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From: TSS ()
Subject: Progress Report from the National Prion Disease Pathology Surveillance Center April 3, 2008
Date: April 21, 2008 at 7:10 pm PST

Progress Report from the National Prion Disease Pathology Surveillance

An Update from Stephen M. Sergay, MB, BCh & Pierluigi Gambetti, MD

April 3, 2008

Dear Member:

Once again we are writing to thank you for your continued support in
enhancing surveillance of prion diseases in the United States and to bring
you up to date on the National Prion Disease Pathology Surveillance Center

In large part because of your support, the number of cases examined by
biopsy, autopsy and 14-3-3 protein determination has increased significantly
over the years (see Tables 1 and 2). We are now able to establish a
definitive diagnosis of prion disease in an estimated 60–70% of the cases in
the United States, a percentage which exceeds that in even some major
surveillance centers. In addition, we receive from you cerebrospinal fluid
(CSF) for 14-3-3 determination, a surrogate protein which is helpful in the
diagnosis of prion disease, probably in most if not all cases of suspected
Creutzfeldt-Jakob disease (CJD). We are making constant efforts to reach our
goal of at least 80% definitively diagnosed cases.

The major obstacle to our further increasing the autopsy rate remains the
inadequate reporting of suspected cases of CJD to the NPDPSC or to the State
Health Department, which in turn would notify us. Since you are the one
likely to request the 14-3-3 test on these cases, please include in your
request the information needed to contact you, which we will do if the test
proves positive. If your institution uses a referral laboratory to send us
the CSF, please provide your name, phone, and fax numbers to the lab, which
will in turn submit it to us along with the sample. If this information is
missing in the request accompanying the CSF sample (as it happens in about
30% of the cases), we will be unable to contact the caregiving physician.
Having your contact information would also allow us to send results directly
to you, thus reducing turnaround times.

If you suspect CJD in a case, but do not plan to request the 14-3-3 test,
please nevertheless notify us of this suspected case; because we try to
contact the caregiving physician in all cases of suspected prion disease in
order to offer support in discussions with the families regarding autopsy,
whenever such discussions are deemed appropriate. According to our data,
families refuse autopsy in fewer than 10% of cases. In fact, they generally
wish to have the autopsy carried out but may be unaware that it is free of
charge. Therefore, if you notify us of every case of suspected prion
disease, we believe that our 80% goal can be achieved.

Most of you may be aware that the usefulness of the 14-3-3 test is limited
because of the large number of tests whose results are ambiguous.
Accordingly, we are working to supplement or replace the 14-3-3 test with
the CSF tau protein test, which will eliminate or very much reduce the
number of ambiguous test results while increasing the overall accuracy of

The importance to public health in the U.S. of timely diagnosis and
monitoring of human prion diseases is unquestionable. Here are some
compelling reasons for this:

Prion surveillance in cattle has been reduced by 90% (from about 470,000 to
40,000 in the U.S. in 2007 out of about 35 million cattle slaughtered).
Termination of human prion surveillance would therefore remove the second
line of surveillance, thereby eliminating prion surveillance in the U.S.
entirely. This development would be extremely worrisome in view of recent
reports that precautions to limit the spread of the prion infectious agent
may not have been followed in some slaughter houses in the U.S.
Cattle affected with bovine spongiform encephalopathy (BSE) continue to be
discovered in Canada, which has more rigorous BSE surveillance than the U.S.
At the same time, Canada imposes few limitations in the trade of potentially
prion-infectious cattle with the U.S.
There has been increased occurrence and recognition in the U.S. of chronic
wasting disease (CWD), an endemic prion disease affecting elk and deer, as
well as uncertainties concerning CWD's transmissibility to humans.
Atypical forms of BSE have emerged which, although rare, appear to be more
virulent than the classical BSE that causes vCJD.
These facts make it very clear that careful monitoring of human prion
diseases is crucial, because currently it is the only means of rigorous
prion surveillance which can promptly detect human exposure to BSE and CWD
in the U.S. should it occur. The mission of the NPDPSC is precisely to
facilitate and expedite this surveillance.

However, in order to accomplish its mission, the NPDPSC must examine as many
cases as possible by analysis of frozen and fixed tissue, which is the only
way to accurately identify and classify prion diseases. This requires that
an autopsy be performed. Our free-of-charge autopsy coordination service
provides assistance in arranging and paying for autopsies, body
transportation, and shipment of brain tissues. Results are reported to the
senders (see Table 3 for turnaround times). It is also important that when
requested, the patient's clinical history be sent to the NPDPSC along with
autopsy and biopsy tissues so that each case can be better diagnosed and
reported to CDC.

