srr wrote;
So you agree that to date Canada has had only 1 death from BSE and the US none. ..........
absolutely not, i dont agree at all. the diagnostic criteria differentiating nvCJD between all the rest, is a joke at best.
don't take my word on it, read what the scientist are saying about it now;
DIAGNOSTIC CRITERIA FOR VARIANT CJD
I
A) PROGRESSIVE NEUROPSYCHIATRIC DISORDER
B) DURATION OF ILLNESS > 6 MONTHS
C) ROUTINE INVESTIGATIONS DO NOT SUGGEST AN ALTERNATIVE DIAGNOSIS
D) NO HISTORY OF POTENTIAL IATROGENIC EXPOSURE
II
A) EARLY PSYCHIATRIC SYMPTOMS *
B) PERSISTENT PAINFUL SENSORY SYMPTOMS **
C) ATAXIA
D) MYOCLONUS OR CHOREA OR DYSTONIA
E) DEMENTIA
III
A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC CJD *** (OR NO EEG
PERFORMED)
B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN
IV
A) POSITIVE TONSIL BIOPSY
DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and
NEUROPATHOLOGICAL CONFIRMATION OF vCJD ****
PROBABLE: I and 4/5 OF II and III A and III B
or I and IV A
* depression, anxiety, apathy, withdrawal, delusions.
** this includes both frank pain and/ or unpleasant dysaesthesia
*** generalised triphasic periodic complexes at approximately one per second
****spongiform change and extensive PrP deposition with florid plaques,
throughout
the cerebrum and cerebellum.
http://www.dh.gov.uk/PublicationsAndSta ... ReleasesNo
tices/fs/en?CONTENT_ID=4132940&chk=ao5pX7
see increase of sporadic CJD over the years ;
http://www.eurocjd.ed.ac.uk/sporadic.htm
USA
notice steady increase, but also notice in 2005, # 7 the 38 pendings cases
through Oct. and #8 includes 53 type pending, 1 type unknown.
if you look at 2003 there were 3 type unknown.
wonder if they were the same or different than the unknown in 2005?
considering the soup that has been brewing over here in the USA for years
via the rendering of BSE and atypical TSE in cattle, CWD, Scrapie, a few TME
cases (not too much due to scent gland, but there were a few rendered, but
all this, and you have one hell of a recipe for a new strains of TSE in
humans. then who knows what 'friendly fire' cases would look like from this
soup via secondary transmission via medical/surgical/dental arena. ...TSS
National Prion Disease Pathology Surveillance Center case exams...
http://www.cjdsurveillance.com/resource ... eport.html
Full Text
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al.
JAMA.2001; 285: 733-734
http://jama.ama-assn.org/cgi/content/fu ... S=10&hits=
10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&
searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
Coexistence of multiple PrPSc types in individuals with
Creutzfeldt-Jakob disease
Magdalini Polymenidou, Katharina Stoeck, Markus
Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi
Summary
Background The molecular typing of sporadic
Creutzfeldt-Jakob disease (CJD) is based on the size
and glycoform
ratio of protease-resistant prion protein (PrPSc), and
on PRNP haplotype. On digestion with proteinase K, type
1 and
type 2 PrPSc display unglycosylated core fragments of
21 kDa and 19 kDa, resulting from cleavage around amino
acids 82 and 97, respectively.
Methods We generated anti-PrP monoclonal antibodies to
epitopes immediately preceding the differential proteinase
K cleavage sites. These antibodies, which were
designated POM2 and POM12, recognise type 1, but not
type 2, PrPSc.
Findings We studied 114 brain samples from 70 patients
with sporadic CJD and three patients with variant CJD.
Every patient classified as CJD type 2, and all variant
CJD patients, showed POM2/POM12 reactivity in the
cerebellum and other PrPSc-rich brain areas, with a
typical PrPSc type 1 migration pattern.
Interpretation The regular coexistence of multiple
PrPSc types in patients with CJD casts doubts on the
validity of
electrophoretic PrPSc mobilities as surrogates for
prion strains, and questions the rational basis of
current CJD
classifications.
snip...
The above results set the existing CJD classifications
into debate and introduce interesting questions about
human CJD types. For example, do human prion types
exist in a dynamic equilibrium in the brains of affected
individuals? Do they coexist in most or even all CJD
cases? Is the biochemically identified PrPSc type simply
the dominant type, and not the only PrPSc species?
Published online October 31, 2005
http://neurology.thelancet.com
Detection of Type 1 Prion Protein in Variant
Creutzfeldt-Jakob Disease
Helen M. Yull,* Diane L. Ritchie,*
Jan P.M. Langeveld,? Fred G. van Zijderveld,?
Moira E. Bruce,? James W. Ironside,* and
Mark W. Head*
From the National CJD Surveillance Unit,* School of
Molecular
and Clinical Medicine, University of Edinburgh, Edinburgh,
United Kingdom; Central Institute for Animal Disease
Control
(CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute
for Animal
Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom
Molecular typing of the abnormal form of the prion
protein (PrPSc) has come to be regarded as a powerful
tool in the investigation of the prion diseases. All
evidence
thus far presented indicates a single PrPSc molecular
type in variant Creutzfeldt-Jakob disease (termed
type 2B), presumably resulting from infection with a
single strain of the agent (bovine spongiform
encephalopathy).
Here we show for the first time that the PrPSc
that accumulates in the brain in variant Creutzfeldt-
Jakob disease also contains a minority type 1 component.
This minority type 1 PrPSc was found in all 21
cases of variant Creutzfeldt-Jakob disease tested,
irrespective
of brain region examined, and was also
present in the variant Creutzfeldt-Jakob disease tonsil.
The quantitative balance between PrPSc types was maintained
when variant Creutzfeldt-Jakob disease was
transmitted to wild-type mice and was also found in
bovine spongiform encephalopathy cattle brain, indicating
that the agent rather than the host specifies their
relative representation. These results indicate that PrPSc
molecular typing is based on quantitative rather than
qualitative phenomena and point to a complex relationship
between prion protein biochemistry, disease phenotype
and agent strain. (Am J Pathol 2006, 168:151-157;
DOI: 10.2353/ajpath.2006.050766)
snip...
Discussion
In the apparent absence of a foreign nucleic acid genome
associated with the agents responsible for transmissible
spongiform encephalopathies or prion diseases,
efforts to provide a molecular definition of agent strain
have focused on biochemical differences in the abnormal,
disease-associated form of the prion protein, termed
PrPSc. Differences in PrPSc conformation and glycosylation
have been proposed to underlie disease phenotype
and form the biochemical basis of agent strain. This
proposal has found support in the observation that the
major phenotypic subtypes of sCJD appear to correlate
with the presence of either type 1 or type 2 PrPSc in
combination with the presence of either methionine or
valine at codon 129 of the prion protein gene.2 Similarly,
the PrPSc type associated with vCJD correlates with the
presence of type 2 PrPSc and is distinct from that found in
sCJD because of a characteristically high occupancy of
both N-linked glycosylation sites (type 2B).6,11 The
means by which such conformational difference is detected
is somewhat indirect; relying on the action of proteases,
primarily proteinase K, to degrade the normal
Figure 6. Type 1 PrPSc is a stable minority component
of PrPSc from the vCJD
brain. Western blot analysis of PrP in a sample of
cerebral cortex from a
case
of vCJD during digestion with proteinase K is shown.
