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Diagnostic accuracy of cerebrospinal fluid protein markers for sporadic Creutzfeldt-Jakob disease in Canada: a 6-year prospectiv

Posted Nov 04 2011 10:33pm
Research article

Diagnostic accuracy of cerebrospinal fluid protein markers for sporadic Creutzfeldt-Jakob disease in Canada: a 6-year prospective study

Michael B Coulthart , Gerard H Jansen , Elina Olsen , Debra L Godal , Tim Connolly , Bernard CK Choi , Zheng Wang and Neil R Cashman

BMC Neurology 2011, 11:133doi:10.1186/1471-2377-11-133

27 October 2011

Abstract (provisional)


To better characterize the value of cerebrospinal fluid (CSF) proteins as diagnostic markers in a clinical population of subacute encephalopathy patients with relatively low prevalence of sporadic Creutzfeldt-Jakob disease (sCJD), we studied the diagnostic accuracies of several such markers (14-3-3, tau and S100B) in 1000 prospectively and sequentially recruited Canadian patients with clinically suspected sCJD.


The study included 127 patients with autopsy-confirmed sCJD (prevalence = 12.7%) and 873 with probable non-CJD diagnoses. Standard statistical measure of diagnostic accuracy were employed, including sensitivity (Se), specificity (Sp), predictive values (PVs), likelihood ratios (LRs), and Receiver Operating Characteristic (ROC) analysis.


At optimal cutoff thresholds (empirically selected for 14-3-3, assayed by immunoblot; 976 pg/mL for tau and 2.5 ng/mL for S100B, both assayed by ELISA), Se and Sp respectively were 0.88 (95% CI, 0.81-0.93) and 0.72 (0.69-0.75) for 14-3-3; 0.91 (0.84-0.95) and 0.88 (0.85-0.90) for tau; and 0.87 (0.80-0.92) and 0.87 (0.84-0.89) for S100B. The observed differences in Sp between 14-3-3 and either of the other 2 markers were statistically significant. Positive LRs were 3.1 (2.8-3.6) for 14-3-3; 7.4 (6.9-7.8) for tau; and 6.6 (6.1-7.1) for S100B. Negative LRs were 0.16 (0.10-0.26) for 14-3-3; 0.10 (0.06-0.20) for tau; and 0.15 (0.09-0.20) for S100B. Estimates of areas under ROC curves were 0.947 (0.931-0.961) for tau and 0.908 (0.888-0.926) for S100B. Use of interval LRs (iLRs) significantly enhanced accuracy for patient subsets [e.g., 41/120 (34.2%) of tested sCJD patients displayed tau levels >10,000 pg/mL, with an iLR of 56.4 (22.8-140.0)], as did combining tau and S100B [e.g., for tau >976 pg/mL and S100B >2.5 ng/mL, positive LR = 18.0 (12.9-25.0) and negative LR = 0.02 (0.01-0.09)].


CSF 14-3-3, tau and S100B proteins are useful diagnostic markers of sCJD even in a low-prevalence clinical population. CSF tau showed better overall diagnostic accuracy than 14-3-3 or S100B. Reporting of quantitative assay results and combining tau with S100B could enhance case definitions used in diagnosis and surveillance of sCJD.

Conclusions In summary, while acknowledging that CSF protein marker testing in the diagnostic investigation of sCJD should always be carefully linked to clinical context, our key finding is that quantitative CSF tau and S100B assays, particularly in combination, have significant value even in clinical settings where the pre-test probability of sCJD is relatively low, and may be an optimal choice for clinical investigations of sCJD, perhaps with prioritization of tau. It may also be timely to consider formally incorporating these markers into sCJD surveillance case definitions. True ante mortem laboratory diagnosis of human prion diseases may eventually be achieved with new approaches based for example on PrPSc [10, 11, 47], other markers suggested by CJD pathobiology [48] or discovered by systematic screening [49], or perhaps a combination of these. In the interim however, optimized application of known diagnostic markers will require judicious quantitative assessment of their performance in realistic clinical settings.

