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From: TSS ()
Subject: UK Strategy for Research and Development on Human and Animal Health Aspects of TSEs 2005-2008
Date: February 12, 2006 at 1:08 pm PST

UK Strategy for Research and Development on Human and Animal Health Aspects of Transmissible Spongiform Encephalopathies

2005-2008

snip...

v6.1

Preface

Since the announcement in 1996 of a possible link between BSE in cattle and vCJD in humans two strategy documents for research and development into transmissible spongiform encephalopathies (TSEs) have been produced by the UK government. TSE research has advanced significantly during the past few years, and as senior representatives of the UK public funders of TSE research, we considered it timely to review the current understanding of these diseases and set out a new research strategy that reflected the changes in knowledge.

This document represents the first UK joint human and animal health strategy for TSE research and addresses issues that affect livestock, the food chain and public health. It highlights the improved co-ordination that has taken place between government departments since the publication of the Phillips Report and reflects the overlapping issues of relevance to both human and animal health.

In the production of this document, we have drawn on a wide range of advice from all of the UK’s major funders of TSE research and from members of specialist advisory committees such as SEAC, which are detailed within. We have also undertaken wide consultation in the UK and overseas in an attempt to ensure the accuracy of the information included. We are particularly indebted to Professor Chris Bostock (formerly director of the Institute for Animal Health) for his 2004 review of the science, which forms the backbone of this document.

With numbers of BSE cases continuing to fall and vCJD cases apparently stabilising in the UK, it would be easy to be complacent. However, the increasing incidence of chronic wasting disease in the USA reinforces the concern that TSEs are an international problem and one that will need to be monitored carefully for a number of years. In the UK, there remain key issues that continue to pose threats to animal and human health. Not least is the possibility of a non-symptomatic carrier state or the emergence of BSE-like illness in another species such as sheep.

While every attempt is made to reduce exposure to disease it is not always possible to eradicate it completely. Disease management is thus often based on risk assessments of potential exposure and these are based on the latest scientific results.

This document aims to highlight the major scientific uncertainties relating to TSEs and how these will be addressed by the research and development strategies of the major UK funders. The necessary experience of managing BSE and producing scientific evidence upon which to base control policies has led to the development of an extensive UK research base in human and animal health aspects of TSEs.

The UK has a special responsibility to share its expertise in TSEs with Europe and the rest of the world to minimise the effects of TSE infection in other countries.

Although considerable progress has been made, further studies are required to fill in the many gaps in our basic understanding of TSEs and in our knowledge of how TSE epidemics can be effectively controlled. It is therefore vital that the UK research base is maintained and that a co-ordinated and effective funding strategy is adopted for new research. Science develops and inevitably this strategy will require regular reassessment.

3v6.1

Professor Sir John Pattison

Director of Research

Department of Health

Dr John Bell

Chief Executive

Food Standards Agency

Professor Colin Blakemore FRS

Chief Executive

Medical Research Council

Professor Julia Goodfellow CBE

Chief Executive

Biotechnology and Biological Sciences Research Council

Professor Howard Dalton FRS

Chief Scientific Adviser

Department for Environment, Food and Rural Affairs

4v6.1

Executive Summary


1. Transmissible spongiform encephalopathies (TSEs) have been present in human and animal populations for centuries. Interest in them has intensified since BSE became significant in British cattle in the 1990s and especially since its human version became a hazard to the UK population.


2. The number of human fatalities from TSEs in the UK is relatively small, in the low hundreds, and on this criterion TSEs currently appear to present a smaller risk to public health risk than vascular disorders such as heart disease or strokes, which are the UK’s biggest killers, or cancers.


3. However, the impact of TSEs has been high and they remain important for a number of reasons. There may be human TSEs with longer latency periods than those that have appeared clinically to date. This could mean a further cost in terms of human life and suffering and to the healthcare system, where considerable resource has already been committed to importing blood products and improving safety measures such as the decontamination of surgical instruments. Identification of another TSE in another species (e.g. BSE in sheep) would affect consumer confidence in British produce, which would add a further burden to a slowly recovering farming and meat industry.


