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From: TSS ()
Subject: Variant Creutzfeldt-Jakob disease in the United Kingdom and elsewhere: situation at the end of 2005
Date: January 26, 2006 at 9:40 am PST

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Variant Creutzfeldt-Jakob disease in the United Kingdom and elsewhere: situation at the end of 2005

AM Molesworth (, NJ Andrews

Health Protection Agency Centre for Infections, London, United Kingdom

By the end of December 2005, a total of 159 cases of variant Creutzfeldt-Jakob disease (vCJD) had been reported in the United Kingdom, of which 153 have so far resulted in death. Elsewhere numbers remain small, with 15 cases in France, 4 in Ireland, 2 in the United States, and 1 each in Canada, Italy, Japan, the Netherlands, Portugal, Saudi Arabia and Spain [1,2].
In the UK, five deaths from vCJD were reported in 2005, four less than the previous year’s total of nine. Results from modelling the incidence of deaths indicate that the current epidemic wave reached a peak of 28 deaths in 2000, and has since declined (Figure). Extrapolating this trend gives an estimate of 2 deaths in the next 12 months (95% prediction interval 0 to 5). With 6 patients alive at the end of 2005, however, a prediction of 2 deaths is likely to be an underestimate [3].

Figure. vCJD deaths by year, and fitted quadratic model for incidence trend.

It is important to note that, to date, all vCJD cases have been methionine homozygote at codon 129 of the prion protein gene. Preclinical vCJD infection has, however, been reported in a heterozygous patient after blood transfusion from a donor who subsequently developed vCJD [4]. Although the initial epidemic wave is now in decline, it is possible that there will be further epidemics of cases in other genetic groups. There is also the possibility of continuing person to person transmission through certain forms of health care (for instance, in relation to surgery, blood transfusion or treatment with plasma products). It is essential, therefore, to maintain and promote active surveillance of CJD to investigate these possibilities.

This article was adapted by the authors from reference 2

The European and Allied Countries Collaborative Study Group of CJD (EUROCJD). (
Health Protection Agency. Variant Creutzfeldt-Jakob disease in the United Kingdom and elsewhere: situation at the end of 2005. CDR Weekly 2006; 16(4): news. (
Andrews NG. Incidence of variant Creutzfeldt-Jakob disease onsets and deaths in the UK. January 1994 – December 2005 . Edinburgh: The National Creutzfeldt-Jakob Disease Surveillance Unit; 19 January 2006. (
Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364:527-9.

[The first patient with the new variant of Creutzfeldt-Jakob's disease in The Netherlands]

[Article in Dutch]

Jansen C, Houben MP, Hoff JI, Sanchez-Juan P, Rozemuller AJ, van Duijn CM.

Afd. Pathologie, Universitair Medisch Centrum Utrecht, Postbus 85.500, 3508 GA Utrecht.

A Dutch woman died at the age of 26 years, after a disease duration of 18 months, due to the new variant of Creutzfeldt-Jakob's disease (vCJD). She had never travelled to the United Kingdom and there was no history of potential iatrogenic exposure. However, she had worked in the catering and food production industry for the previous 6 years and had frequently consumed raw meat. The disease course showed the classical clinical picture of vCJD, which was confirmed by post-mortem examination of the brain. Contrary to classical sporadic CJD, patients with the variant disease are usually younger and present predominantly with psychiatric symptoms. Sensory complaints like pain and dysaesthesiae usually follow soon. Only later are these symptoms followed by rapidly progressive neurological symptoms and signs. All patients genotyped so far are homozygous for methionine on codon 129 of the prion protein gene. Recognition of the disease is of particular importance because of possible transmission via blood and tissues. In patients with rapidly progressive psychiatric symptoms and unexplained neurological signs, particularly sensory complaints, one must consider the possibility of vCJD.

Patient in the Netherlands diagnosed with variant Creutzfeldt-Jakob Disease
Press release, 22/04/2005

A patient at the Mesos Medisch Centrum in Utrecht was diagnosed today with variant Creutzfeldt-Jakob Disease (vCJD), the human form of mad cow disease (BSE). This is the first known case of vCJD in the Netherlands.

The case was reported by Rotterdam’s Erasmus Medisch Centrum, the national surveillance centre that monitors the disease in the Netherlands. The European surveillance centre for (variant) CJD in Edinburgh confirmed the diagnosis based on brain x-rays and the course of the disease. The Dutch National Health Inspectorate has launched an investigation to determine whether the disease may have been transmitted to others. The Dutch government has also notified European authorities of the case.

