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From: TSS ()
Subject: Father of vCJD victim criticises Harney IRELAND
Date: January 15, 2006 at 8:17 am PST

Father of vCJD victim criticises Harney

By Evelyn Ring
THE father of one of the Irish victims of the human form of mad cow disease yesterday criticised Health Minister Mary Harney for "brushing aside" their plea for compensation for the families involved.

At an inquest into the death of Mr Robert Moran's 24-year-old son, Jason, the coroner raised the possibility of a cluster of vCJD victims.

Dublin County Coroner, Kieran Geraghty, revealed that the only three Irish vCJD victims lived or had family within five miles of each other and called for a State investigation into his discovery.

Mr Moran from Shankill, Co Dublin, said he met with the Tánaiste last September, two months after the death of his son and asked her to provide funding for the victims' families.

He said the minister told him that the State was not responsible for the deaths of the vCJD victims because of safeguards that had been put in place in 1990.

"I had asked her to put in place some form of funding for the families involved but she just brushed it aside," he said.

Mr Moran said his son, like the rest of the family, ate the same meals - meat and vegetables that came from two local supermarkets, and had never spent time in Britain.

A spokesperson for Ms Harney said the Irish situation differed fundamentally from that in Britain, where there was a compensation scheme.

"There is no firm evidence to date on the source of infection in the Irish cases," he said and added that the situation was under constant review by the relevant public health experts.

Consultant neurologist, Dr Michael Hutchinson, said that while it was likely the very first victim to die from vCJD had contracted the disease in Britain, the other two appeared to be indigenous cases.

Asked about the cluster of vCJD victims identified by the coroner, Dr Hutchinson said that while it was probably a coincidence that two of the indigenous cases occurred close to each other the matter should still be investigated even if it turned out to be unproductive.

Dr Hutchinson said it was most likely that Irish BSE was responsible for two of the vCJD cases. "Any public health concerns should be addressed," he stressed.

Dr Hutchinson said the number of vCJD cases had levelled off and it seemed most unlikely that there would be an epidemic. Ireland, however, could expect to see one or two more cases over the next 10 years.

He said experts agreed humans developed vCJD as a result of eating the meat of an animal that had Bovine Spongiform Encephalopathy (BSE) and, as yet, there was no evidence of any effective therapy.


Q: What is Variant Creutzfeldt-Jakob disease (vCJD)?

A: It is a rare and fatal human disease that causes the brain to waste away. It was first described in March 1996 and linked with eating meat from cattle affected by so-called "mad cow" disease.

Q: What is the disease's incubation period?

A: Believed to be eight to 10 years.

Q: How are people affected by the disease?

A: Early psychiatric symptoms most commonly take the form of depression and less often a schizophrenia-like psychosis. Other symptoms include unsteadiness, difficulty walking and involuntary movements. By the time of death, patients are completely immobile and mute.

Q: What is the State doing to protect consumers?

A: The Food Safety Authority of Ireland say controls in place in Ireland since 1996 are very strict and there are robust controls to ensure maximum consumer protection in relation to BSE.

No change in blood policy after vCJD

by Donal Bergin
Dublin County Coroner Dr Kieran Geraghty’s call for a vCJD “cluster” investigation will not alter the Blood Bank’s safeguards against vCJD, its medical chief has said.

Dr Geraghty last week returned a verdict of misadventure at an inquest into the death of Mr Jason Moran from Shankill, Dublin, who died last June from vCJD.

Mr Moran’s family and another man with vCJD live within a few miles of each other, as do relations of a woman who is thought to have acquired the disease in the UK.

But it would be almost impossible to be find the source of infection for a variety of reasons, National Medical Director of the Irish Blood Transfusion Service Dr William Murphy told IMN.

Meanwhile, Dr Murphy said clinical trials were underway in Irish hospitals on a new vCJD prion filter for red cells. He said it hoped to roll out the filter later on this year.

Dr Murphy said the initial part of the trial, which started last month, involved around 60 patients, and the second phase would involve a significant expansion of the testing.


lets look at these questions and answers again with more modern up to date science;


Q: What is Variant Creutzfeldt-Jakob disease (vCJD)?