Time points assayed
are indicated in minutes (T0, 5, 10, 30, 60, 120, 180).
Duplicate blots were
probed with 3F4, which detects both type 1 and type 2
PrPSc, and with 12B2,
which detects type 1. The insert shows a shorter
exposure of the same time
course study from a separate experiment also probed
with 3F4. Both blots
included samples of cerebral cortex from a case of
sporadic CJD MM1 (Type
1) and molecular weight markers (Markers) indicate
weights in kd.
Figure 7. A minority type 1-like PrPSc is found in vCJD
tonsil, vCJD
transmitted
to mice and in BSE. Western blot analysis of PrPSc in a
concentrated
sample of tonsil from a case of vCJD (Tonsil), in a
concentrated brain
sample
of a wild-type mouse (C57BL) infected with vCJD and in
a sample of cattle
BSE brain (BSE) is shown. Tissue extracts were digested
with proteinase K.
Duplicate blots were probed with either 3F4 or 6H4,
both of which detect
type 1 and type 2 PrPSc, and with 12B2, which detects
type 1. The blots
included samples of cerebral cortex from a case of
sporadic CJD MM1 (Type
1) and molecular weight markers (Markers) indicate
weights in kd.
Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155
AJP January 2006, Vol. 168, No. 1
cellular form of PrP and produce a protease-resistant
core fragment of PrPSc that differs in the extent of its
N-terminal truncation according to the original
conformation.
A complication has recently arisen with the finding that
both type 1 and type 2 can co-exist in the brains of
patients with sCJD.2,5-8 More recently this same phenomenon
has been demonstrated in patients with iatrogenically
acquired and familial forms of human prion disease.
9,10 The existence of this phenomenon is now
beyond doubt but its prevalence and its biological
significance
remain a matter of debate.
Conventional Western blot analysis using antibodies
that detect type 1 and type 2 PrPSc has severe quantitative
limitations for the co-detection of type 1 and type 2
PrPSc in individual samples, suggesting that the prevalence
of co-occurrence of the two types might be underestimated.
We have sought to circumvent this problem by
using an antibody that is type 1-specific and applied this
to the sole remaining human prion disease where the
phenomenon of mixed PrPSc types has not yet been
shown, namely vCJD.
These results show that even in vCJD where susceptible
individuals have been infected supposedly by a
single strain of agent, both PrPSc types co-exist: a
situation
reminiscent of that seen when similarly discriminant
antibodies were used to analyze experimental BSE in
sheep.14,17 In sporadic and familial CJD, individual
brains can show a wide range of relative amounts of the
two types in samples from different regions, but where
brains have been thoroughly investigated a predominant
type is usually evident.2,6,10 This differs from this
report
on vCJD, where type 1 is present in all samples
investigated
but always as a minor component that never
reaches a level at which it is detectable without a type
1-specific antibody. It would appear that the relative
balance
between type 1 and type 2 is controlled within
certain limits in the vCJD brain. A minority type-1-like
band is also detected by 12B2 in vCJD tonsil, in BSE
brain and in the brains of mice experimentally infected
with vCJD, suggesting that this balance of types is agent,
rather than host or tissue, specific. Interestingly the
"glycoform
signature" of the type 2 PrPSc found in vCJD (type
2B) is also seen in the type 1 PrPSc components, suggesting
that it could legitimately be termed type 1B.
PrPSc isotype analysis has proven to be extremely
useful in the differential diagnosis of CJD and is
likely to
continue to have a major role in the investigation of human
prion diseases. However, it is clear, on the basis of
these findings, that molecular typing has quantitative
limitations
and that any mechanistic explanation of prion
replication and the molecular basis of agent strain
variation
must accommodate the co-existence of multiple
prion protein conformers. Whether or not the different
conformers we describe here correlate in a simple and
direct way with agent strain remains to be determined. In
principle two interpretations present themselves: either
the two conformers can be produced by a single strain of
agent or vCJD (and, therefore, presumably BSE) results
from a mixture of strains, one of which generally
predominates.
Evidence for the isolation in mice of more than one
strain from individual isolates of BSE has been presented
previously.18,19
One practical consequence of our findings is that the
correct interpretation of transmission studies will depend
on a full examination of the balance of molecular types
present in the inoculum used to transmit disease, in
addition
to a thorough analysis of the molecular types that
arise in the recipients. Another consequence relates to
the diagnostic certainty of relying on PrPSc molecular
type alone when considering the possibility of BSE
infection
or secondary transmission in humans who have a
genotype other than methionine at codon 129 of the
PRNP gene. In this context it is interesting to note
that this
minority type 1B component resembles the type 5 PrPSc
described previously to characterize vCJD transmission
into certain humanized PRNP129VV transgenic mouse
models.12,20 This apparently abrupt change in molecular
phenotype might represent a selection process imposed
by this particular transgenic mouse model. Irrespective of
whether this proves to be the case, the results shown
here point to further complexities in the relationship
between
the physico-chemical properties of the prion protein,
human disease phenotype, and prion agent strain.
Acknowledgments
snip...
Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157
AJP January 2006, Vol. 168, No. 1 ...TSS
http://ajp.amjpathol.org/cgi/content/ab ... HITS=10&hi
ts=10&RESULTFORMAT=&fulltext=prion&searchid=1136646133963_237&FIRSTINDEX=0&v
olume=168&issue=1&journalcode=amjpathol
Neuropathology and Applied Neurobiology
(2005),
31
, 565-579 doi: 10.1111/j.1365-2990.2005.00697.x
© 2005 Blackwell Publishing Ltd
565
Blackwell Science, LtdOxford, UKNANNeuropathology and
Applied Neurobiology0305-1846Blackwell Publishing Ltd, 2005
316565579
Review article
Phenotypic variability in human prion diseases
J. W. Ironside, D. L. Ritchie and M. W. Head
National Creutzfeldt-Jakob Disease Surveillance Unit,
Division of Pathology, University of Edinburgh,
Edinburgh, UK
J. W. Ironside, D. L. Ritchie and M. W. Head (2005)
Neuropathology and Applied Neurobiology
31,
565-579
Phenotypic variability in human prion diseases
Human prion diseases are rare neurodegenerative disorders
that can occur as sporadic, familial or acquired disorders.
Within each of these categories there is a wide range
of phenotypic variation that is not encountered in other
neurodegenerative disorders. The identification of the
prion protein and its key role in the pathogenesis of this
diverse group of diseases has allowed a fuller
understanding
of factors that influence disease phenotype. In particular,
the naturally occurring polymorphism at codon 129
in the prion protein gene has a major influence on the
disease
phenotype in sporadic, familial and acquired prion
diseases, although the underlying mechanisms remain
unclear. Recent technical advances have improved our
ability to study the isoforms of the abnormal prion protein
in the brain and in other tissues. This has lead to the
concept
of molecular strain typing, in which different isoforms
of the prion protein are proposed to correspond to
individual strains of the transmissible agent, each with
specific biological properties. In sporadic
Creutzfeldt-Jakob
disease there are at least six major combinations of codon
129 genotype and prion protein isotype, which appear to
relate to distinctive clinical subgroups of this disease.