Again, we thank you very much for your continued help in reporting to our
Center all cases of possible prion disease. If you have any concerns or
questions, please call the NPDPSC at 216-368-0587 or e-mail at The website is

Pierluigi Gambetti, MD
Director, National Prion Disease Pathology Surveillance Center

Stephen M. Sergay, MB, BCh
President, American Academy of Neurology

Table 1
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 or earlier 42 32 25 4 0 0
1997 115 68 56 9 0 0
1998 93 53 45 7 1 0
1999 114 69 61 8 0 0
2000 151 103 89 14 0 0
2001 209 117 108 9 0 0
2002 258 146 119 22 2 0
2003 274 176 132 41 0 0
2004 335 184 155 21 0 13
2005 349 194 147 39 1 0
2006 385 193 151 31 0 14
2007 357 200 144 21 0 0
Totals 26825 15356 1232 226 4 2

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 acquired in Saudi Arabia; 5 Includes 11 cases in which the diagnosis
is pending, and 18 inconclusive cases; 6 Includes 26 cases with type
determination pending (2 from 2006, 24 from 2007), and 45 cases with
adequate tissue to establish the diagnosis of prion disease, but not the
type; in all these cases, vCJD could be excluded.

Table 2

Table 3
Test on biopsy tissue Turnaround times
Western Blot (WB) of the prion protein (PrP). (Establishes presence and type
of scrapie PrP; frozen tissue required) 3–5 business days
Histology and PrP immunohistochemistry (IHC). (Establish presence and
distribution of scrapie PrP on fixed tissue) 4 business days
14-3-3 determination in CSF 5 business days
Test on autopsy tissue Turnaround times
WB of PrP 14 business days
Histology and IHC of PrP 21 business days
PrP gene sequencing. (Identifies mutations and codon 129 genotype needed for
precise prion disease type diagnosis) 4–8 weeks (biopsies and autopsies)
Summary report with prion disease type diagnosis based on all above tests
6–10 weeks (biopsies and autopsies)

P03.135] CSF Findings in a Large United States Sporadic CJD Cohort

Michael Geschwind, Aissa Haman, Charles Torres-Chae, Benjamin J. Raudabaugh,
Gillian Devereux, Bruce Miller, San Francisco, CA

OBJECTIVE: Determine the CSF profile and the diagnostic sensitivity and
specificity of various CSF proteins in a US sCJD cohort (n=196). BACKGROUND:
The diagnostic utility of various biomarkers for CJD is controversial. We
examined the sensitivity and specificity for various CSF proteins in 800
potential prion cases referred to our center over the past five years.
DESIGN/METHODS: Medical records were reviewed and/or patients were evaluated
at our center. Data was stored in a secure clinical relational database that
was queried for CSF findings, including cell count, protein, IgG index,
oligoclonal bands (OCBs), 14-3-3, neuron specific enolase (NSE), Total Tau
(T-Tau) in patients with probable or definite sporadic CJD and non-prion
rapidly progressive dementias (RPD), most of whom were referred as suspected
CJD cases. T-Tau positive if >1300 pg/ml; NSE positive if >35 ng/ml.
Probable sCJD diagnosis was based on modifications to WHO 1998 criteria,
allowing other focal cortical signs (e.g., aphasia, apraxia, neglect) AND a
positive MRI or EEG (14-3-3 not used for diagnosis). RESULTS: 14-3-3 protein
(n=131) sensitivity was only 50% (47% for definite; 52% for probable sCJD).
NSE (n=34) sensitivity was 59% (65% for definite; 50% for probable sCJD).
T-Tau (n=18) was the most sensitive at 72% (78% for definite; 67% for
probable sCJD). The specificity of these biomarkers among our CJD and RPD
controls (n=68) was 70% for 14-3-3 (n=33), 80% for NSE (n=15), and 100% for
T-Tau (n=4). The 14-3-3 had the lowest sensitivity and specificity.
CONCLUSIONS/RELEVANCE: Our data is contrary to other published data
suggesting high sensitivity and specificity of these proteins for sCJD. DWI
MRI has better sensitivity and specificity and should be used in diagnostic
criteria. We question the utility of these CSF proteins for CJD diagnosis. A
prion-specific test is needed. Supported by: John Douglas French Foundation
for Alzheimers Research, the McBean Foundation, NIA K23AG021989-01,
NIH-NINDS contract N01-NS-0-2328.
Category - Aging and Dementia
SubCategory - Clinical

Tuesday, May 1, 2007 4:00 PM

Poster Sessions: HIV and Prion Diseases (4:00 PM-7:30 PM)

The embargo for all abstracts to be presented at the 59th Annual Meeting is
in effect until the date and time of the presentation unless otherwise noted
on the abstract and/or press release. If there are questions, please contact
the AAN media and public relations team.