A: It is a rare and fatal human disease that causes the brain to waste away. It was first described in March 1996 and linked with eating meat from cattle affected by so-called "mad cow" disease. ...

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

disease in the United States

Email Terry S. Singeltary:

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

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

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

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

phenotype that is indistinguishable from type 2 PrPSc, the commonest

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

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

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

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

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

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

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

intracerebral inoculation. With the known incubation periods in other

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

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

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

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

should be drastic measures to safeguard the medical and surgical arena

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

CJDs in the USA are type 2 PrPSc?

-------- 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, LONDON W2 1PG

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

New e-mail: (active from now)



full text ;

AND the new findings of BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic

Creutzfeldt-Jakob disease

Adaptation of the bovine spongiform encephalopathy agent to primates
and comparison with Creutzfeldt- Jakob disease: Implications for
human health

THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*,
Virginie Nouvel*,

Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger

] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique

Dormont*, and Jean-Philippe Deslys* et al, that 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;

Characterization of two distinct prion strains
derived from bovine spongiform encephalopathy
transmissions to inbred mice

Q: What is the disease's incubation period?

A: Believed to be eight to 10 years. ...

Predictability of the UK Variant


Disease Epidemic

Jerome N. Huillard dÕAignaux,* Simon N. Cousens, Peter G. Smith

Back-calculation analysis of the variant Creutzfeldt-Jakob disease epidemic in

the United Kingdom is used to estimate the number of infected individuals and

future disease incidence. The model assumes a hazard of infection proportional

to the incidence of bovine spongiform encephalopathy in the United Kingdom

and accounts for precautionary control measures and very wide ranges of

incubation periods. The model indicates that current case data are compatible

with numbers of infections ranging from a few hundred to several millions. In

the latter case, the model suggests that the mean incubation period must be

well beyond the human life-span, resulting in disease epidemics of at most

several thousand cases.

Variant Creutzfeldt-Jakob disease (vCJD) is

caused by an agent that is currently indistinguishable

from that responsible for bovine

spongiform encephalopathy (BSE) in cattle.

However, 5 years after the identification of

vCJD, great uncertainty remains over how

many individuals have been infected with the

agent and how many of these individuals will

go on to develop clinical disease (1–5).

In the absence of a test for infection, one

approach to estimating the number of infected

individuals is provided by back-calculation,

a statistical technique developed in the

context of the HIV/AIDS (human immunodeficiency

virus/acquired immunodeficiency

syndrome) epidemic (6, 7). This approach

makes use of the fact that the number and

timing of cases of disease that occur depend

on three factors: (i) how many people were

infected, (ii) when they were infected, and

(iii) how long it takes from infection for

disease to become apparent—the incubation

period. To use this approach to estimate the

number of individuals infected with the vCJD

agent, it is necessary to make assumptions

about when people were exposed to infection

and how long it takes them to develop disease.

Previous work has shown that the estimated

number of infections/cases produced

by this approach is very sensitive to the assumptions

made about the incubation period

distribution (2, 8, 9).

We have developed a family of backcalculation

models (10) to explore the prevalence

of infection with the vCJD agent and

the incidence of clinical vCJD in the UK. The

main features of these models are as follows:

(i) The hazard of infection was assumed to

have been proportional to the incidence of

BSE (11). We did not consider onward, human-

to-human transmission of the infectious

agent. (ii) The incubation period of the disease

was assumed to follow an offset generalized

F distribution, which has five parameters.

We also investigated the lognormal,

Weibull, and gamma distributions as special

cases of this distribution (12). (iii) We assumed

that the incubation period was independent

of age at infection (13). (iv) The

model was restricted to the 40% (approximately)

of the UK population assumed to be

methionine homozygous at codon 129 of the

prion protein (PrP) gene. (All cases of vCJD

identified to date have been of this genotype.)

(v) To minimize the impact of reporting delays,

we fitted the models to the data on the

82 cases with onsets before 2000 that had

been identified by 31 December 2000.

The back-calculation model had seven

parameters in total [five for the incubation

period distribution, one for the hazard of

infection, and one for the effect of the

specified bovine offals (SBO) ban in 1989].