Risk.10: CSF Proteins and Diagnosis of Sporadic Creutzfeldt-Jakob Disease in Canada

Michael B. Coulthart,1,† Gerard H. Jansen,2 Elina Olsen,3 Deborah L. Godal,1 Tim Connolly,3 Bernard C. Choi,3 Zheng Wang3 and Neil R. Cashman4

1Public Health Agency of Canada; Winnipeg, MB Canada; 2University of Ottawa; Ottawa, ON Canada; 3Public Health Agency of Canada; Ottawa, ON Canada; 4University of British Columbia; Vancouver, BC Canada†Presenting author; Email:

Background. With its range of initial symptoms that may accompany other conditions, and a frequent need for timely diagnosis, sporadic Creutzfeldt-Jakob disease (sCJD) can present the clinician with significant challenges. Particularly widely employed for this purpose are assays for certain brain proteins in cerebrospinal fluid (CSF). Data are needed to better support systematic revision of diagnostic probabilities for sCJD on the basis of CSF protein assay results, in patient populations that also include diverse subacute encephalopathies eliciting a clinical suspicion of sCJD.

Methods. CSF 14-3-3, total Tau and S-100B proteins were studied prospectively in 948 Canadian patients suspected of having sCJD, including 121 with autopsy-confirmed sCJD and 827 with probable non-CJD diagnoses. Various metrics of diagnostic accuracy including sensitivity, specificity, predictive values and likelihood ratios were estimated.

Results. Estimated diagnostic accuracy for individual markers were mostly consistent with those of previously published studies at optimal cutoff thresholds for this study population (empirically defined for 14-3-3 immunoblot; 976 pg/mL for Tau; 2.5 ng/mL for S-100B). Sensitivity and specificity estimates respectively at these thresholds were 0.88 (95% CI, 0.81–0.93) and 0.71 (0.68–0.74) for 14-3-3; 0.90 (0.83–0.95) and 0.87 (0.85–0.90) for Tau; and 0.86 (0.78–0.91) and 0.86 (0.84–0.89) for S-100B; thus, the only outlier was 14-3-3 specificity (~0.7). Positive likelihood ratio (LR+) estimates were low to moderate: 3.0 (2.8–3.3) for 14-3-3; 7.1 (6.6–7.6) for Tau and 6.3 (5.8–6.8) for S-100B at optimal cutoff thresholds. Negative likelihood ratios were moderate: 0.17 (0.10–0.30) for 14-3-3; 0.12 (0.07–0.2) for Tau; and 0.17 (0.10–0.30) for S-100B. Interval LR estimates strengthened accuracy for patient subsets—for example, 31.4% of sCJD patients displayed extreme CSF Tau levels (>12 000 pg/mL), associated with an LR of 64.0 (23.3–175.9). Combining Tau and S-100B results, even at intermediate values, also enhanced accuracy; e.g., LR+ = 55.6 (20.1–153.7) with Tau > 5000 pg/mL and S-100B > 5.0 ng/mL.

Conclusions. CSF Tau and S-100B show comparable or better diagnostic accuracy compared to 14-3-3 in a heterogeneous patient population with low average pre-test probability of sCJD. Tau and S-100B may be optimal choices for many sCJD case investigations. Reporting of quantitative assay results as well as combining Tau and S-100B could enhance the clinical utility of surveillance case definitions for sCJD.