4. The five major UK funders of TSE research each have their own remits, strategies and approaches. The Department of Health and the Department for Environment, Food and Rural Affairs are government departments with responsibility for human and animal health, the environment and the agricultural industry. The Food Standards Agency is a public body established to protect the public from food hazards. The Medical Research Council and the Biotechnology and Biological Sciences Research Council are non-departmental public bodies that fund research in human and animal biology and health.


5. These bodies have different but related interests in TSE research. Although the research councils pay attention to the applicability of the research they fund, they have a strong interest in pursuing excellent science independently of its possible use. The three government departments have responsibilities for human and animal health, and for the environmental and economic ramifications of TSEs, and require sound scientific information on which to base their policies.


6. These organisations are currently (2004/05) spending approximately £35M per year on TSE research. The programmes supported by the five funders are coordinated and discussed with other interested organisations, including devolved UK administrations, the voluntary sector, industry and organisations outside the UK, including the European Commission and research groups in the USA. Central to this cooperation is the TSE R & D Funders Co-ordination Group.


7. Research on TSEs will continue to be necessary in part because of their economic consequences for agriculture, an industry that is already under pressure from a variety of sources. The National Scrapie Plan, which involves eliminating scrapie from the UK sheep flock by removing sheep with lower levels of genetic resistance to it, is costly and requires an adequate base of research knowledge. Furthermore, as a large proportion of the UK population may have been exposed to BSE-contaminated material, the implications for public health and the additional burden on the NHS could be severe. Consequently it is imperative that accurate estimates of the size of the human epidemic are obtained, methods to prevent its spread are continually updated and potential treatments investigated.

5v6.1


8. Research in this area, especially that funded by the research councils, forms part of the general process of advancing knowledge as well as being of practical value. It has been informed by, and in turn informs, advances in our understanding of protein and gene science, and knowledge of human and animal epidemiology. It illuminates important areas of knowledge such as the strength and nature of species barriers and infection processes, including species-to-species and possible mother-to-offspring transmission.


9. Currently, TSEs are one of the rare disease groups where infection leads invariably to death. For this reason, possible treatments are a target for both human and animal TSE research. These might take the form of drug therapy or immunological interventions such as vaccines. If developed for the human population, such interventions would have a high value for patients and their families despite the small number of people affected.


10. TSE research is a growing international field in which the UK has made a significant contribution. The UK is likely to be a valued partner in TSE research for other nations and for international organisations. TSE research has featured in previous European Commission framework programmes for research and is likely to be further funded under the sixth framework programme. The UK is a leader in TSE science and in the cross-agency organisation needed to support the full range of TSE research.


11. The approach to TSE research described in this report includes a number of short-term targets. One of the most pressing is the need for a preclinical diagnostic test for humans and animals. Also important is work on the safety of medical instruments, which is needed by the Department of Health and the UK National Health Service. Other health-related research is directed towards the needs of agencies such as the National Blood Service, which has an interest in blood transfusion hazards. Research is also being pursued on methods for monitoring food for TSE hazards, on animal feed hazards and on animal slaughter practices. This is of interest to Defra and the FSA. Defra has a strong interest in research to support the National Scrapie Plan, to investigate the possibility of BSE in sheep and to establish the risk of TSEs in other farmed animals.


12. The aim of this research is to uncover the science of TSEs, in particular their nature and means of transmission; to develop countermeasures at many points in the food chain; to protect the health of the UK population; and to engage the public in the research and its application.