The model was fitted by the maximum

likelihood method, assuming a Poisson

likelihood. Because of a very severe parameter

identifiability problem, we estimated

the incubation period distribution parameters

for fixed values of the hazard of infection

(corresponding to total numbers of infections

ranging from 100 to 12 million)

and for fixed effects of the SBO ban ranging

from 0 to 90%. Allowing a very flexible

incubation period distribution (offset generalized

F), we found that the cases observed

to date were almost equally compatible

with any number of infections up to

several millions. However, when a very

large number of infections was considered,

the model indicated that the average incubation

period was likely to be extremely

long and, in most instances, well beyond

the normal human life-span. As a result, the

corresponding epidemic sizes (clinical cases)

lay within a much narrower range, from

a few hundred to a few thousand cases

(Table 1).

When making stronger assumptions about

London School of Hygiene and Tropical Medicine,

Infectious Disease Epidemiology Unit, Keppel Street,

London WC1E 7HT, UK.

*To whom correspondence should be addressed. E-mail:

Table 1. Estimates of numbers of infections, numbers of clinical cases, incubation period parameters, and prediction intervals by assumed incubation period (IP)

distribution. Values shown are calculated assuming a SBO ban efÞciency of 80%.


the form of the incubation period distribution

(i.e., reducing the number of parameters from

five), the range for the number of infections

with which the observed cases are compatible

becomes narrower. For example, using a simple

generalized F distribution led to a point

estimate of the total number of infections of a

few hundred, with an upper 95% confidence

limit of about 1000 (and upper 99% confidence

limit of 7000). Using an offset lognormal

distribution again led to a point estimate

of the total number of infections of a few

hundred. The predicted course of the vCJD

epidemic was calculated under different assumptions

about the incubation period distribution

(14). No matter which incubation period

distribution is used, the point estimates

obtained from the model suggest that the

epidemic of cases of vCJD is very close to its

peak. However, the expected numbers of cases

corresponding to the upper limits of infection

(14) indicate that the data are also compatible

with an epidemic whose peak, many

years hence, is determined by mortality

among infected individuals from competing

causes. Table 1 also presents approximate

prediction intervals (15) for annual numbers

of cases at different times in the future. These

indicate that the annual incidence of vCJD is

unlikely ever to be much more than 100 cases


None of our models suggest that the number

of primary cases of vCJD in methionine

homozygotes is likely to be more than a few

thousand, even though the number of primary

infections could be anything from a few hundred

to many thousands or even millions. In

interpreting these results, and extrapolating

them to other codon 129 genotypes, we must

bear in mind our model assumptions. Our key

finding that, regardless of the number of infections

that have occurred, the number of

clinical cases is unlikely to exceed a few

thousand (in any one genotype) is sensitive to

a number of assumptions.

First, we have assumed that in codon 129

methionine homozygotes, the incubation period

for vCJD has a unimodal distribution.