VCJD is a variant of Creutzfeldt-Jakob Disease. Characterized by a spongy degeneration of the brain, the disease is caused by special protein structures (prions). It can be transmitted by tissue transplants and contaminated hospital instruments, especially during neurosurgical procedures.

Recently, speculation has arisen that vCJD may be transmitted by blood based on two cases in the United Kingdom, where this may have occurred. However, no conclusive scientific evidence has been found to date.

The patient concerned was never a blood or tissue donor, and never received any blood transfusions or tissue transplants. In light of that, it is highly improbable that this patient infected others or contracted the disease from someone else.

In recent years, the Netherlands has introduced various measures to minimize the risk of transmission by blood:

As of 1 September 2001: removal of white blood cells from all blood products (General Leukocyte Depletion).
As of 1 November 2001: exclusion of donors who lived in the United Kingdom for over six months between 1980 and 1996.
As of 1 February 2005: exclusion of blood donors who personally received a blood transfusion after 1 January 1980.
Investigations into the contraction of vCJD are focusing on the consumption of tainted beef as a cause. To date, it is unclear whether this particular case is attributable to contaminated beef. Further investigation will be needed to determine whether the cause is traceable.
The Netherlands ensures the safety of its beef by testing all vulnerable cattle for BSE. In addition, the brains and spinal cords of cattle are separated and destroyed during the slaughtering process, as these could be infectious. The Ministry of Health, Welfare and Sports has informed the Ministry of Agriculture, Nature and Food Quality.

Other cases of vCJD have emerged in the past in European countries, starting in England. Ireland, France, Italy, Japan, Canada and the United States have also witnessed the occurrence of the disease.

The Ministry of Agriculture, Nature and Food Quality’s website,, provides additional information on BSE.

First case of Creutzfeldt-Jakob Disease in the Netherlands
Newsitem, 26/04/2005

The first probable case of variant Creutzfeldt-Jakob (vCJD) disease in a patient in the Netherlands was reported on April 22nd 2005 by the Dutch Ministry of Health, Welfare and Sport. The patient is currently being treated at a hospital in Utrecht.

The case, in a 26 year old woman, was detected through national surveillance of CJD, coordinated by the Erasmus Medical Centre in Rotterdam, and the probable diagnosis is based on magnetic resonance imaging (MRI) and clinical signs. The diagnosis was reviewed by the United Kingdom's National Creutzfeldt-Jakob Disease Surveillance Unit, which runs The European and Allied Countries Collaborative Study Group of CJD. The Netherlands has informed the European authorities via the European Early Warning and Response System (EWRS).
The patient has never donated or received blood or tissue, and the likelihood that any other people have been exposed to this infection is reported to be very small.

Netherlands Reports

First vCJD Case

The Netherlands has become the fifth

European country affected by variant

Creutzfeldt-Jakob disease (vCJD), the

human counterpart of bovine spongiform

encephalopathy (BSE).On 21 April, health

authorities reported that a 26-year-old

woman had been diagnosed with the fatal

brain affliction.The Netherlands has registered

at least 77 cases of BSE.

Of 171 cases of vCJD so far, 155 have

occurred in the United Kingdom, nine in

France, two in Italy, and one in Ireland. Four

additional patients from outside Europe

had all lived in the U.K. for varying periods.



Animal Prion Diseases Relevant to Humans (unknown types?)
Thu Oct 27, 2005 12:05

About Human Prion Diseases /
Animal Prion Diseases Relevant to Humans

Bovine Spongiform Encephalopathy (BSE) is a prion disease of cattle. Since 1986, when BSE was recognized, over 180,000 cattle in the UK have developed the disease, and approximately one to three million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent and given to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Infected cattle and feed exported from the UK have resulted in smaller epidemics in other European countries, where control measures were applied later.

Compelling evidence indicates that BSE can be transmitted to humans through the consumption of prion contaminated meat. BSE-infected individuals eventually develop vCJD with an incubation time believed to be on average 10 years. As of November 2004, three cases of BSE have been reported in North America. One had been imported to Canada from the UK, one was grown in Canada, and one discovered in the USA but of Canadian origin. There has been only one case of vCJD reported in the USA, but the patient most likely acquired the disease in the United Kingdom. If current control measures intended to protect public and animal health are well enforced, the cattle epidemic should be largely under control and any remaining risk to humans through beef consumption should be very small. (For more details see Smith et al. British Medical Bulletin, 66: 185. 2003.)