Debate Continues as New Studies Support MRI, Not CSF Markers, to Diagnose

Neurology Today
5 June 2007; Volume 7(11); pp 6,10-11
Hurley, Dan

article in brief
study protocols
experts comment
mri as a diagnostic tool
View Article PDF


1. ? Two new studies aim to improve diagnosis of Creutzfeldt-Jakob Disease
(CJD): one found a low sensitivity and specificity for CSF biomarkers for
sporadic CJD; another study found MRI an effective diagnostic tool in a
small number of patients with familial CJD.

BOSTON-A new, larger study by a San Francisco neurologist who previously
challenged the use of the 14-3-3 protein in CSF for diagnosing sporadic
Creutzfeldt-Jakob Disease (CJD) has again found a disappointingly low
sensitivity and specificity for the biomarker.

Although the specificity and sensitivity of two other biomarkers, neuron
specific enolase (NSE) and Total Tau (T-Tau), proved better than those of
14-3-3, neither were good enough to make them useful in diagnosing CJD,
concluded Michael D. Geschwind, MD, PhD, assistant professor of neurology at
the Memory and Aging Center of the University of California-San Francisco
(UCSF). The findings were presented in a poster session here at the AAN
annual meeting in May.

MRI appears to be a more reliable diagnostic tool, Dr. Geschwind said, and
that view was supported by another poster at the meeting reporting high
sensitivity and specificity for familial CJD with diffusion tensor imaging

Dr. Geschwind and colleagues examined the sensitivity and specificity for
CSF in potential prion cases referred to the UCSF center in the past five
years. Among 142 patients tested for 14-3-3, the sensitivity was only 49
percent overall - 47 percent for those with a diagnosis of sporadic CJD, and
50 percent for those with probable CJD.

Among the 40 tested for NSE, sensitivity was 63 percent (64 percent for
definite CJD; 60 percent for probable CJD). Among the 20 tested for T-Tau,
sensitivity was 70 percent (67 percent for definite CJD; 75 percent for
probable CJD).

The specificity of the three biomarkers was 66 percent among the 44 controls
tested for 14-3-3, 83 percent among the 18 controls tested for NSE, and 100
percent for the four controls tested for T-Tau.

Our data are contrary to other published results suggesting high sensitivity
and specificity of these proteins for sporadic CJD, according to Dr.
Geschwind and colleagues. We question the utility of these CSF proteins for
CJD diagnosis.

But two neurologists who have led other studies with more positive findings
said their views remain unchanged - that the biomarkers are a useful, though
imperfect, tool for diagnosing CJD.

The data have limitations but also strengths, said Allen J. Aksamit Jr., MD,
associate professor of neurology at the Mayo Clinic College of Medicine in
Rochester, MN. If you have a select patient group who fit the clinical
criteria for CJD and exclude every other possible diagnosis, it's a fairly
sensitive and specific test. You use it as a weight to put on one side for
or against the diagnosis.

In 2003, Dr. Aksamit espoused a similar view in an Archives of Neurology
editorial (60:803-804) accompanying Dr. Geschwind's first paper challenging
the clinical value of the 14-3-3 protein for diagnosis of sporadic CJD. In
that study, Dr. Geschwind reviewed 32 pathologically confirmed cases on
which 14-3-3 testing had been performed; only 17 cases had a positive
result, a sensitivity of only 53 percent (Arch Neurol 2003;60:813-816).

Figure. Dr. Allen J. Aksamit Jr.: The data have limitations but also
strengths. If you have a select patient group who fit the clinical criteria
for CJD and exclude every other possible diagnosis, it's a fairly sensitive
and specific test. You use it as a weight to put on one side for or against
the diagnosis.