This is a key assumption that is open to

question (16). In mice, there are genetic factors

lying outside the coding region of the PrP

gene that have an important influence on the

incubation period of transmissible spongiform

encephalopathies (17–20). It is possible,

therefore, that among human codon 129 methionine

homozygotes there are other, presently

unknown genetic factors that influence

the vCJD incubation period. We have used

the generalized F distribution, which can take

a wide range of unimodal forms. If, across

the methionine-homozygous population, the

mixture of other genetic factors affecting incubation

period results in an overall incubation

period distribution that is close to unimodal,

we would be confident that, broadly,

our findings with respect to the numbers of

clinical cases hold. If, however, the overall

incubation period distribution is strongly

multimodal, there might be many more clinical

cases of vCJD than our models predict. If

the latter is the case, then the development of

reliable back-calculation models will be possible

only when the relevant genetic factors

have been identified and measured in the

population. Strong multimodality is most

likely to apply if only a small number of other

genetic factors are involved and there was

little variation between infected individuals

in the infecting dose to which they were


Second, we have assumed that the incubation

period distribution does not vary with

age at infection. Experimental evidence in

mice indicates that, for a fixed dose, incubation

period does vary with age at inoculation

(21). However, this variation is small, with

young mice having incubation periods 7 days

longer than older mice, compared with mean

incubation periods of several hundred days. If

vCJD infections occurred through diet, as we

have implicitly assumed, infected individuals

may have been exposed to a very wide range

of infectious doses whose impact on incubation

period is likely to dwarf any small age


Third, to extrapolate from codon 129 methionine

homozygotes to other genotypes, we

need to assume that across codon 129 genotypes

the relation between the mean and the

variance of the incubation period distribution

does not vary greatly. If other genotypes have

longer mean incubation periods but with lower

variance, then we might observe larger

numbers of cases in these genotypes. It is,

however, unusual for the variance of a distribution

to decrease as the mean increases. If

this is not the case, then to extend our results

to include all genotypes one could, as a

worst-case scenario, multiply our predictions

by about 2.5 to obtain a figure for the whole


A further assumption of the model is that

infection was essentially through diet and that

the amount of infectivity consumed in food

during any given period was proportional to

the number of BSE cases occurring up until

1996. In the absence of ongoing human-tohuman

transmission of the vCJD agent, our

findings are likely to be much less sensitive

to this assumption than they are to the assumptions

about incubation period.

The upper limits of our estimates differ

from those presented by Ghani et al. (1).

These authors used simulation to identify a

range of scenarios compatible with the actual

observed incidence. One advantage of this

approach is that it allows the incorporation

into the model of several parameters that

could not be estimated. However, it does not

enable any probability statement to be made

about the coverage of the range of epidemics

that it produces, and running more simulations

can only increase the range of scenarios

that are plausible. We believe the most likely

explanation for the different ranges of cases

coming out of our work and that of Ghani et

al. is that the coverage probabilities of those

intervals are different.

Our models suggest that the number of

primary cases of vCJD in methionine homozygotes

is unlikely to exceed a few thousand,

but that considerably greater uncertainty

surrounds the number of primary vCJD

infections that have occurred. Whether a few

hundred or many more people have been

infected has important consequences for public

health and, in particular, for the risk of

secondary transmission (22). If secondary

transmission does occur, the mean incubation

period in secondary cases may be much

shorter than in primary cases (23). In the

absence of a reliable test for asymptomatic

infection, considerable uncertainty about the

number of infected individuals may remain

for a number of years.

References and Notes


Estimation of Epidemic Size and

Incubation Time Based on Age

Characteristics of vCJD in the

United Kingdom

Alain-Jacques Valleron,1 Pierre-Yves Boelle,1 Robert Will,2

Jean-Yves Cesbron3

The size of the variant Creutzfeldt-Jakob Disease (vCJD) epidemic in the United

Kingdom is a major public health concern and a subject of speculation. The cases

are young (mean age 5 28). Assuming that the risk of developing the disease

in susceptible exposed subjects decreases exponentially with age after age 15,

that all infections occurred between 1980 and 1989, and that the distribution

of the incubation period is lognormal, we estimate that the mean duration of

the incubation period is 16.7 years [95% conÞdence interval (CI): 12.4 to 23.2]

and that the total number of cases will be 205 (upper limit of the 95% CI: 403).


The distribution of the vCJD incubation period

that best fits the data within the framework

of our model has a mean of 16.7 years, with a

standard deviation of 2.6 years. The 95% upper

percentile of this distribution is 21.4 years. The

95% confidence interval (CI) of the estimates of

the mean and standard deviation is relatively

narrow: The 95% CI for the estimate of the

mean incubation period is 12.4 to 23.2 years,

and the 95% CI of the standard deviation is

0.9 to 8 years (10). The decrease in susceptibility

to infection in exposed subjects older

than 15 years, as estimated from the parameter

a, was found to be very sharp: 16% per

year of age (CI: 12 to 23%). This means that,

under the best fitting hypothesis, an individual

aged 20 years in 1981 had 55% less risk

of becoming infected than a child aged 15

years (99.9% for an individual aged 70).

The model predictions fit the past cumulated

incidences, as shown in Fig. 2. Similarly,

there is a good fit to the observed age distribution

(10), as the model predicts that 22 out of

the first 97 diagnosed cases should be less than

20 years of age (19 in the surveillance data set)

and 82 should be less than 40 years of age (87

in the surveillance data set).