6v6.1

Introduction

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2.15.3.2 It is difficult to ensure that all cases of vCJD are correctly diagnosed and reported and there is always the worry that some could be missed. Variant CJD occurs in a much younger age group than sporadic CJD68 and it is a concern that cases are perhaps being missed in children and older adults. A survey of over 1,000 children with progressive intellectual and neurological deterioration (PIND), a group that would include vCJD patients, found only previously reported cases of vCJD, indicating that vCJD in children is not being missed68, 314. Although vCJD has been diagnosed in a 74 year old patient315, the possibility remains that cases of vCJD are being missed amongst the elderly. One attempt to estimate the prevalence of infection, as opposed to the incidence of clinical vCJD, is based on a search for the characteristic presence of PrPSc in infected lymphoid tissue in archived specimens of tonsils and appendices removed from patients aged 10 to 50 between 1995 and 1999. The interim findings of this study reported one PrPSc-positive appendix amongst 8318 samples examined, which gives an estimated detectable prevalence of PrPSc accumulation in 120 per million of the population316. However, the finding of a further two PrPSc-positive samples, giving a total of three positive samples in 12 674 samples examined, confirm the wisdom of screening the larger number of samples being collected as part of the National Tonsil Archive333.

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2.2 The prion and other hypotheses

2.2.1 An animal with a TSE infection commonly exhibits an abnormal form (PrPSc or prion) of the cellular prion protein (PrPC). Deposits of PrPSc can take many forms ranging from diffuse widespread distribution to local concentrations of highly ordered aggregates, called amyloid plaques. Deposits of PrPSc can be identified under the microscope in sections of body tissue by selective staining and can be separated from PrPC because PrPSc is insoluble and relatively resistant to protease enzymes used to digest proteins.

2.2.2 The correlation between TSE infection and PrPSc led to the prion hypothesis, that the abnormal form of prion protein is the infectious agent8, 9, 10. Although accepted by many in

19v6.1

the field today, it was highly contentious at first because it went against the then-accepted view that all inherited biological information must be encoded in nucleic acid, DNA or RNA. Alternative hypotheses for the infectious agent include a conventional virus of unknown type11 or a "virino"- an informational molecule, expected to be a small piece of nucleic acid, which is not encoded in the host and which codes for its own replication and binds to the prion protein12.

2.2.3 To date neither a virus nor a virino nucleic acid has been found and most research has focussed on the PrP molecule. Although progress has been made in understanding the structure, function and role in disease of various forms of PrP, the molecular basis of its suggested infectiousness and how it is propagated have not been described. Nor has normal PrP been converted into an infectious form in a test tube in a laboratory, which would provide a formal proof of the hypothesis.

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2.5.4 Many strains of TSEs, even those that have been biologically cloned by repeated passage within a species, can change their characteristics when transmitted from one species to another. This is perhaps not surprising, if the prion hypothesis is correct, given that different species have PrPCs with different amino acid sequences. BSE has been transmitted to a number of different species either "naturally", through contaminated food, as with cats, exotic ruminants, and humans, or experimentally, through injection or feeding, for example sheep, goats and pigs. Each of these species has a different PrPC, but where it has been tested, the strain characteristics of their BSE-derived TSEs are the same as for BSE from cattle. This "stability" of the BSE strain in different PrP backgrounds challenges the notion that shape of PrP in PrPSc encodes the properties of a strain. The shape that, according to the prion hypothesis, defines the BSE strain must be independent of differences, often large, between the amino acid sequence in PrPC. Alternatively, there may be one or more other molecules (yet to be identified) that associate with PrP to determine the strain properties. Knowing the molecular basis of TSE strains is, therefore, at the heart of understanding the nature of the TSE agent.

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3.3.2.4 The prion protein has not been unequivocally shown to be the infectious agent of TSE disease. Although some work is investigating the correlation between PrPSc and infectivity, using transgenic mouse models, this remains a fundamental gap in knowledge. The unequivocal identification of the TSE agent would have a profound effect on the development of appropriate diagnostic tests. For this reason, the search for a non-PrPSc marker for disease is important. Some work is ongoing in the search for alternative markers, using approaches such as metabolomics and proteomics. These approaches search for consistent differences between control and infected animals at several stages of the incubation period. However, an alternative marker for the detection of the disease has not yet been identified. Further characterisation of different conformers of PrP after digestion with proteases and the development and application of other conformation-dependent techniques for detecting PrPSc may allow a better understanding of the significance of atypical results observed in large-scale surveillance studies.