[ Click here to enlarge ]
The largest data set published so far on biomarkers in CJD patients comes
from a European consortium led by Inga Zerr, MD, a neurologist at
Georg-August University in Götingen, Germany. She and colleagues reported
last year on 1,859 patients with sporadic, genetic, iatrogenic, and variant
CJD and 1,179 controls, finding a sensitivity of 85 percent for 14-3-3, 86
percent for T-Tau, and 93 percent when the results of both tests were
combined with S100b and NSE (Neurology 2006;67:637-643).

I am aware that the sensitivity of the tests in Dr. Geschwind's laboratory
is lower than we reported and I have discussed this with him on several
occasions, Dr. Zerr said in an e-mail. I have no idea why the data are so

One possible explanation, she and Dr. Aksamit suggested, is that at UCSF - a
referral institution where many patients go for a second opinion - Dr.
Geschwind is seeing more patients with slowly progressing disease than in
the European group. Dr. Zerr's data showed, as have previous studies, that
the sensitivity of the biomarkers is highest in patients with the shortest
disease duration.

Another possible reason the two studies have reached such different
conclusions is that Dr. Zerr included patients with genetic, iatrogenic, and
variant CJD, whereas Dr. Geschwind's group includes only sporadic cases.
Different case definitions and different testing methods might also
contribute to the different findings.

Figure. Dr. Isak Prohovnik: MRI does seem to have better sensitivity and
specificity than the biomarkers. But neither our group nor his [Dr.
Geschwind's] have sufficient numbers yet.

[ Click here to enlarge ]
In an interview with Neurology Today, Dr. Geschwind said of the European
group's findings, I think they may have a selection bias. Every time they
publish a study, their sensitivity goes lower and lower. Eventually it will
hit ours.

He added in an e-mail, I believe there are occasional cases in which these
biomarkers, such as the 14-3-3, total-tau or NSE, may be helpful in
diagnosing CJD. The problem is that because these CSF proteins clearly can
be elevated in other diseases that clinically mimic CJD, one must be very
thorough in ruling out other conditions. Some of these conditions include
cancers, neurologic autoimmune (paraneoplastic and non-paraneoplastic)
dementias, sarcoid, Hashimoto encephalopathy, and even atypically rapid
presentations of other neurodegenerative diseases.

After speaking with Dr. Geschwind in front of his poster, Dr. Aksamit Jr.
told Neurology Today: It's all in the selection of the patient population
being reviewed, and how high you set the bar for these laboratory tests. If
you set the bar high, you'll get higher specificity but lower sensitivity.
Our recommendation at Mayo is to set the bar high, to enhance specificity at
the expense of sensitivity.

Dr. Aksamit noted, however, that 14-3-3 is no longer being tested at Mayo,
because the reagents for a quantitative version of the test, which the
institution had preferred over the standard Western blot, are no longer
available. Instead, Mayo is testing NSE.

Despite the questions raised by Dr. Geschwind's paper, Dr. Zerr said: I
completely agree with Dr. Aksamit that biomarkers in CSF are useful, when
tested in the right populations. This is what we always stress when we are
talking with physicians: Use CSF in the right differential diagnosis; that
is, in dementia.

The one point on which all three neurologists agreed is that MRI seems to be
a powerful diagnostic tool. Although MRI is not part of the clinical
criteria for CJD yet, said Dr. Zerr, we strongly recommend that neurologists
have the MRI done and consider it as an additional test.

Another poster presented at the meeting shared the results of DTI testing on
a small group of patients with familial CJD. Isak Prohovnik, PhD, professor
of psychiatry and radiology at Mount Sinai School of Medicine in New York
City, reported that DTI was abnormal in the basal ganglia of ten of 11
patients, eight of 11 in different cortical areas, and six of 11 in the
thalami. No involvement was seen in the brain stem or cerebellum.

When correlated with the clinical findings, DTI was positive for the frontal
cortex in eight of nine patients, and for the motor cortex in seven of nine
patients. In the basal ganglia, the DTI was positive in 10 patients,
although clinical findings were present in only eight. Clinical cerebellar
signs were seen in 11 patients and brain-stem signs in seven of the 11,
although no positive findings showed up in those regions on either DTI or
other MRI sequences.

MRI does seem to have better sensitivity and specificity than the
biomarkers, Dr. Prohovnik said, noting that Dr. Geschwind has also used MRI.
But neither our group nor his have sufficient numbers yet.

