of prion disease by a factor
of 1.3–1.5. Tau, on the other hand, increases the
probability of prion disease by a factor of 2.4 at
1,150 pg/mL and larger with higher tau values. More
detail is presented in appendix e-4.
The cutpoint of an assay affects sensitivity, speci-
ficity, and predictive values. As the cutpoint is raised
sensitivity, negative predictive value, and false-
positives all decrease. Previous studies have used a
higher tau cutpoint than we have, leading to a lower
sensitivity.22Our assay used a tau cutpoint of 1,150
pg/mL for maximum efficiency, but a lower cutpoint
in a surveillance setting may be desired to minimize
falsely rejecting patients with prion disease at a cost
of more false-positives.
On the basis of this study, the value of tau as a
diagnostic test for prion disease may have been un-
derestimated. In this study, by ROC curve and diag-
nostic test statistical analysis, including Bayesian
considerations, the tau test appears superior to the
14-3-3 protein test.
Tau vs 14-3-3 protein—Adjuncts for the diagnosis of CJD
Creutzfeldt-Jakob disease (CJD) has an annual incidence of 1 per million
persons. With ?300 US cases per year, and over 15,000 neurologists, we see a
patient with CJD, by chance, once in 50 years of clinical practice. How does the
accuracy of CSF tau vs 14–3-3 protein affect clinical diagnosis?
There are 2 critical reasons to diagnose CJD accurately: first, to assure adequate
precautions to avoid the spread of disease by transmissible material; second, to
eliminate the diagnosis of CJD in similar non-CJD subacute dementing disorders
for which there are effective treatments. The ideal test would have sensitivity and
specificity approaching 100%. Hamlin et al.1examined the diagnostic accuracy of
CSF tau and 14–3-3 protein, and concluded that tau protein was more “accurate”
than 14–3-3, although neither is a perfect predictor of CJD.
A problem with the qualitative 14–3-3 test is that 30% of results are
“ambiguous.” When ambiguous results are considered positive, the 14–3-3 test is
highly sensitive, but has many false-positives. Tau is more specific, with fewer
false-positives, but more false-negatives; overall, it is more accurate. Statistical
accuracy aside, however, the “costs” of false-negative and false-positive tests differ.
For hospital safety, a highly sensitive test minimizing false-negatives is desirable;
for identification of non-CJD diagnoses, a highly specific test, with the fewest false-
positives, is preferable.
Neither tau nor 14–3-3 is appropriate as a screening test. The positive
predictive value of both decreases dramatically if they are used in populations with
low true prevalence of CJD, and they should be used as adjunctive tests when CJD
is strongly suspected. The clinical picture of a rapidly progressive dementia, often
with ataxia, visual disturbances, extrapyramidal features, and startle-evoked
myoclonus, positive basal ganglia DWI changes on MRI, and a periodic sharp-wave
EEG pattern, most often establishes the diagnosis well before the laboratory has
returned the CSF results.
1. Hamlin C, Puoti G, Berry S, et al. A comparison of tau and 14-3-3 protein in the
diagnosis of Creutzfeldt-Jakob disease. Neurology 2012;79:547–552.
David A. Drachman, MD
The author reports no disclosures relevant to the manuscript. Go to Neurology.org
for full disclosures.
Neurology 79 August 7, 2012
AUTHOR CONTRIBUTIONS Download full-text
C. Hamlin serves as primary corresponding author and was responsible
for the overview and writing of the manuscript. G. Puoti provided analysis
of the supplementary data. S. Berri redesigned the database utilized for the
study, provided oversight for case data and manuscript content, as well as
contributed to data analysis. E. Sting redesigned the database, provided
statistical and data analysis, and contributed to all final table and figure
designs and content. C. Harris contributed to the original establishment of
the database used for the study and the study design parameters and contrib-
uted to the data analysis. M. Cohen provided analysis of histopathological
diagnostic evaluations. C. Spear assisted Dr. Cohen in preparation of histo-
pathologic staining needed for diagnostic evaluations. A. Bizzi was the neuro-
radiologist who reviewed all relevant case MRIs of the study and provided
input that was utilized in the Discussion. S. Debanne provided statistical
analysis over case data and content of the manuscript. D. Rowland provided
statistical analysis over case data and content of the manuscript.
P. Gambetti, MD, contributed to the characterization of the cases used in
this study, and provided analysis of histopathological diagnostic evalua-
tions. J. Blevins, BA, provided query data input for study database. F.
Zamayla, BSc, contributed to the establishment of the quality control
parameters and the assays performed in the study, as well as performed the
assays of the test study. J. Xiao, BSc, also performed the assays of the test
study. K. Glisic, BA, prepared the paper for publication submission by
ensuring proper formatting per the journal’s requirements.
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received July 20, 2011. Accepted in final form December 29, 2011.
1. Schapira AH, Tolosa E. Molecular and clinical prodrome
of Parkinson disease: implications for treatment. Nat Rev
2. Hampel H, Frank R, Broich K, et al. Biomarkers for Alz-
heimer’s disease: academic, industry and regulatory per-
spectives. Nat Rev Drug Discov 2010;9:560–574.