Risk.49: Creutzfeldt-Jakob Disease in Canada, 1998–2009

Zheng Wang,1,† Gerard Jansen,1, 2 Elina Olsen,1 Stacy Sabourin,1 Rolande D’Amour,1 Tim Connolly,1 Jennifer Kruse,1 Neil Cashman3 and Michael Coulthart1

1The Canadian Creutzfeldt-Jakob Disease Surveillance System; Public Health Agency of Canada; Ottawa, ON Canada; 2Department of Pathology; Ottawa Hospital; Ottawa, ON Canada; 3Brain Research Centre; University of British Columbia; Vancouver, BC Canada†Presenting author; Email:

Background. Creutzfeldt-Jakob Disease (CJD) is a fatal, transmissible neurodegenerative disease with sporadic, genetic and acquired forms. In 1998, Canada launched comprehensive national CJD surveillance to assess the characteristics of CJD in Canada and its risks to the health of Canadians. This study describes the broad characteristics of CJD in Canada from 1998–2009.

Methods. Case ascertainment was based on internationally accepted criteria. Demographic information and risk-factor data were collected by standardized questionnaire and medical chart review. Poisson regression, descriptive analysis, and case investigation were employed.

Results. A total of 453 CJD deaths in Canadian residents were registered from 1998–2009. Four hundred and fifteen (92%) were sporadic (sCJD), 33 (7%) were genetic and five (1%) were acquired. Average annual sCJD mortality was 1.1 per million population, increasing gradually from 0.9 in 1999 to 1.4 in 2009 (P = 0.27). All provinces saw average annual mortalities ranging from 1.0 to 1.5 (P = 0.85), except three territories where population is small (~25,000 to ~45,000), sCJD occurred equally in both genders at 1.1. sCJD was rare under 50 years of age with only 11 cases identified (2.7%). Mortality increased after 50 and peaked at 8 per million in the 70–74 age group. Median age at death was 69 and median duration of illness was 4 months. Genetic TSE accounted for 33 deaths: 19 were GSS (P102L: 5, D202N: 2, P105T: 2, Q217R:1, A117V: 1, unknown mutation: 8); 13 were familial CJD (E200K: 9, D178N: 2, V203I: 1, V189I:1); one was FFI (D178N). Median age for genetic TSE was 59 and median duration of illness was 27 months. For the five acquired cases of CJD, four were associated with dura mater procedures (3 Lyodura, 1 Tutoplast) and were identified from 1998–2003 in patients aged 14–59. Investigation indicated the infections possibly occurred from 1981–1992 with incubation times from 10–16 years. One biochemically and neuropathologically confirmed variant CJD death occurred in 2002 in a person under 40 years old, likely acquired overseas.

Discussion and Conclusion. Characteristics of CJD in Canada are consistent with those observed in other countries. The increase in sCJD mortality can be at least partly attributed to increased awareness of CJD among referring clinicians. The finding of four dura matter associated CJD cases and one imported vCJD case in Canada demonstrate risks to Canadians from acquired CJD exist. Continued surveillance for iatrogenic risks and novel forms of CJD is warranted.


Envt.05: Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque

Emmanuel Comoy,1,† Valérie Durand,1 Evelyne Correia,1 Sophie Freire,1 Jürgen Richt,2 Justin Greenlee,3 Juan-Maria Torres,4 Paul Brown,1 Bob Hills5 and Jean-Philippe Deslys1

1Atomic Energy Commission; Fontenay-aux-Roses, France; 2Kansas State University; Manhattan, KS USA; 3USDA; Ames, IA USA; 4INIA; Madrid, Spain; 5Health Canada; Ottawa, ON Canada†Presenting author; Email:

The epidemiology of Transmissible mink encephalopathy (TME) indicates an alimentary origin. Several inter-species transmission experiments have not succeeded in establishing with certainty any natural reservoir of this prion strain, although both ovine and bovine sources have been suspected. Cattle exposed to TME develop a spongiform encephalopathy that is distinct from classical Bovine Spongiform Encephalopathy (c-BSE).

Inoculation of c-BSE to cynomolgus macaque provided early evidence of a possible risk to humans, and remains an important model to define the risk of both primary (oral transmission from cattle to primate) and secondary (intravenous intra-species transmission) exposures. We have also evaluated the transmissibility of other cattle prion strains to macaques, including L- and H- atypical forms of BSE, namely BSE-L and BSE-H, and cattle-adapted TME.