Chronic Wasting Disease (CWD) is a prion disease of elk and deer, both free range and in captivity. CWD is endemic in areas of Colorado, Wyoming, and Nebraska, but new foci of this disease have been detected in Nebraska, South Dakota, New Mexico, Wisconsin, Mississippi Kansas, Oklahoma, Minnesota, Montana, and Canada. Since there are an estimated 22 million elk and deer in the USA and a large number of hunters who consume elk and deer meat, there is the possibility that CWD can be transmitted from elk and deer to humans. As of November 2004, the NPDPSC has examined 26 hunters with a suspected prion disease. However, all of them appeared to have either typical sporadic or familial forms of the disease. The NPDPSC coordinates with the Centers for Disease Control and state health departments to monitor cases from CWD-endemic areas. Furthermore, it is doing experimental research on CWD transmissibility using animal models. (For details see Sigurdson et al. British Medical Bulletin. 66: 199. 2003 and Belay et al. Emerging Infectious Diseases. 10(6): 977. 2004.)

SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM 1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is with a human TSE surveillance system that is terrible flawed. in 1997 cases of the _reported_ cases of cjd were at 54, to 163 _reported_ cases in 2004. see stats here;

p.s. please note the 47 PENDING CASES to Sept. 2005

p.s. please note the 2005 Prion D. total 120(8) 8=includes 51 type pending, 1 TYPE UNKNOWN ???

p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN???

p.s. please note 2004 prion disease (6) 6=7 TYPE UNKNOWN???


AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.




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


Full Text
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al.
JAMA.2001; 285: 733-734

Coexistence of multiple PrPSc types in individuals with

Creutzfeldt-Jakob disease

Magdalini Polymenidou, Katharina Stoeck, Markus
Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi


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



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

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

and Clinical Medicine, University of Edinburgh, Edinburgh,

United Kingdom; Central Institute for Animal Disease

(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

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

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,

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)



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

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

to mice and in BSE. Western blot analysis of PrPSc in a

sample of tonsil from a case of vCJD (Tonsil), in a
concentrated brain

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


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

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

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

on vCJD, where type 1 is present in all samples

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

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

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

and that any mechanistic explanation of prion

replication and the molecular basis of agent strain

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

Evidence for the isolation in mice of more than one

strain from individual isolates of BSE has been presented


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

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

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

the physico-chemical properties of the prion protein,

human disease phenotype, and prion agent strain.



Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157

AJP January 2006, Vol. 168, No. 1 ...TSS

Neuropathology and Applied Neurobiology



, 565-579 doi: 10.1111/j.1365-2990.2005.00697.x

© 2005 Blackwell Publishing Ltd


Blackwell Science, LtdOxford, UKNANNeuropathology and
Applied Neurobiology0305-1846Blackwell Publishing Ltd, 2005


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



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

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

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

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

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


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

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.


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

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

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

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


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


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

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

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; (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.



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...

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:

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,

Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: (until 9/12/02)

New e-mail: (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.



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


John Collinge

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.


Journal of General Virology (2004), 85, 2471-2478 DOI

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,

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: .


Phenotypic Similarities Between BASE and sCJD. The

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

the identity of TSE strains is underscored by several

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

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

may also propagate a distinctive PrPSc type, with a

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

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

PrPSc types. Strains of TSE agents may be better

characterized upon passage to transgenic mice. In the

until this is accomplished, our present findings
suggest a strict

epidemiological surveillance of cattle TSE and sCJD
based on

molecular criteria.

Published online before print March 20, 2001,

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)


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.


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


1: J Infect Dis 1980 Aug;142(2):205-8

Oral transmission of kuru, Creutzfeldt-Jakob disease,
and scrapie to nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and
scrapie disease of sheep and goats were transmitted to
squirrel monkeys (Saimiri sciureus) that were exposed
to the infectious agents only by their nonforced
consumption of known infectious tissues. The
asymptomatic incubation period in the one monkey
exposed to the virus of kuru was 36 months; that in the
two monkeys exposed to the virus of Creutzfeldt-Jakob
disease was 23 and 27 months, respectively; and that in
the two monkeys exposed to the virus of scrapie was 25
and 32 months, respectively. Careful physical
examination of the buccal cavities of all of the
monkeys failed to reveal signs or oral lesions. One
additional monkey similarly exposed to kuru has
remained asymptomatic during the 39 months that it has
been under observation.