Details of the variation in the risk function

(14) with age and time up to 2012 are shown in

Fig. 3: The model predicts that the peak of the

epidemic will be in 2000/2001 and that the

annual number of cases should gradually decrease

after this date. The total number of expected

vCJD cases is, according to our model,

low at 205 cases (upper limit of the 95% CI:

403). One prediction from the model is that in

the next few years, the age distribution will

become bimodal and that the proportion of older

patients will increase.

The model presented here addresses human

infections occurring between 1980 and 1989, as

we assume that the likelihood of new human

infection with BSE after the bovine SRM ban in

1989 should have been considerably reduced.

The strength of the method used in this

report is that it is focused on the most striking

epidemiological characteristic of vCJD, namely,

the age distribution of the cases. In contrast

to other models, which are based primarily on

scenarios related to dietary exposures to BSE in

the United Kingdom, our method does not

make any assumptions about this parameter that

cannot currently be estimated.

To express the necessary dependence between

age and force of infection, we made one

of the most parsimonious choices possible, i.e.,

a function beginning with a plateau during

childhood, followed by an exponential decrease.

The sensitivity analysis in which all possible

alternatives to the 15-year age limit were tested

ruled out an even simpler model with only one

exponential function (age limit 5 0) and found

as the optimal value an age limit of 16. We

have no clear physiological explanation for

this age limit: Although a relation with puberty

may be hypothesized, experimental evidence

should be sought to support such a


The results presented here are based on a

lognormal distribution of the incubation period,

which is commonly used in the epidemiology

of infectious diseases. However, we repeated

the estimation process assuming that the incubation

period was Gamma distributed and

found almost identical values for the incubation

parameters, the future epidemic size of the epidemic,

and the occurrence of a bimodal age

distribution in the future (10).

The incubation time we find for vCJD is

longer than in human growth hormone–related

CJD, which is between 9 and 10 years (15) in

the sensitive homozygous genotypes. It is shorter

than the one estimated in Kuru (16), which

may exceed three decades, although, a priori,

one would have expected a longer value because

in Kuru, there is no species barrier and the

disease was transmitted orally as in vCJD. The

PRNP 129 genotype has a crucial importance in

determining the risk of developing CJD. Yet to

date, all tested vCJD patients have been homozygous

for methionine at codon 129, as are

about 40% of the total UK population. If there

are two subpopulations of vCJD patients, one

with “short” incubation times and methionine

homozygosity, the other with “long” incubation

times and valine homozygosity or heterozygosity,

our method would not identify the second

distribution parameters, because cases of vCJD

with genotypes other than methionine homozygosity

have not yet been identified.

Our age-risk model allows an estimate of the

future size of the epidemic. If we independently

introduce our estimates of the incubation period

in the Ghani or Cousens models, we find similar

“low” predictions: 80 to 630 cases with the

Ghani model and 801 with the Cousens model

(17). In conclusion, our prediction of the epidemic

of vCJD lies in the “optimistic” end of the

ranges of previously published figures, and this

low value is in favor of a large species barrier

between cattle and humans.

References and Notes


SEAC Statement
7th August 2004


Summary of SEAC’s discussion on the second presumed case of blood transfusion-associated infection with vCJD


13. SEAC noted that the patient was heterozygous at codon 129 of the PRNP gene and that this was the first time infection with the vCJD agent had been reported in an individual not methionine homozygous. This indicated that genotypes other than the methionine homozygous were susceptible to infection with the vCJD agent. Uncertainties remain as to the relative susceptibility of heterozygotes to food borne (or other) infection or the possible outcomes of infection. The committee agreed that the similarities between the western blot band analysis and PrPres glycoprofile seen in this case and in cases of vCJD who were methionine homozygous was reassuring with respect to the ability to make the diagnosis of vCJD in those of genotypes other than methionine homozygous.

Early phase of vCJD infection in blood transfusion recipients
Position statement on Early phase of vCJD infection in blood transfusion recipients (31 KB)

Q: How are people affected by the disease?