BSE-L induced a neurological disease distinct from c-BSE. Peripheral exposures demonstrate the transmissibility of BSE-L by oral, intravenous, and intra-cerebral routes, with incubation periods similar to c-BSE. Cattle-adapted TME also induced a rapid disease in cynomolgus macaque. The clinical features, lesion profile, and biochemical signature of the induced disease was similar to the features observed in animals exposed to BSE-L, suggesting a link between the two prion strains. Secondary transmissions to a common host (transgenic mouse overexpressing bovine PrP) of cattle-TME and BSE-L before or after passage in primates induced diseases with similar incubation periods: like the c-BSE strain, these cattle strains maintained their distinctive features regardless of the donor species and passages.

If the link between TME and BSE-L is confirmed, our results would suggest that BSE-L in North America may have existed for decades, and highlight a possible preferential transmission of animal prion strains to primates after passage in cattle.

===================== Prion

Thursday, October 27, 2011

Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

doi:10.1016/j.jcpa.2011.09.004 | How to Cite or Link Using DOI

Experimentally induced disease

EFSA Journal 2011 The European Response to BSE: A Success Story

This is an interesting editorial about the Mad Cow Disease debacle, and it's ramifications that will continue to play out for decades to come ;

Monday, October 10, 2011

EFSA Journal 2011 The European Response to BSE: A Success Story


EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.


see follow-up here about North America BSE Mad Cow TSE prion risk factors, and the ever emerging strains of Transmissible Spongiform Encephalopathy in many species here in the USA, including humans ;

Monday, September 26, 2011

L-BSE BASE prion and atypical sporadic CJD

Thursday, August 4, 2011

Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011


CJD Deaths Reported by CJDSS1, 1994-20112 As of January 31, 2011

3. Final classification of 49 cases from 2009, 2010, 2011 is pending.


USA 2011


National Prion Disease Pathology Surveillance Center

Cases Examined1

(November 1, 2010)

Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD

1996 & earlier 51 33 28 5 0 0

1997 114 68 59 9 0 0

1998 87 51 43 7 1 0

1999 121 73 65 8 0 0

2000 146 103 89 14 0 0

2001 209 119 109 10 0 0

2002 248 149 125 22 2 0

2003 274 176 137 39 0 0

2004 325 186 164 21 0 13

2005 344 194 157 36 1 0

2006 383 197 166 29 0 24

2007 377 214 187 27 0 0

2008 394 231 205 25 0 0

2009 425 258 215 43 0 0

2010 333 213 158 33 0 0

TOTAL 38315 22656 1907 328 4 3

1 Listed based on the year of death or, if not available, on year of referral;

2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted;

3 Disease acquired in the United Kingdom;

4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia in the other case;

5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;

6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.

Please notice where sporadic CJD cases in 1996 went from 28 cases, to 215 cases in 2009, the highest recorded year to date. sporadic CJD is on a steady rise, and has been since 1996.

I also urge you to again notice these disturbing factors in lines 5 and 6 ;

5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;

6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.


Saturday, March 5, 2011


Sunday, August 21, 2011

The British disease, or a disease gone global, The TSE Prion Disease

(see video here)


(see video at bottom)

Sunday, September 6, 2009



Tuesday, November 01, 2011

Could we face the return of CJD? Experts fear it may lie dormant in thousands

Monday, September 26, 2011

L-BSE BASE prion and atypical sporadic CJD

Monday, September 26, 2011

Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS, gCJD, hvCJD, sCJD, TSE, PRION, update 2011

Sunday, September 25, 2011

Mad Cow Scaremongers

Mad Cow Scaremongers by Terry S. Singeltary Sr. a review of the TSE prion agent 2003-2011

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