However, these relationships are proving to be more complex
than first considered, particularly in cases with more
than a single prion protein isotype in the brain. Further
work is required to clarify these relationships and to
explain the mechanism of neuropathological targeting of
specific brain regions, which accounts for the diversity of
clinical features within human prion diseases.
© 2005 Blackwell Publishing Ltd, Neuropathology and
Applied Neurobiology, 31, 565-579
BSE prions propagate as either variant CJD-like or
sporadic CJD-like prion strains in transgenic mice
expressing human prion protein
The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002
Emmanuel A.Asante, Jacqueline M.Linehan,
Melanie Desbruslais, Susan Joiner,
Ian Gowland, Andrew L.Wood, Julie Welch,
Andrew F.Hill, Sarah E.Lloyd,
Jonathan D.F.Wadsworth and
John Collinge1
MRC Prion Unit and Department of Neurodegenerative Disease,
Institute of Neurology, University College, Queen Square,
London WC1N 3BG, UK
1Corresponding author
e-mail:
[email protected]
Variant Creutzfeldt±Jakob disease (vCJD) has been
recognized to date only in individuals homozygous for
methionine at PRNP codon 129. Here we show that
transgenic mice expressing human PrP methionine
129, inoculated with either bovine spongiform
encephalopathy (BSE) or variant CJD prions, may
develop the neuropathological and molecular phenotype
of vCJD, consistent with these diseases being
caused by the same prion strain. Surprisingly, however,
BSE transmission to these transgenic mice, in
addition to producing a vCJD-like phenotype, can also
result in a distinct molecular phenotype that is
indistinguishable
from that of sporadic CJD with PrPSc
type 2. These data suggest that more than one BSEderived
prion strain might infect humans; it is therefore
possible that some patients with a phenotype consistent
with sporadic CJD may have a disease arising
from BSE exposure.
snip...
These studies further strengthen the evidence that vCJD
is caused by a BSE-like prion strain. Also, remarkably, the
key neuropathological hallmark of vCJD, the presence of
abundant ¯orid PrP plaques, can be recapitulated on BSE
or vCJD transmission to these mice. However, the most
surprising aspect of the studies was the ®nding that an
alternate pattern of disease can be induced in 129MM
Tg35 mice from primary transmission of BSE, with a
molecular phenotype indistinguishable from that of a
subtype
of sporadic CJD. This ®nding has important potential
implications as it raises the possibility that some humans
infected with BSE prions may develop a clinical disease
indistinguishable from classical CJD associated with type 2
PrPSc. This is, in our experience, the commonest molecular
sub-type of sporadic CJD. In this regard, it is of interest
that the reported incidence of sporadic CJD has risen
in the
UK since the 1970s (Cousens et al., 1997). This has been
attributed to improved case ascertainment, particularly as
much of the rise is reported from elderly patients and
similar rises in incidence were noted in other European
countries without reported BSE (Will et al., 1998).
However, it is now clear that BSE is present in many
European countries, albeit at a much lower incidence than
was seen in the UK. While improved ascertainment is
likely to be a major factor in this rise, that some of
these
additional cases may be related to BSE exposure cannot be
ruled out. It is of interest in this regard that a 2-fold
increase in the reported incidence of sporadic CJD in 2001
has recently been reported for Switzerland, a country that
had the highest incidence of cattle BSE in continental
Europe between 1990 and 2002 (Glatzel et al., 2002). No
epidemiological case±control studies with strati®cation of
CJD cases by molecular sub-type have yet been reported.
It will be important to review the incidence of sporadic
CJD associated with PrPSc type 2 and other molecular
subtypes
in both BSE-affected and unaffected countries in the
light of these ®ndings. If human BSE prion infection can
result in propagation of type 2 PrPSc, it would be expected
that such cases would be indistinguishable on clinical,
pathological and molecular criteria from classical CJD. It
may also be expected that such prions would behave
biologically like those isolated from humans with sporadic
CJD with type 2 PrPSc. The transmission properties of
prions associated with type 2 PrPSc from BSE-inoculated
129MM Tg35 mice are being investigated by serial
passage.
We consider these data inconsistent with contamination
of some of the 129MM Tg35 mice with sporadic CJD
prions. These transmission studies were performed according
to rigorous biosafety protocols for preparation of
inocula and both the inoculation and care of mice, which
are all uniquely identi®ed by sub-cutaneous transponders.
However, crucially, the same BSE inocula have been used
on 129VV Tg152 and 129MM Tg45 mice, which are
highly sensitive to sporadic CJD but in which such
transmissions producing type 2 PrPSc were not observed.
Furthermore, in an independent experiment, separate
inbred lines of wild-type mice, which are highly resistant
to sporadic CJD prions, also propagated two distinctive
PrPSc types on challenge with either BSE or vCJD. No
evidence of spontaneous prion disease or PrPSc has been
seen in groups of uninoculated or mock-inoculated aged
129MM Tg35 mice.
While distinctive prion isolates have been derived from
BSE passage in mice previously (designated 301C and
301V), these, in contrast to the data presented here, are
propagated in mice expressing different prion proteins
(Bruce et al., 1994). It is unclear whether our ®ndings
indicate the existence of more than one prion strain in
individual cattle with BSE, with selection and preferential
replication of distinct strains by different hosts, or that
`mutation' of a unitary BSE strain occurs in some types of
host. Western blot analysis of single BSE isolates has not
shown evidence of the presence of a proportion of
monoglycosylated dominant PrPSc type in addition to the
diglycosylated dominant pattern (data not shown).
Extensive strain typing of large numbers of individual
BSE-infected cattle either by biological or molecular
methods has not been reported.
Presumably, the different genetic background of the
different inbred mouse lines is crucial in determining
which prion strain propagates on BSE inoculation. The
transgenic mice described here have a mixed genetic
background with contributions from FVB/N, C57BL/6 and
129Sv inbred lines; each mouse will therefore have a
different genetic background. This may explain the
differing response of individual 129MM Tg35 mice, and
the difference between 129MM Tg35 and 129MM Tg45
mice, which are, like all transgenic lines, populations
derived from single founders. Indeed, the consistent
distinctive strain propagation in FVB and C57BL/6 versus
SJL and RIIIS lines may allow mapping of genes relevant
to strain selection and propagation, and these studies
are in
progress.
That different prion strains can be consistently isolated
in different inbred mouse lines challenged with BSE
prions argues that other species exposed to BSE may
develop prion diseases that are not recognizable as being
caused by the BSE strain by either biological or molecular
strain typing methods. As with 129MM Tg35 mice, the
prions replicating in such transmissions may be
indistinguishable
from naturally occurring prion strains. It
remains of considerable concern whether BSE has transmitted
to, and is being maintained in, European sheep
¯ocks. Given the diversity of sheep breeds affected by
scrapie, it has to be considered that some sheep might have
become infected with BSE, but propagated a distinctive
strain type indistinguishable from those of natural sheep
scrapie. ...