3. 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;335:924–930.
4. Sanchez-Juan P, Sa ´nchez-Valle R, Green A, et al. Influence
of timing on CSF tests value for Creutzfeldt-Jakob disease
diagnosis. J Neurol 2007;254:901–906.
5. Collins J, Sanchez-Juan P, Masters CL, et al. Determinants
of diagnostic investigation sensitivities across the clinical
spectrum of sporadic Creutzfeldt-Jakob disease. Brain
6.Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Spo-
radic and familial CJD: classification and characterisation.
Br Med Bull 2003;66:213–239.
7.Gmitterova K, Heinemann U, Bodemer M, et al. 14-3-3
CSF levels in sporadic Creutzfeldt-Jakob disease differ
across molecular subtypes. Neurobiol Aging 2009;30:
8.Van Everbroeck B, Quoilins, Boon J, Martin JJ, Cras P. A
prospective study of CSF markers in 250 patients with
possible Creutzfeldt-Jakob disease. J Neurol Neurosurg
9. Chapman T, McKeel DW Jr, Morris JC. Misleading re-
sults with the 14-3-3 assay for the diagnosis of Creutzfeldt-
Jakob disease. Neurology 2000;55:1396–1397.
10.Geschwind M, Martindale J, Miller D, et al. Challenging
the clinical utility of the 14-3-3 protein for the diagnosis of
sporadic Creutzfeldt-Jakob disease. Arch Neurol 2003;60:
Kenney K, Brechtel C, Takahashi H, Kuroharak K, Ander-
son P, Gibbs CJ Jr. An enzyme-linked immunosorbent
assay to quantify 14-3-3 proteins in the cerebrospinal fluid
of suspected Creutzfeldt-Jakob disease patients. Ann Neu-
Otto M, Wiltfang J, Cepek L, et al. Tau protein and 14-
3-3 protein in the differential diagnosis of Creutzfeldt-
Jakob disease. Neurology 2002;58:192–197.
Bahl JM, Heegaard NH, Falkenhorst G, et al. The diag-
nostic efficiency of biomarkers in sporadic Creutzfeldt-
Jakob disease compared to Alzheimer’s disease. Neurobiol
Beaudry P, Cohen P, Brandel JP, et al. 14-3-3 protein,
neuron-specific enolase, and S-100 protein in cerebrospi-
nal fluid of patients with Creutzfeldt-Jakob disease. De-
ment Geriatr Cogn Disord 1999;10:40–46.
Kropp S, Zerr I, Schulz-Schaeffer WJ, et al. Increase of
neuron-specific enolase in patients with Creutzfeldt-Jakob
disease. Neurosci Lett 1999;261:124–126.
Kohira I, Tsuji T, Ishizu H, et al. Elevation of neuron-
specific enolase in serum and cerebrospinal fluid of early
stage Creutzfeldt-Jakob disease. Acta Neurol Scand 2000;
Otto M, Wiltfang J, Tumani H, et al. Elevated levels of
tau-protein in cerebrospinal fluid of patients with
Creutzfeldt-Jakob disease. Neurosci Lett 1997;225:210–
Parchi P, Giese A, Capellari S, et al. Classification of spo-
radic Creutzfeldt-Jakob Disease based on molecular and
phenotypic analysis of 300 subjects. Ann Neurol 1999;46:
Monari L, Chen SG, Brown P. Fatal familial insomnia and
familial Creutzfeldt-Jakob disease: different prion proteins
determined by a DNA polymorphism. Natl Acad Sci
Ironside JW, Head MW. Neuropathology and molecular
biology of variant Creutzfeldt-Jakob disease. Curr Top
Microbiol Immunol 2004;284:133–159.
Chitravas N, Jung RS, Kofskey DM, et al. Treatable neu-
rological disorders misdiagnosed as Creutzfeldt-Jakob dis-
ease. Ann Neurol 2011;70:437–444.
Sanchez-Juan P, Green A, Ladogana A, et al. CSF tests in
the differential diagnosis of Creutzfeldt-Jakob disease.
Van Everbroeck B, Boons J, Cras P. Cerebrospinal fluid
biomarkers in Creutzfeldt-Jakob disease. Clin Neurol
Skinningsrud A, Stenset V, Gundersen AS, Fladby T. Ce-
rebrospinal fluid markers in Creutzfeldt-Jakob disease. Ce-
rebrospinal Fluid Res 2008;5:14.
Wang GR, Gao C, Shi Q, et al. Elevated levels of tau
protein in cerebrospinal fluid of patients with probable in
Creutzfeldt-Jakob disease. Am J Med Sci 2010;340:291–
Boesenberg-Grosse C, Shulz-Schaeffer WJ, Bodemer M, et
al. Brain-derived proteins in CSF: do they correlate with
brain pathology in CJD? BMC Neurol 2006;6:35.
Neurology 79 August 7, 2012