In 2005, Dr. Geschwind co-authored a paper on diffusion-weighted imaging
(DWI) and fluid-attenuated inversion recovery (FLAIR) in CJD, finding them
to be 91 percent sensitive, 95 percent specific, and 94 percent accurate (Am
J Neuroradiol 26:1551-1562). In 2005, Dr. Zerr was the senior author on a
paper published in Brain (128:2026-2033), which concluded that FLAIR and DWI
improved the clinical diagnosis and should be incorporated in the World
Health Organization's diagnostic criteria for sporadic CJD.

• Aksamit AJ. Cerebrospinal fluid 14-3-3 protein: Variability of sporadic
Creutzfeldt-Jakob disease, laboratory standards, and quantitation.

• Geschwind MD, Martindale BS, Miller BL, et al. Challenging the clinical
utility of the 14-3-3 protein for the diagnosis of sporadic
Creutzfeldt-Jakob disease.

• Sanchez-Juan P, Green A, Zerr I, et al. CSF tests in the differential
diagnosis of Creutzfeldt-Jakob disease.

• Young GS, Geschwind MD, Dillon WP, et al. Diffusion-weighted and
fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease:
High sensitivity for diagnosis.

• Tschampa HJ, Kellenberg K, Zerr I, et al. MRI in the diagnosis of sporadic
Creutzfeldt-Jakob disease: A study on inter-observer agreement.


*Acquired in UK
** Acquired in Saudi Arabia
*** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007.
**** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1
from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36
type pending (2 from 2005, 8 from 2006, 26 from 2007).


-- Cases are listed based on the year of death when available. If the
year of death is not available, the year of sample receipt is used.

-- Referrals: Cases with possible or probable prion disease from
which brain tissue or blood in the case of familial disease were submitted.

-- Inconclusive: Cases in which the samples were not sufficient to
make a diagnosis.

-- Non-vCJD type unknown are cases in which the tissue submitted was
adequate to establish the presence but not the type; in all cases,
vCJD could be excluded.

Communicated by:
Terry S. Singeltary Sr.

[In submitting these data, Terry S. Singeltary Sr. draws attention to
the steady increase in the "type unknown" category, which, according
to their definition, comprises cases in which vCJD could be excluded.
The total of 26 cases for the current year (2007) is disturbing,
possibly symptomatic of the circulation of novel agents.
Characterization of these agents should be given a high priority. - Mod.CP],F2400_P1001_PUB_MAIL_ID:1010,39963

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.


MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to

comment on the CDC's attempts to monitor the occurrence of emerging

forms of CJD. Asante, Collinge et al [1] have reported that BSE

transmission to the 129-methionine genotype can lead to an alternate

phenotype that is indistinguishable from type 2 PrPSc, the commonest

sporadic CJD. However, CJD and all human TSEs are not reportable

nationally. CJD and all human TSEs must be made reportable in every

state and internationally. I hope that the CDC does not continue to

expect us to still believe that the 85%+ of all CJD cases which are

sporadic are all spontaneous, without route/source. We have many TSEs in

the USA in both animal and man. CWD in deer/elk is spreading rapidly and

CWD does transmit to mink, ferret, cattle, and squirrel monkey by

intracerebral inoculation. With the known incubation periods in other

TSEs, oral transmission studies of CWD may take much longer. Every

victim/family of CJD/TSEs should be asked about route and source of this

agent. To prolong this will only spread the agent and needlessly expose

others. In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?


Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under-
counts CJD, Schonberger conceded that the current surveillance system
has errors but stated that most of the errors will be confined to the older

Copyright © 2003 Published by Elsevier Ltd.

Tracking spongiform encephalopathies in North America

Xavier Bosch

Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463

"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my
mom to hvCJD (Heidenhain variant CJD) and have been searching for answers
ever since. What I have found is that we have not been told the truth. CWD
in deer and elk is a small portion of a much bigger problem." ...

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.

Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first
150 words of the full text and any section headings.

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported
that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has
been stable since 1985. These estimates, however, are based only on reported
cases, and do not include misdiagnosed or preclinical cases. It seems to me
that misdiagnosis alone would drastically change these figures. An unknown
number of persons with a diagnosis of Alzheimer disease in fact may have
CJD, although only a small number of these patients receive the postmortem
examination necessary to make this diagnosis. Furthermore, only a few states
have made CJD reportable. Human and animal transmissible spongiform
encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr
Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL

2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.

APHIS-2006-0041-0006 TSE advisory committee for the meeting December 15,

Subject: [Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk
Materials for Human Food and Requirement for the Disposition of
Non-Ambulatory Disabled Cattle


Sunday, March 16, 2008

MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or
Italian L-BASE



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