The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002
6358 ãEuropean Molecular Biology Organization
http://embojournal.npgjournals.com/cgi/ ... 21/23/6358
J Neuropsychiatry Clin Neurosci 17:489-495, November 2005
doi: 10.1176/appi.neuropsych.17.4.489
© 2005 American Psychiatric Publishing, Inc.
Psychiatric Manifestations of Creutzfeldt-Jakob
Disease: A 25-Year Analysis
Christopher A. Wall, M.D., Teresa A. Rummans, M.D.,
Allen J. Aksamit, M.D.,
Lois E. Krahn, M.D. and V. Shane Pankratz, Ph.D.
Received April 20, 2004; revised September 9, 2004;
accepted September 13,
2004. From the Mayo Clinic, Department of Psychiatry
and Psychology,
Rochester, Minnesota; Mayo Clinic, Department of
Neurology, Rochester,
Minnesota. Address correspondence to Dr. Wall, Mayo
Clinic, Department of
Psychiatry and Psychology, Mayo Building-W11A, 200
First St., SW, Rochester,
MN 55905;
[email protected] (E-mail).
This study characterizes the type and timing of
psychiatric manifestations
in sporadic Creutzfeldt-Jakob disease (sCJD).
Historically, sCJD has been
characterized by prominent neurological symptoms, while
the variant form
(vCJD) is described as primarily psychiatric in
presentation and course: A
retrospective review of 126 sCJD patients evaluated at
the Mayo Clinic from
1976-2001 was conducted. Cases were reviewed for
symptoms of depression,
anxiety, psychosis, behavior dyscontrol, sleep
disturbances, and
neurological signs during the disease course. Eighty
percent of the cases
demonstrated psychiatric symptoms within the first 100
days of illness, with
26% occurring at presentation. The most commonly
reported symptoms in this
population included sleep disturbances, psychotic
symptoms, and depression.
Psychiatric manifestations are an early and prominent
feature of sporadic
CJD, often occurring prior to formal diagnosis.
snip...
CONCLUSIONS
Historically, psychiatric manifestations have been
described as a relatively
infrequent occurrence in the sporadic form of
creutzfeldt-Jakob disease.
However, our findings suggest otherwise. In this study,
a vast majority of
the cases were noted to have at least one psychiatric
symptom during the
course of illness, with nearly one-quarter occurring in
the prodromal or
presenting phase of the illness. After comparing the
frequency of
neuropsychiatric symptoms in sporadic CJD to studies
describing the variant
form of CJD, we found that there are fewer clinical
differences than
previously reported.5-7 While the age of patients
with vCJD presentation
is significantly younger and the course of illness is
longer, the type and
timing of psychiatric manifestations appear similar
between these two
diseases. ...snip...
http://neuro.psychiatryonline.org/cgi/c ... t/17/4/489
Polish Journal of Neurology and Neurosurgery 6/2005
abstract:
CASE REPORT
Mental disorders in a female patient with probable Creutzfeldt-Jakob disease
Neurol Neurochirur Pol 2005; 39, 6: 520–523
authors: Marek Gronkowski, Bozena Spila, Alina Nowicka, Piotr Machala,
Grzegorz Przywara,
The paper presents an overview of the current knowledge about the etiology,
classification of Creutzfeldt-Jakob disease, abnormalities in the results of
the EEG, MR and laboratory examinations in patients with this disease. The
diagnostic value of the CSF examination for presence of protein 14-3-3 is
underlined. The article is based on both Polish and foreign literature,
describing mainly the diagnostics of CJD. The case of a female patient with
dementia, mental disorders and neurological symptoms in the course of
probable CJD, who was hospitalized at the Psychogeriatric Department of the
Neuropsychiatric Hospital in Lublin is described.
Polish Journal of Neurology and Neurosurgery 6/2005
full text of the article:
http://www.termedia.pl/showpdf.php?arti ... enia%20psy
ch.pdf&priority=1
First case of vCJD reported in a Japanese patient: update
Editorial team (
[email protected]), Eurosurveillance
editorial office
A detailed description of the first case of variant Creutzfeldt-Jakob
disease (vCJD) in Japan, originally reported in February 2005, has just been
published [1,2]. The patient was a 51 year old man, who had spent around 24
days in the United Kingdom in 1990, during the bovine spongiform
encephalopathy (BSE) outbreak. He is known to have eaten mechanically
recovered meat during his visit, and although exposure in other European
countries he visited, including France and Japan, cannot be excluded, it is
thought that he may have been exposed to the BSE agent during his UK visit.
If exposure in the UK was the source of his infection, then the incubation
period to illness onset was 11.5 years.
It is also noted that the patient's illness duration was unusually long, at
42 months, and that periodic synchronous discharges (PSD), which have not
been reported in other vCJD cases, appeared on the patient's
electroencephalogram, 12 months before death. The working group reporting on
the case suggest that the World Health Organization vCJD case definition [3]
be revised to state that PSD does not exclude the possibility of vCJD.
This article is adapted from reference 1
References:
Yamada M, Variant CJD Working Group. The first Japanese case of variant
Creutzfeldt-Jakob disease showing periodic electroencephalogram. Lancet
2006; 367: 874.
Eurosurveillance. First case of vCJD reported in a Japanese patient.
Eurosurveillance 2005; 10(2): 050210.
(
http://www.eurosurveillance.org/ew/2005/050210.asp#1)
The Revision of the Surveillance Case Definition for Variant
Creutzfeldt-Jakob Disease (vCJD). Report of a WHO consultation, Edinburgh,
United Kingdom 17 May 2001. WHO/CDS/CSR/EPH/2001.5. Geneva: World Health
Organization; 2001
(
http://www.who.int/csr/resources/public ... h20015.pdf)
http://www.eurosurveillance.org/ew/2006/060316.asp#3
Personal Communication
-------- Original Message --------
Subject: re-BSE prions propagate as
either variant CJD-like or sporadic CJD Date: Thu, 28
Nov 2002 10:23:43
-0000 From: "Asante, Emmanuel A" To:
"'
[email protected]'"
Dear Terry,
I have been asked by Professor Collinge to respond to
your request. I am
a Senior Scientist in the MRC Prion Unit and the lead
author on the
paper. I have attached a pdf copy of the paper for your
attention. Thank
you for your interest in the paper.
In respect of your first question, the simple answer
is, yes. As you
will find in the paper, we have managed to associate
the alternate
phenotype to type 2 PrPSc, the commonest sporadic CJD.
It is too early to be able to claim any further
sub-classification in
respect of Heidenhain variant CJD or Vicky Rimmer's
version. It will
take further studies, which are on-going, to establish
if there are
sub-types to our initial finding which we are now
reporting. The main
point of the paper is that, as well as leading to the
expected new
variant CJD phenotype, BSE transmission to the
129-methionine genotype
can lead to an alternate phenotype which is
indistinguishable from type
2 PrPSc.
I hope reading the paper will enlighten you more on the
subject. If I
can be of any further assistance please to not hesitate
to ask. Best wishes.