PMID: 6997404


Interspecies Transmission of Chronic Wasting Disease
Prions to

Squirrel Monkeys (Saimiri sciureus)

Richard F. Marsh,1? Anthony E. Kincaid,2 Richard A.
Bessen,3 and Jason C. Bartz4*

Department of Animal Health and Biomedical Sciences,
University of Wisconsin, Madison 537061; Department of

Physical Therapy2 and Department of Medical
Microbiology and Immunology,4 Creighton University, Omaha,

Nebraska 68178; and Department of Veterinary Molecular
Biology, Montana

State University, Bozeman, Montana 597183

Received 3 May 2005/Accepted 10 August 2005

Chronic wasting disease (CWD) is an emerging prion
disease of deer and elk. The risk of CWD transmission

to humans following exposure to CWD-infected tissues is
unknown. To assess the susceptibility of nonhuman

primates to CWD, two squirrel monkeys were inoculated
with brain tissue from a CWD-infected mule deer. The

CWD-inoculated squirrel monkeys developed a progressive
neurodegenerative disease and were euthanized at

31 and 34 months postinfection. Brain tissue from the
CWD-infected squirrel monkeys contained the abnormal

isoform of the prion protein, PrP-res, and displayed
spongiform degeneration. This is the first reported

transmission of CWD to primates.


JOURNAL OF VIROLOGY, Nov. 2005, p. 13794-13796 Vol.
79, No. 21


Copyright © 2005, American Society for Microbiology.
All Rights Reserved.


The EMBO Journal, Vol. 19, No. 17 pp. 4425-4430, 2000
© European Molecular Biology Organization

Evidence of a molecular barrier limiting
susceptibility of humans, cattle and sheep to
chronic wasting disease

G.J. Raymond1, A. Bossers2, L.D. Raymond1, K.I. O?Rourke3,
L.E. McHolland4, P.K. Bryant III4, M.W. Miller5, E.S.
Williams6, M.
and B. Caughey1,7

1NIAID/NIH Rocky Mountain Laboratories, Hamilton, MT
3USDA/ARS/ADRU, Pullman, WA 99164-7030, 4USDA/ARS/ABADRL,
Laramie, WY 82071, 5Colorado Division of Wildlife,
Wildlife Research
Center, Fort Collins, CO 80526-2097, 6Department of
Veterinary Sciences,
University of Wyoming, Laramie, WY 82070, USA and
Institute for Animal Science and Health, Lelystad, The
7Corresponding author e-mail: Received
June 7, 2000;
revised July 3, 2000; accepted July 5, 2000.


Chronic wasting disease (CWD) is a transmissible
spongiform encephalopathy (TSE) of deer and elk,
and little is known about its transmissibility to other
species. An important factor controlling
interspecies TSE susceptibility is prion protein (PrP)
homology between the source and recipient
species/genotypes. Furthermore, the efficiency with which
the protease-resistant PrP (PrP-res) of one
species induces the in vitro conversion of the normal PrP
(PrP-sen) of another species to the
protease-resistant state correlates with the cross-species
transmissibility of TSE agents. Here we
show that the CWD-associated PrP-res (PrPCWD) of cervids
readily induces the conversion of recombinant cervid
molecules to the protease-resistant state in accordance
with the known transmissibility of CWD between cervids.
In contrast,
PrPCWD-induced conversions of human and bovine PrP-sen
much less efficient, and conversion of ovine PrP-sen was
intermediate. These results demonstrate a barrier at the
molecular level that should limit the susceptibility of
these non-cervid
species to CWD.


Clearly, it is premature to draw firm conclusions about
passing naturally into humans, cattle and sheep, but
the present
results suggest that CWD transmissions to humans would
be as
limited by PrP incompatibility as transmissions of BSE
or sheep
scrapie to humans. Although there is no evidence that
scrapie has affected humans, it is likely that BSE has
caused variant
CJD in 74 people (definite and probable variant CJD
cases to
date according to the UK CJD Surveillance Unit). Given the
presumably large number of people exposed to BSE
the susceptibility of humans may still be very low
compared with
cattle, which would be consistent with the relatively
conversion of human PrP-sen by PrPBSE. Nonetheless, since
humans have apparently been infected by BSE, it would
seem prudent
to take reasonable measures to limit exposure of humans
(as well as sheep and cattle) to CWD infectivity as has
recommended for other animal TSEs.


Neurology 1999;52:1757
© 1999 American Academy of Neurology


Expedited Publication

A subtype of sporadic prion disease mimicking fatal
familial insomnia
P. Parchi, MD, S. Capellari, MD, S. Chin, MD, PhD, H.
B. Schwarz, MD, N. P. Schecter, MD, J. D. Butts, MD, P.
Hudkins, MD, D. K. Burns MD, J. M. Powers, MD and P.
Gambetti, MD

Volume 43 Issue 12 Page 1687 - December 2003

Similar levels of infectivity in the blood of mice
infected with
human-derived vCJD and GSS strains of transmissible
Larisa Cervenakova, Oksana Yakovleva, Carroll McKenzie,
Kolchinsky, Lisa McShane, William N. Drohan, and Paul Brown




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