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3.3.3 Prospects for treatment

3.3.3.1 Current strategies involve screening large pharmaceutical libraries to identify possible therapeutic compounds. However, a better understanding of the structures of prion proteins and their biology could lead to a more targeted approach, allowing the design of small molecules which could block abnormal prion protein formation. Approaches underpinning the development of therapeutics remain a priority for the research councils. The identification of a natural mechanism for clearing infectivity from the body could also be exploited for therapeutic purposes.

3.3.3.2 It seems unlikely that a treatment will become available soon to repair damage to the CNS. The research councils fund work on the generic development of stem cell therapy. However, therapies that seek to repair damaged tissue are far in the future and even then would only be of value once infection had been halted. While several strategies to develop a therapeutic are aimed at inhibiting PrPC to PrPSc conversion, success is likely to be improved by the development of good diagnostics to identify individuals with pre-clinical infection.

3.3.3.3 The development and evaluation of a potential therapy is a detailed process that usually takes many years. In addition to continued support for such work, DH and MRC are establishing the infrastructure for rapid clinical evaluation of any agents that have demonstrated anti-prion activity in animals or in vitro. To this end a clinical trial protocol has been developed in conjunction with families and carers through the Medical Research Council's Prion Unit and Clinical Trials Unit, and building capacity for undertaking such work remains a priority.

53

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3.4.0.7 The possibility of an infectious carrier state in apparently healthy animals and humans highlights our limited knowledge of TSE diseases. Work on TSEs may also produce results that have significance for the understanding of other groups of diseases

54v6.1

such as the neurodegenerative changes involved in Alzheimer’s and other amyloid brain diseases. A full understanding of TSE transmission is likely to require advances in the understanding of the immune system and will provide insights into aspects of human and animal genetic variability. The Research Councils (BBSRC and MRC) support this underpinning biomedical science.

snip...

3.4.2 The MRC has identified the following key areas in which it would like to continue to receive innovative research proposals:


• The biological and epidemiological relationship between CJD and BSE;


• Epidemiological modelling of CJD;


• The analysis, perception and communication of risk in relation to CJD;


• Early disease progression and diagnosis in life including in vivo imaging approaches, with a focus on the development of non-invasive pre-clinical tests for human TSE diseases, particularly vCJD, e.g. a blood test or throat swab;*


• Integrated molecular, epidemiological and clinical approaches to understanding the cause or causes of sporadic CJD and the relationship with atypical dementias;


• Molecular, genetic, cellular and functional approaches to elucidating mechanisms of TSEs transmission, PrP replication, pathogenesis and clinical progression, with a view to improving understanding of how TSEs cause disease, particularly during the very early stages;*


• The biological function of normal prion protein (PrP);*


• The molecular structure of the prion proteins;*


• Development and improvement of animal models and cell culture systems;*


• Development of approaches to reduce secondary (iatrogenic) infection;*


• Rational approaches to developing therapy including vaccine based treatment approaches.*

* Council has approved programmes of work within these areas at the MRC Prion Unit

55

http://www.mrc.ac.uk/pdf-about-tse_uk_strategy_june2005.pdf

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

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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: j.collinge@prion.ucl.ac.uk

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; wall.chris@mayo.edu (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:
"'flounder@wt.net'"

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:

e.asante@ic.ac.uk (until 9/12/02)

New e-mail: e.asante@prion.ucl.ac.uk (active from now)

____________________________________


Human Prion Protein with

Valine 129 Prevents Expression

of Variant CJD Phenotype

Jonathan D. F. Wadsworth, Emmanuel A. Asante,

Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner,

Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd,

Andrew F. Hill,* Sebastian Brandner, John Collinge.

Variant Creutzfeldt-Jakob disease (vCJD) is a unique
and highly distinctive

clinicopathological and molecular phenotype of human
prion disease

associated with infection with bovine spongiform
encephalopathy (BSE)-like

prions. Here, we found that generation of this
phenotype in transgenic mice

required expression of human prion protein (PrP) with
methionine 129.