Emmanuel Asante
<> ____________________________________
Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics
Dept. Imperial
College School of Medicine (St. Mary's) Norfolk Place,
LONDON W2 1PG
Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email:
[email protected] (until 9/12/02)
New e-mail:
[email protected] (active from now)
____________________________________
Human Prion Protein with
Valine 129 Prevents Expression
of Variant CJD Phenotype
Jonathan D. F. Wadsworth, Emmanuel A. Asante,
Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner,
Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd,
Andrew F. Hill,* Sebastian Brandner, John Collinge.
Variant Creutzfeldt-Jakob disease (vCJD) is a unique
and highly distinctive
clinicopathological and molecular phenotype of human
prion disease
associated with infection with bovine spongiform
encephalopathy (BSE)-like
prions. Here, we found that generation of this
phenotype in transgenic mice
required expression of human prion protein (PrP) with
methionine 129.
Expression of human PrP with valine 129 resulted in a
distinct phenotype and,
remarkably, persistence of a barrier to transmission of
BSE-derived prions on
subpassage. Polymorphic residue 129 of human PrP
dictated propagation of
distinct prion strains after BSE prion infection. Thus,
primary and secondary
human infection with BSE-derived prions may result in
sporadic CJD-like or
novel phenotypes in addition to vCJD, depending on the
genotype of the prion
source and the recipient.
snip...
3 DECEMBER 2004 VOL 306 SCIENCE
http://www.sciencemag.org
Characterization of two distinct prion strains
derived from bovine spongiform encephalopathy
transmissions to inbred mice
Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais,
Susan Joiner, Jennifer Buckell, Sebastian Brandner,
Jonathan D. F. Wadsworth and John Collinge
Correspondence
John Collinge
[email protected]
MRC Prion Unit and Department of Neurodegenerative
Disease, Institute of Neurology,
University College, London WC1N 3BG, UK
Received 9 December 2003
Accepted 27 April 2004
Distinct prion strains can be distinguished by
differences in incubation period, neuropathology
and biochemical properties of disease-associated prion
protein (PrPSc) in inoculated mice.
Reliable comparisons of mouse prion strain properties
can only be achieved after passage in
genetically identical mice, as host prion protein
sequence and genetic background are known
to modulate prion disease phenotypes. While multiple
prion strains have been identified in
sheep scrapie and Creutzfeldt-Jakob disease, bovine
spongiform encephalopathy (BSE) is
thought to be caused by a single prion strain. Primary
passage of BSE prions to different lines
of inbred mice resulted in the propagation of two
distinct PrPSc types, suggesting that two
prion strains may have been isolated. To investigate
this further, these isolates were
subpassaged in a single line of inbred mice (SJL) and
it was confirmed that two distinct prion
strains had been identified. MRC1 was characterized by
a short incubation time (110±3 days),
a mono-glycosylated-dominant PrPSc type and a
generalized diffuse pattern of PrP-immunoreactive
deposits, while MRC2 displayed a much longer incubation
time (155±1 days),
a di-glycosylated-dominant PrPSc type and a distinct
pattern of PrP-immunoreactive deposits
and neuronal loss. These data indicate a crucial
involvement of the host genome in modulating
prion strain selection and propagation in mice. It is
possible that multiple disease phenotypes
may also be possible in BSE prion infection in humans
and other animals.
snip...
Journal of General Virology (2004), 85, 2471-2478 DOI
10.1099/vir.0.79889-0
http://vir.sgmjournals.org/cgi/content/ ... /85/8/2471
Medical Sciences
Identification of a second bovine amyloidotic
spongiform encephalopathy: Molecular similarities with
sporadic Creutzfeldt-Jakob disease
Cristina Casalone *, Gianluigi Zanusso , Pierluigi
Acutis *, Sergio Ferrari , Lorenzo Capucci , Fabrizio
Tagliavini ¶, Salvatore Monaco ||, and Maria Caramelli *
*Centro di Referenza Nazionale per le Encefalopatie
Animali, Istituto Zooprofilattico Sperimentale del
Piemonte, Liguria e Valle d'Aosta, Via Bologna, 148,
10195 Turin, Italy; Department of Neurological and
Visual Science, Section of Clinical Neurology,
Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134
Verona, Italy; Istituto Zooprofilattico Sperimentale
della Lombardia ed Emilia Romagna, Via Bianchi, 9,
25124 Brescia, Italy; and ¶Istituto Nazionale
Neurologico "Carlo Besta," Via Celoria 11, 20133 Milan,
Italy
Edited by Stanley B. Prusiner, University of
California, San Francisco, CA, and approved December
23, 2003 (received for review September 9, 2003)
Transmissible spongiform encephalopathies (TSEs), or
prion diseases, are mammalian neurodegenerative
disorders characterized by a posttranslational
conversion and brain accumulation of an insoluble,
protease-resistant isoform (PrPSc) of the host-encoded
cellular prion protein (PrPC). Human and animal TSE
agents exist as different phenotypes that can be
biochemically differentiated on the basis of the
molecular mass of the protease-resistant PrPSc
fragments and the degree of glycosylation.
Epidemiological, molecular, and transmission studies
strongly suggest that the single strain of agent
responsible for bovine spongiform encephalopathy (BSE)
has infected humans, causing variant Creutzfeldt-Jakob
disease. The unprecedented biological properties of the
BSE agent, which circumvents the so-called "species
barrier" between cattle and humans and adapts to
different mammalian species, has raised considerable
concern for human health. To date, it is unknown
whether more than one strain might be responsible for
cattle TSE or whether the BSE agent undergoes
phenotypic variation after natural transmission. Here
we provide evidence of a second cattle TSE. The
disorder was pathologically characterized by the
presence of PrP-immunopositive amyloid plaques, as
opposed to the lack of amyloid deposition in typical
BSE cases, and by a different pattern of regional
distribution and topology of brain PrPSc accumulation.
In addition, Western blot analysis showed a PrPSc type
with predominance of the low molecular mass glycoform
and a protease-resistant fragment of lower molecular
mass than BSE-PrPSc. Strikingly, the molecular
signature of this previously undescribed bovine PrPSc
was similar to that encountered in a distinct subtype
of sporadic Creutzfeldt-Jakob disease.
----------------------------------------------------------------------------
----
C.C. and G.Z. contributed equally to this work.
||To whom correspondence should be addressed.
E-mail:
[email protected] .
http://www.pnas.org/cgi/doi/10.1073/pnas.0305777101
snip...
Phenotypic Similarities Between BASE and sCJD. The
transmissibility
of CJD brains was initially demonstrated in primates
(27), and
classification of atypical cases as CJD was based on
this property
(28). To date, no systematic studies of strain typing
in sCJD have
been provided, and classification of different subtypes
is based
on clinical, neuropathological, and molecular features
(the polymorphic
PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19).
