##################### Bovine Spongiform Encephalopathy #####################
Subject: Creutzfeldt Jakob disease statistics Monday 6 March 2006 Reference number: 2006/0088
Date: March 6, 2006 at 3:22 pm PST
Monthly Creutzfeldt Jakob disease statistics
Published:
Monday 6 March 2006
Reference number:
2006/0088
The Department of Health is today issuing the latest information about the numbers of known cases of Creutzfeldt Jakob disease. This includes cases of variant Creutzfeldt Jakob disease (vCJD) - the form of the disease thought to be linked to BSE. The position is as follows:
Definite and probable CJD cases in the UK:
As at 3 March 2006
Summary of vCJD cases
Deaths
Deaths from definite vCJD (confirmed): 110
Deaths from probable vCJD (without neuropathological confirmation): 44
Deaths from probable vCJD (neuropathological confirmation pending): 0
Number of deaths from definite or probable vCJD (as above): 154
Alive
Number of probable vCJD cases still alive: 6
Total number of definite or probable vCJD (dead and alive): 160
The next table will be published on Monday 3rd April 2006
Referrals: a simple count of all the cases which have been referred to the National CJD Surveillance Unit for further investigation in the year in question. CJD may be no more than suspected; about half the cases referred in the past have turned out not to be CJD. Cases are notified to the Unit from a variety of sources including neurologists, neuropathologists, neurophysiologists, general physicians, psychiatrists, electroencephalogram (EEG) departments etc. As a safety net, death certificates coded under the specific rubrics 046.1 and 331.9 in the 9th ICD Revisions are obtained from the Office for National Statistics in England and Wales, the General Register Office for Scotland and the General Register Office for Northern Ireland.
Deaths: All columns show the number of deaths that have occurred in definite and probable cases of all types of CJD and GSS in the year shown. The figures include both cases referred to the Unit for investigation while the patient was still alive and those where CJD was only discovered post mortem (including a few cases picked up by the Unit from death certificates). There is therefore no read across from these columns to the referrals column. The figures will be subject to retrospective adjustment as diagnoses are confirmed.
Definite cases: this refers to the diagnostic status of cases. In definite cases the diagnosis will have been pathologically confirmed, in most cases by post mortem examination of brain tissue (rarely it may be possible to establish a definite diagnosis by brain biopsy while the patient is still alive).
Probable vCJD cases: are those who fulfil the 'probable' criteria set out in the Annex and are either still alive, or have died and await post mortem pathological confirmation. Those still alive will always be shown within the current year's figures.
Sporadic: Classic CJD cases with typical EEG and brain pathology. Sporadic cases appear to occur spontaneously with no identifiable cause and account for 85% of all cases.
Probable sporadic: Cases with a history of rapidly progressive dementia, typical EEG and at least two of the following clinical features; myoclonus, visual or cerebellar signs, pyramidal/extrapyramidalsigns or akinetic mutism.
Iatrogenic: where infection with classic CJD has occurred accidentally as the result of a medical procedure. All UK cases have resulted from treatment with human derived pituitary growth hormones or from grafts using dura mater (a membrane lining the skull).
Familial: cases occurring in families associated with mutations in the PrP gene (10 - 15% of cases).
GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare inherited autosomal dominant disease, typified by chronic progressive ataxia and terminal dementia. The clinical duration is from 2 to 10 years, much longer than for CJD.
vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered by the National CJD Surveillance Unit and reported in The Lancet on 6 April 1996. This is characterised clinically by a progressive neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or chorea) without the typical EEG appearance of CJD. Neuropathology shows marked spongiform change and extensive florid plaques throughout the brain.
Definite vCJD cases still alive: These will be cases where the diagnosis has been pathologically confirmed (by brain biopsy).
Related links
Download CJD statistics March 2006 (PDF, 12K)
Notes to editor
ANNEX
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.