Expression of human PrP with valine 129 resulted in a
distinct phenotype and,

remarkably, persistence of a barrier to transmission of
BSE-derived prions on

subpassage. Polymorphic residue 129 of human PrP
dictated propagation of

distinct prion strains after BSE prion infection. Thus,
primary and secondary

human infection with BSE-derived prions may result in
sporadic CJD-like or

novel phenotypes in addition to vCJD, depending on the
genotype of the prion

source and the recipient.

snip...

3 DECEMBER 2004 VOL 306 SCIENCE

http://www.sciencemag.org


Characterization of two distinct prion strains

derived from bovine spongiform encephalopathy

transmissions to inbred mice

Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais,

Susan Joiner, Jennifer Buckell, Sebastian Brandner,

Jonathan D. F. Wadsworth and John Collinge

Correspondence

John Collinge

j.collinge@prion.ucl.ac.uk

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: salvatore.monaco@mail.univr.it .

www.pnas.org/cgi/doi/10.1073/pnas.0305777101

snip...

Phenotypic Similarities Between BASE and sCJD. The
transmissibility

of CJD brains was initially demonstrated in primates
(27), and

classification of atypical cases as CJD was based on
this property

(28). To date, no systematic studies of strain typing
in sCJD have

been provided, and classification of different subtypes
is based

on clinical, neuropathological, and molecular features
(the polymorphic

PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19).

The importance of molecular PrPSc characterization in
assessing

the identity of TSE strains is underscored by several
studies,

showing that the stability of given disease-specific
PrPSc types is

maintained upon experimental propagation of sCJD, familial

CJD, and vCJD isolates in transgenic PrP-humanized mice (8,

29). Similarly, biochemical properties of BSE- and
vCJDassociated

PrPSc molecules remain stable after passage to mice

expressing bovine PrP (30). Recently, however, it has been

reported that PrP-humanized mice inoculated with BSE
tissues

may also propagate a distinctive PrPSc type, with a
''monoglycosylated-

dominant'' pattern and electrophoretic mobility of the

unglycosylated fragment slower than that of vCJD and
BSE (31).

Strikingly, this PrPSc type shares its molecular
properties with the

a PrPSc molecule found in classical sCJD. This
observation is at

variance with the PrPSc type found in MV2 sCJD cases and in

cattle BASE, showing a monoglycosylated-dominant
pattern but

faster electrophoretic mobility of the
protease-resistant fragment

as compared with BSE. In addition to molecular properties

of PrPSc, BASE and MV2 sCJD share a distinctive pattern of

intracerebral PrP deposition, which occurs as
plaque-like and

amyloid-kuru plaques. Differences were, however,
observed in

the regional distribution of PrPSc. While inMV2 sCJD
cases the

largest amounts of PrPSc were detected in the cerebellum,

brainstem, and striatum, in cattle BASE these areas
were less

involved and the highest levels of PrPSc were recovered
from the

thalamus and olfactory regions.

In conclusion, decoding the biochemical PrPSc signature of

individual human and animal TSE strains may allow the
identification

of potential risk factors for human disorders with

unknown etiology, such as sCJD. However, although BASE and

sCJD share several characteristics, caution is dictated
in assessing

a link between conditions affecting two different mammalian

species, based on convergent biochemical properties of
diseaseassociated

PrPSc types. Strains of TSE agents may be better

characterized upon passage to transgenic mice. In the
interim

until this is accomplished, our present findings
suggest a strict

epidemiological surveillance of cattle TSE and sCJD
based on

molecular criteria.

http://www.pnas.org/cgi/reprint/0305777101v1

Published online before print March 20, 2001,
10.1073/pnas.041490898

Neurobiology
Adaptation of the bovine spongiform encephalopathy
agent to primates and comparison with Creutzfeldt-
Jakob disease: Implications for human health
Corinne Ida Lasmézas*,, Jean-Guy Fournier*, Virginie
Nouvel*, Hermann Boe*, Domíníque Marcé*, François
Lamoury*, Nicolas Kopp, Jean-Jacques Hauw§, James
Ironside¶, Moira Bruce, Dominique Dormont*, and
Jean-Philippe Deslys*