The importance of molecular PrPSc characterization in
assessing
the identity of TSE strains is underscored by several
studies,
showing that the stability of given disease-specific
PrPSc types is
maintained upon experimental propagation of sCJD, familial
CJD, and vCJD isolates in transgenic PrP-humanized mice (8,
29). Similarly, biochemical properties of BSE- and
vCJDassociated
PrPSc molecules remain stable after passage to mice
expressing bovine PrP (30). Recently, however, it has been
reported that PrP-humanized mice inoculated with BSE
tissues
may also propagate a distinctive PrPSc type, with a
''monoglycosylated-
dominant'' pattern and electrophoretic mobility of the
unglycosylated fragment slower than that of vCJD and
BSE (31).
Strikingly, this PrPSc type shares its molecular
properties with the
a PrPSc molecule found in classical sCJD. This
observation is at
variance with the PrPSc type found in MV2 sCJD cases and in
cattle BASE, showing a monoglycosylated-dominant
pattern but
faster electrophoretic mobility of the
protease-resistant fragment
as compared with BSE. In addition to molecular properties
of PrPSc, BASE and MV2 sCJD share a distinctive pattern of
intracerebral PrP deposition, which occurs as
plaque-like and
amyloid-kuru plaques. Differences were, however,
observed in
the regional distribution of PrPSc. While inMV2 sCJD
cases the
largest amounts of PrPSc were detected in the cerebellum,
brainstem, and striatum, in cattle BASE these areas
were less
involved and the highest levels of PrPSc were recovered
from the
thalamus and olfactory regions.
In conclusion, decoding the biochemical PrPSc signature of
individual human and animal TSE strains may allow the
identification
of potential risk factors for human disorders with
unknown etiology, such as sCJD. However, although BASE and
sCJD share several characteristics, caution is dictated
in assessing
a link between conditions affecting two different mammalian
species, based on convergent biochemical properties of
diseaseassociated
PrPSc types. Strains of TSE agents may be better
characterized upon passage to transgenic mice. In the
interim
until this is accomplished, our present findings
suggest a strict
epidemiological surveillance of cattle TSE and sCJD
based on
molecular criteria.
http://www.pnas.org/cgi/reprint/0305777101v1
Published online before print March 20, 2001,
10.1073/pnas.041490898
Neurobiology
Adaptation of the bovine spongiform encephalopathy
agent to primates and comparison with Creutzfeldt-
Jakob disease: Implications for human health
Corinne Ida Lasmézas*,, Jean-Guy Fournier*, Virginie
Nouvel*, Hermann Boe*, Domíníque Marcé*, François
Lamoury*, Nicolas Kopp, Jean-Jacques Hauw§, James
Ironside¶, Moira Bruce, Dominique Dormont*, and
Jean-Philippe Deslys*
* Commissariat à l'Energie Atomique, Service de
Neurovirologie, Direction des Sciences du
Vivant/Département de Recherche Medicale, Centre de
Recherches du Service de Santé des Armées 60-68, Avenue
du Général Leclerc, BP 6, 92 265 Fontenay-aux-Roses
Cedex, France; Hôpital Neurologique Pierre Wertheimer,
59, Boulevard Pinel, 69003 Lyon, France; § Laboratoire
de Neuropathologie, Hôpital de la Salpêtrière, 83,
Boulevard de l'Hôpital, 75013 Paris, France; ¶
Creutzfeldt-Jakob Disease Surveillance Unit, Western
General Hospital, Crewe Road, Edinburgh EH4 2XU, United
Kingdom; and Institute for Animal Health,
Neuropathogenesis Unit, West Mains Road, Edinburgh EH9
3JF, United Kingdom
Edited by D. Carleton Gajdusek, Centre National de la
Recherche Scientifique, Gif-sur-Yvette, France, and
approved December 7, 2000 (received for review October
16, 2000)
Abstract
There is substantial scientific evidence to support the
notion that bovine spongiform encephalopathy (BSE) has
contaminated human beings, causing variant
Creutzfeldt-Jakob disease (vCJD). This disease has
raised concerns about the possibility of an iatrogenic
secondary transmission to humans, because the
biological properties of the primate-adapted BSE agent
are unknown. We show that (i) BSE can be transmitted
from primate to primate by intravenous route in 25
months, and (ii) an iatrogenic transmission of vCJD to
humans could be readily recognized pathologically,
whether it occurs by the central or peripheral route.
Strain typing in mice demonstrates that the BSE agent
adapts to macaques in the same way as it does to humans
and confirms that the BSE agent is responsible for vCJD
not only in the United Kingdom but also in France. The
agent responsible for French iatrogenic growth
hormone-linked CJD taken as a control is very different
from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate. These data
will be key in identifying the origin of human cases of
prion disease, including accidental vCJD transmission,
and could provide bases for vCJD risk assessment.
snip...
Characterization of the CJD and Scrapie Strains.
Controls were set up by transmitting one French and one
U.S. scrapie isolate from ruminants as well as French
sCJD and iCJD cases from humans. None of these revealed
a lesion profile or transmission characteristics
similar or close to those of BSE or vCJD, respectively,
thus extending to the present French scrapie isolate
the previous observation that the BSE agent was
different from all known natural scrapie strains (4, 24).
The lesion profiles of sCJD and iCJD differed only
slightly in severity of the lesions, but not in shape
of the profile, revealing the identity of the causative
agents. One of us reported the absence of similarity
between sCJD (six cases) and U.K. scrapie (eight cases)
in transmission characteristics in mice (4). Herein, we
made the striking observation that the French natural
scrapie strain (but not the U.S. scrapie strain) has
the same lesion profile and transmission times in
C57BL/6 mice as do the two human TSE strains studied.
This strain "affiliation" was confirmed biochemically.
There is no epidemiological evidence for a link between
sheep scrapie and the occurrence of CJD in humans (25).
However, such a link, if it is not a general rule,
would be extremely difficult to establish because of
the very low incidence of CJD as well as the existence
of different isolates in humans and multiple strains in
scrapie. Moreover, scrapie is transmissible to nonhuman
primates (26). Thus, there is still a possibility that
in some instances TSE strains infecting humans do share
a common origin with scrapie, as pointed out by our
findings.
snip...
http://www.pnas.org/cgi/content/full/041490898v1
May 2003
A bizarre misshapen protein
The story of the mysterious, devastating prion in a new book from Springer
In the space of 12 months, Stephen Churchill lost his focus, his memory,
most of his speech, then even the ability to dress, feed, and clean
himself. He developed an excessive fear of water and sharp objects and
refused to bathe or shave. And before long, with his unsteady gait and
his tendency to fall, he spent his days slumped in a wheelchair or
confined to a bed. To the staff of the nursing home where Stephen lived,
the relentless decline was depressingly familiar-it had the earmarks of
Alzheimer's disease. But something in the picture did not fit. The
patient, when he died, was only 19 years old.
Doctors later discovered that Stephen had succumbed to a new kind of
killer, the prion, now known to be the cause of mad cow disease in
cattle, chronic wasting disease in American deer and elk,
Creutzfeldt-Jakob disease and fatal insomnia in humans, among other
exotic ailments. Doctors and researchers have been aware of some of
these diseases for a century and more, but only in the last two decades
have scientists even begun to understand just how the pathological
protein spreads to new species and kills its victims.