Reference number:
2006/0088
http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4131172&chk=EejSdT
ALL CJD * As at 3rd March 2006 (see increase in sCJD)
http://www.dh.gov.uk/assetRoot/04/13/11/73/04131173.pdf
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/resources-casereport.html
HUMAN and ANIMAL TSE Classifications i.e. mad cow
disease and the UKBSEnvCJD only theory
TSEs have been rampant in the USA for decades in many
species, and they all have been rendered and fed back
to animals for human/animal consumption. I propose that
the current diagnostic criteria for human TSEs only
enhances and helps the spreading of human TSE from the
continued belief of the UKBSEnvCJD only theory in 2005.
With all the science to date refuting it, to continue
to validate this myth, will only spread this TSE agent
through a multitude of potential routes and sources
i.e. consumption, surgical, blood, medical, cosmetics
etc. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis,
Marsh, et al and many more, that the world of TSE
Tranmissible Spongiform Encephalopathy is far from an
exact science, but there is enough proven science to
date that this myth should be put to rest once and for
all, and that we move forward with a new classification
for human and animal TSE that would properly identify
the infected species, the source species, and then the
route. This would further have to be broken down to
strain of species and then the route of transmission
would further have to be broken down. Accumulation and
Transmission are key to the threshold from subclinical
to clinical disease, and of that, I even believe that
physical and or blunt trauma may play a role of onset
of clinical symptoms in some cases, but key to all
this, is to stop the amplification and transmission of
this agent, the spreading of, no matter what strain.
BUT, to continue with this myth that the U.K. strain of
BSE one strain in cows, and the nv/v CJD, one strain in
humans, and that all the rest of human TSE is one
single strain i.e. sporadic CJD (when to date there are
6 different phenotypes of sCJD), and that no other
animal TSE transmits to humans, to continue with this
masquerade will only continue to spread, expose, and
kill, who knows how many more in the years and decades
to come. ONE was enough for me, My Mom, hvCJD, DOD
12/14/97 confirmed, which is nothing more than another
mans name added to CJD, like CJD itself, Jakob and
Creutzfeldt, or Gerstmann-Straussler-Scheinker
syndrome, just another CJD or human TSE, named after
another human. WE are only kidding ourselves with the
current diagnostic criteria for human and animal TSE,
especially differentiating between the nvCJD vs the
sporadic CJD strains and then the GSS strains and also
the FFI fatal familial insomnia strains or the ones
that mimics one or the other of those TSE? Tissue
infectivity and strain typing of the many variants of
the human and animal TSEs are paramount in all variants
of all TSE. There must be a proper classification that
will differentiate between all these human TSE in order
to do this. With the CDI and other more sensitive
testing coming about, I only hope that my proposal will
some day be taken seriously.
My name is Terry S. Singeltary Sr. and I am no
scientist, no doctor and have no PhDs, but have been
independently researching human and animal TSEs since
the death of my Mother to the Heidenhain Variant of
Creutzfeldt Jakob Disease on December 14, 1997
'confirmed'. ...TSS
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
SOURCES
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/full/285/6/733?maxtoshow=&HITS=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/abstract/168/1/151maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1136646133963_237&FIRSTINDEX=0&volume=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/reprint/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/content/abstract/17/4/489
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)
____________________________________TSS
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/abstract/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]. .
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
[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
03-025IFA
03-025IFA-2
Terry S. Singeltary
Page 1 of 17
From: Terry S. Singeltary Sr. [
[email protected]]
Sent: Thursday, September 08, 2005 6:17 PM
To:
[email protected].
Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements
for the Disposition of Non-Ambulatory Disabled Cattle
Greetings FSIS,
I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and
Requirements for the Disposition of Non-Ambulatory Disabled Cattle
THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle
Broken bones and such may be the first signs of a sub clinical BSE/TSE Non-Ambulatory Disabled Cattle ;
SUB CLINICAL PRION INFECTION
MRC-43-00
Issued: Monday, 28 August 2000
NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH
FINDINGS RELEVANT TO CJD AND BSE
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
9/13/2005
snip...
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
SNIP...END...TSS
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