* Commissariat à l'Energie Atomique, Service de
Neurovirologie, Direction des Sciences du
Vivant/Département de Recherche Medicale, Centre de
Recherches du Service de Santé des Armées 60-68, Avenue
du Général Leclerc, BP 6, 92 265 Fontenay-aux-Roses
Cedex, France; Hôpital Neurologique Pierre Wertheimer,
59, Boulevard Pinel, 69003 Lyon, France; § Laboratoire
de Neuropathologie, Hôpital de la Salpêtrière, 83,
Boulevard de l'Hôpital, 75013 Paris, France; ¶
Creutzfeldt-Jakob Disease Surveillance Unit, Western
General Hospital, Crewe Road, Edinburgh EH4 2XU, United
Kingdom; and Institute for Animal Health,
Neuropathogenesis Unit, West Mains Road, Edinburgh EH9
3JF, United Kingdom

Edited by D. Carleton Gajdusek, Centre National de la
Recherche Scientifique, Gif-sur-Yvette, France, and
approved December 7, 2000 (received for review October
16, 2000)


Abstract


There is substantial scientific evidence to support the
notion that bovine spongiform encephalopathy (BSE) has
contaminated human beings, causing variant
Creutzfeldt-Jakob disease (vCJD). This disease has
raised concerns about the possibility of an iatrogenic
secondary transmission to humans, because the
biological properties of the primate-adapted BSE agent
are unknown. We show that (i) BSE can be transmitted
from primate to primate by intravenous route in 25
months, and (ii) an iatrogenic transmission of vCJD to
humans could be readily recognized pathologically,
whether it occurs by the central or peripheral route.
Strain typing in mice demonstrates that the BSE agent
adapts to macaques in the same way as it does to humans
and confirms that the BSE agent is responsible for vCJD
not only in the United Kingdom but also in France. The
agent responsible for French iatrogenic growth
hormone-linked CJD taken as a control is very different
from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate. These data
will be key in identifying the origin of human cases of
prion disease, including accidental vCJD transmission,
and could provide bases for vCJD risk assessment.

snip...

Characterization of the CJD and Scrapie Strains.
Controls were set up by transmitting one French and one
U.S. scrapie isolate from ruminants as well as French
sCJD and iCJD cases from humans. None of these revealed
a lesion profile or transmission characteristics
similar or close to those of BSE or vCJD, respectively,
thus extending to the present French scrapie isolate
the previous observation that the BSE agent was
different from all known natural scrapie strains (4, 24).

The lesion profiles of sCJD and iCJD differed only
slightly in severity of the lesions, but not in shape
of the profile, revealing the identity of the causative
agents. One of us reported the absence of similarity
between sCJD (six cases) and U.K. scrapie (eight cases)
in transmission characteristics in mice (4). Herein, we
made the striking observation that the French natural
scrapie strain (but not the U.S. scrapie strain) has
the same lesion profile and transmission times in
C57BL/6 mice as do the two human TSE strains studied.
This strain "affiliation" was confirmed biochemically.
There is no epidemiological evidence for a link between
sheep scrapie and the occurrence of CJD in humans (25).
However, such a link, if it is not a general rule,
would be extremely difficult to establish because of
the very low incidence of CJD as well as the existence
of different isolates in humans and multiple strains in
scrapie. Moreover, scrapie is transmissible to nonhuman
primates (26). Thus, there is still a possibility that
in some instances TSE strains infecting humans do share
a common origin with scrapie, as pointed out by our
findings.

snip...

http://www.pnas.org/cgi/content/full/041490898v1


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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract


NOTES

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.

snip...

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

0022-538X/05/$08.00!0
doi:10.1128/JVI.79.21.13794-13796.2005

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

=============================================


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

http://www.neurology.org/cgi/eletters/60/2/176#535

LANCET INFECTIOUS DISEASE JOURNAL


Volume 3, Number 8 01 August 2003


Newsdesk


Tracking spongiform encephalopathies in North America


http://infection.thelancet.com/journal/journal.isa

BMJ

http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2

BMJ

http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1


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