In The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly
Prion Diseases, Philip Yam describes the history of the scientific
effort to track down and understand the prion, and the medical effort,
still underway, to devise treatments for those who suffer from its ravages.
Philip Yam has been writing and editing for Scientific American since
1989 and is currently the magazine's news editor. This is his first book.
Detailed information and order possibility:
Philip Yam
The Pathological Protein
Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases
2003. Hardcover, 285 pp.
Euro 29.95 (net price); £21.00; $27.50; sFr 51.50
ISBN 0-387-95508-9
Contact and review copies:
Joan Robinson
Springer-Verlag Press and Public Relations
Tel.: +49- (0) 6221-487-8130,
Fax: +49- (0) 6221-487-8141,
E-mail:
[email protected]
http://www.springer.de/press/newbooks/protein.html
The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly
Prion Diseases
Philip Yam
List Price: $27.50
Our Price: $19.25
You Save: $8.25 (30%)
Availability: Usually ships within 24 hours.
http://www.target.com/gp/detail.html/sr ... 0387955089
snip...
CHAPTER 14
Laying Odds
Are prion diseases more prevalent than we thought?
Researchers and government officials badly underestimated the threat
that mad cow disease posed when it first appeared in Britain. They
didn't think bovine spongifbrm encephalopathy was a zoonosisan
animal disease that can sicken people. The 1996 news that BSE could
infect humans with a new form of Creutzfeldt-Jakob disease stunned
the world. It also got some biomedical researchers wondering whether
sporadic CJD may really be a manifestation of a zoonotic sickness.
Might it be caused by the ingestion of prions, as variant CJD is?
Revisiting Sporadic CJD
It's not hard to get Terry Singeltary going. "I have my conspiracy theo-
ries," admitted the 49-year-old Texan.1 Singeltary is probably the
nation's most relentless consumer advocate when it comes to issues in
prion diseases. He has helped families learn about the sickness and
coordinated efforts with support groups such as CJD Voice and the
CJD Foundation. He has also connected with others who are critical of
the American way of handling the threat of prion diseases. Such critics
include Consumers Union's Michael Hansen, journalist John Stauber,
and Thomas Pringle, who used to run the voluminous
http://www.mad-
cow.orgWeb site. These three lend their expertise to newspaper and
magazine stories about prion diseases, and they usually argue that
223
224 CHAPTER 14
prions represent more of a threat than people realize, and that the gov-
ernment has responded poorly to the dangers because it is more con-
cerned about protecting the beef industry than people's health.
Singeltary has similar inclinations, but unlike these men, he doesn't
have the professional credentials behind him. He is an 11-grade
dropout, a machinist who retired because of a neck injury sustained at
work. But you might not know that from the vast stores of information
in his mind and on his hard drive. Over the years, he has provided unac-
knowledged help to reporters around the globe, passing on files to such
big-time players as The New Tork Times, Newsweek, and USA Today. His
networking with journalists, activists, and concerned citizens has
helped medical authorities make contact with suspected CJD victims.
He has kept scientists informed with his almost daily posting of news
items and research abstracts on electronic newsgroups, including the
bulletin board on
http://www.vegsource.com and the BSE-listserv run out of
the University of Karlsruhe, Germany. His combative, blunt, opinion-
ated style sometimes borders on obsessive ranting that earns praise
from some officials and researchers but infuriates othersespecially
when he repeats his conviction that "the government has lied to us, the
feed industry has lied to usall over a buck." As evidence, Singeltary
cites the USDA's testing approach, which targets downer cows and
examined 19,900 of them in 2002. To him, the USDA should test 1 mil-
lion cattle, because the incidence of BSE may be as low as one in a mil-
lion, as it was in some European countries. That the U.S. does not, he
thinks, is a sign that the government is really not interested in finding
mad cows because of fears of an economic disaster.
Singeltary got into the field of transmissible spongiform encepha-
lopathy in 1997, just after his mother died of sporadic CJD. She had an
especially aggressive versionthe Heidenhain variantthat first
causes the patient to go blind and then to deteriorate rapidly She died
just ten weeks after her symptoms began. Singeltary, who said he had
watched his grandparents die of cancer, considered her death by CJD
to be much, much worse: "It's something you never forget." Her uncon-
trollable muscle twitching became so bad "that it took three of us to
hold her one time," Singeltary recalled. "She did everything but levitate
in bed and spin her head." Doctors originally diagnosed Alzheimer's
disease, but a postmortem neuropathological exam demanded by
Singeltary revealed the true nature other death.
Laying Odds 225
Classifying a disease as "sporadic" is another way for doctors to say
they don't know the cause. Normal prion proteins just turn rogue in the
brain for no apparent reason. The term "sporadic" is often particularly
hard for the victims' families to accept, especially when the patient was
previously in robust health. Maybe it was something in the water, they
wonder, or in the air, or something they atethe same questions CJD
researchers tried to answer decades ago. The names "sporadic CJD"
and "variant CJD" also confuse the public and raise suspicions that U.S.
authorities are hiding something when they say there have been no
native variant CJD cases in the country.
Singeltary suspected an environmental cause in his mother's
demise a feeling reinforced a year later when a neighbor died of spo-
radic CJD. For years, the neighbor had been taking nutritional supple-
ments that contained cow brain extracts. Researchers from the
National Institutes of Health collected samples of the supplement,
Singeltary recounted, and inoculated suspensions into mice. The mice
remained healthywhich only means that those supplement samples
tested were prion-free.
Scientists have made several attempts during the past few decades to
find a connection between sporadic CJD and the environment. Often,
these studies take the form of asking family members about CJD vic-
timstheir diet, occupation, medical history, hobbies, pets, and so
forthand comparing them with non-CJD subjects. Such case-control
CJD studies have produced some intriguingand sometimes contra-
dictoryresults. In 1985, Carleton Gajdusek and his NIH colleagues
reported a correlation between CJD and eating a lot of roast pork, ham,
hot dogs, and lamb, as well as rare meats and raw oysters.2 Yet they also
recognized that the findings were preliminary and that more studies
were needed.
Following up, Robert Will of the U.K. National CJD Surveillance
Unit and others pooled this data with those from two other case-con-
trol studies on CJD (one from Japan and one from the U.K.). In particu-
lar, they figured the so-called odds ratiocalculated by dividing the fre-
quency of a possible factor in the patient group by the frequency of the
factor in the control group. An odds ratio greater than I means that the
factor may be significant. In their study, Will and his collaborators
found an increase of CJD in people who have worked as health profes-
sionals (odds ratio of 1.5) and people who have had contact with cows
226 CHAPTER 14
(1.7) and sheep (1.6). Unfortunately, those connections were not statisti-
cally significant: The numbers of pooled patients (117) and control sub-
jects (333) were so small that the researchers felt the odds ratios needed
to reach 2.5 to 8 (depending on the assumptions) before they could be
deemed statistically significant. The only statistically significant corre-
lations they found were between CJD and a family history of either
CJD (19.1) or other psychotic disease (9.9), although the latter might
simply be correlated because psychotic disease may be an early symp-
tom of undiagnosed CJD.3 In contrast with earlier findings, the team
concluded that there was no association between sporadic CJD and the
consumption of organ meats, including brains (0.6).
Although these case-control studies shed a certain amount of light
on potential risk factors for CJD, it's impossible to draw firm conclu-
sions. Obtaining data that produces statistically meaningful results can
be difficult because of the rarity of CJD and hence the shortage of sub-
jects. Human memory is quite fragile, too, so patients' families may not
accurately recall the lifestyle and dietary habits of their loved ones over
the course of a decade or more. Consequently, researchers must cope
with data that probably contain significant biases. In a review paper on
CJD, Joe Gibbs of the NIH and Richard T.Johnson of Johns Hopkins
University concluded that "the absence of geographic differences in
incidence is more convincing evidence against major dietary factors,
since large populations eschew pork and some consume no meat or
meat products."A CJD study of lifelong vegetarians, they proposed,
could produce some interesting data.4
The inconclusive results of case-control studies do not completely
rule out the environment as a possible cause of CJD. "Dr. Prusiner's
theory does fit much of the data of spontaneous generation of [mal-
formed] PrP somewhere in the brain," Will remarkedthat is, the idea
that sporadic CJD just happens by itself falls within the realm of the
prion theory. Still, "it's very odd, if you look at all the forms of human
prion diseases there are, all of them are transmissible in the laboratory
and could be due to some sort of infectious agent."5 One of the great
difficulties, he explained, is that "given that this is a disease of an
extraordinarily long incubation period, are we really confident that we
can exclude childhood exposure that is transmitted from person to
person, as people move around? It's difficult to be sure about that."
There might a "carrier state" that leaves people healthy yet still able to
Laying Odds 227
infect others. If so, "you would never be able to identify what's causing
the spread of the disease," concluded Will, who hasn't stopped looking
for a possible environmental link. He has some preliminary data based
on studies that trace CJD victims' lives well before the time symptoms
beganup to 70 years; they suggest some degree of geographic cluster-
ing, but no obvious candidates for a source of infection.
A Case for Undercounting
The difficulty in establishing causal links in sporadic prion diseasesif
there are any in the first placeunderlines the importance of thorough
surveillance. The U.K. has an active program, and when a victim of CJD
is reported, one of Robert Will's colleagues visits and questions the
victim's family. "No one has looked for CJD systematically in the U.S.,"
the NIH's Paul Brown noted. "Ever."6 The U.S., through the Centers
for Disease Control and Prevention, has generally maintained a more
passive system, collecting information from death certificates from the
National Center for Health Statistics. Because CJD is invariably fatal,
mortality data is considered to be an effective means of tabulating
cases. The CDC assessed the accuracy of such data by comparing the
numbers with figures garnered through an active search in 1996: Teams
covering five regions of the U.S. contacted the specialists involved and
reviewed medical records for CJD cases between 1991 and 1995.
Comparing the actively garnered data with the death certificate infor-
mation showed that "we miss about 14 percent," said CDC epidemiolo-
gist Lawrence Schonberger. "That's improving. Doctors are becoming
more knowledgeable," thanks to increased scientific and media atten-
tion given to prion diseases.7
The active surveillance study of 1996, however, only looked at cases
in which physicians attributed the deaths to CJD. Misdiagnosed
patients or patients who never saw a neurologist were not tabulated
thus CJD may be grossly underreported. Many neurological ailments
share symptoms, especially early on. According to various studies,
autopsies have found that CJD is misdiagnosed as other ills, such as
dementia or Alzheimer's disease, 5 to 13 percent of the time. The CDC
finds that around 50,000 Americans die from Alzheimer's each year
228 CHAPTER 14
(about 4 million have the disease, according to the Alzheimer's
Association). Therefore, one could argue that thousands of CJD cases
are being missed. (On the flip side, CJD could be mistakenly diagnosed
as Alzheimer's disease or dementia, but the number of CJD patients is
so small that they wouldn't dramatically skew the statistics for other
neurological ills.)
In part to address the issue of misdiagnosis, CJD families have asked
the CDC to place the disease on the national list of officially notifiable
illnesses, which tends to include more contagious conditions such as
AIDS, tuberculosis, hepatitis, and viral forms of encephalitis.
Currently, only some states impose this requirement. CDC officials
have discounted the utility of such an approach, arguing that it would
duplicate the mortality data, which is more accurate than early diag-
noses of CJD, anyway. Moreover, mandatory reporting of CJD cases
does not necessarily guarantee the end to missed cases.8
One clue suggests that the passive system is undercounting CJD in
the U.S.: racial difference. The number of black CJD victims is about 38
percent that of white victims. Rather than sporadic CJD being a one-
in-a-million lottery, it's more like one-in-2.5-million for African-
Americans. Access to medical care might be one reason. Schonberger
recounted that the CDC had asked other countries with substantial
black populations to submit CJD figures for comparison but found that
the surveillance in those countries was inadequate. "We haven't been
able to find any comparable literature on this issue, so it's still up
in the
air," Schonberger said. On the other hand, Alzheimer's disease is more
common among black people than whites, with an estimated higher
prevalence ranging from 14 percent to almost 100 percent, according to
a February 2002 report by the Alzheimer's Association. Are some black
CJD cases being misdiagnosed as Alzheimer's?
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
population. As Schonberger pointed out, no doctor would misdiagnose a
30-year-old CJD patient as having Alzheimer's. The average age of the
first 100 variant CJD victims was 29; should the epidemiology of vCJD
changeif older people start coming down with itthen there would
be problems. "The adequacy of our overall CJD surveillance would be
Laying Odds 229
greatly reduced should the proportion of older individuals affected by
variant CJD substantially increase," Schonberger explained.9
To date, only brain autopsies can confirm CJD. To encourage the
necessary neuropathological studies, in 1997 the CDC helped establish
the National Prion Disease Pathology Surveillance Center at Case
Western Reserve University, under the directorship of Pierluigi
Gambetti. But the number of brains examined has fallen far short of
the number of CJD cases in the U.S.: Gambetti's lab, which receives
brains based on referrals from local physicians and families, looked at
only 99 sporadic CJD cases in 2000 and 138 in 2001, when about 300
each year are expected. "I'm very unhappy with the numbers,"
Gambetti lamented. "European countries see 100 or 90 percent of all
the cases suspected. We see 30 to 40 percent."10
Most families don't think about having an autopsy done (which can
cost upward of $1,500 if the hospitals don't pick up the tab), and mem-
bers of the support group CJD Voice have said they were too distraught
to think of shipping a loved one's brain by Federal Express to
Gambetti's lab. (For accurate analyses of brain tissue, the autopsy must
be performed within 72 hours of death, assuming the body has been
kept refrigerated.) Moreover, physicians often do not suggest an
autopsy, perhaps because of liability fears should the postmortem
reveal that the original diagnosis was wrong. Gambetti has been work-
ing on establishing a network that would enable postmortems to be
done near where the deceased person lived and without cost to