A: Early psychiatric symptoms most commonly take the form of depression and less often a schizophrenia-like psychosis. Other symptoms include unsteadiness, difficulty walking and involuntary movements. By the time of death, patients are completely immobile and mute. ...

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...end

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)



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 concentrated

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 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


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.



Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157

AJP January 2006, Vol. 168, No. 1 ...TSS
volume=168&issue=1&journalcode=amjpathol Published online October 31, 2005

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

Q: What is the State doing to protect consumers?

A: The Food Safety Authority of Ireland say controls in place in Ireland since 1996 are very strict and there are robust controls to ensure maximum consumer protection in relation to BSE.

Another probable case of variant CJD announced in Ireland

Editorial team (, Eurosurveillance Editorial Office

Another case of probable variant Creutzfeldt-Jakob disease (vCJD) has been identified in Ireland [1]. Three cases of vCJD have now been reported in Ireland, although the first, in 1999, was thought not to be indigenous as the patient had lived in England for several years during the high risk period [2]. If the recent probable case is indigenous, this will be Ireland’s second.
Ireland has the second highest rate of bovine spongiform encephalopathy (BSE) in cattle in the world. In 2003, an expert team at the Irish National CJD Surveillance Unit ( modelled the possible risk to the Irish population based on relative exposure to BSE contaminated meat and infectivity of bovine tissue. Their analysis estimated that one case of vCJD (95% CI:0-15) would be expected [3].

vCJD appears to be transmissible by blood transfusion, as demonstrated by a case in the United Kingdom in 2003 [4]. The patient had donated blood and two patients were treated with different components of this donation. One recipient patient subsequently died shortly afterwards of an unrelated underlying condition. The recipient of the other blood component has been informed [5].

People who spent even just one year in the United Kingdom between 1980 and 1996 have been excluded from giving blood in Ireland since November 2004 (people who spent 5 years in the UK during this time have been barred since 2001, people who spent 3 years since May 2004). All people who ever received a blood transfusion since 1980 were also excluded from donating in May 2004.

Department of Health and Children, Ireland. Probable case of variant CJD. Press release 1 July 2005. (
Birchard. Variant Creutzfeldt-Jakob disease found in Ireland. Lancet 1999; 353: 2221. (
Probable case of indigenous vCJD diagnosed in Ireland. Eurosurveillance Weekly 2004; 8(46): 11/11/2004 (
Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;363:417-21.
Irish Blood Transfusion Service. Press release. 30 June 2005.

There was one case of BSE disclosed in the week-ending Friday, 13TH January 2006, bringing the total number of cases for the year to 5.

Age Profile County Breakdown Herd Type
1 10 years Kilkenny Dairy

The total number of cases in 2005 was 69. This compares with 126 cases for 2004 which represents a year-on-year reduction of 44% in the number of confirmed cases. The equivalent number of cases was 186 in 2003 and 333 cases for the equivalent period in 2002.

This week's case was identified under the active surveillance programme. Under the active surveillance programme, testing of a proportion of fallen stock and cattle destined for human consumption was initiated in July 2000. This was extended in January 2001 to test all cattle over 30 months destined for human consumption and all casualty animals. Since July 2001 all fallen cattle are also tested. Over 2.75 million tests have been carried out up to the end of 2004 under the active surveillance programme (over 662,000 in 2001; over 688,000 in 2002; over 700,000 in 2003 and over 701,000 tests were carried out during 2004). Over 676,000 tests were carried out between January and November 2005.

The underlying trend remains positive and the increasing age profile of animals confirmed with the disease indicates that the enhanced controls introduced in 1996 and early 1997 are proving effective. The effectiveness of Ireland's BSE controls was recognised by the EU's Scientific Steering Committee which indicated, in a report on Ireland's BSE risk published in May 2000, that controls in this country were stable from 1996 onwards, very stable from 1997 onwards, and optimally stable since 1st January, 1998.

The range of controls in place to protect consumers and to eradicate the disease continues to be rigorously enforced. In particular it should be noted that specified risk material is removed fromall cattle slaughtered.

Department of Agriculture and Food
Kildare Street
Dublin 2

BSE in Ireland - Information Note

1: Details of BSE confirmations for week-ending 16th December 2005
Date BSE
suspects Fallen
cattle OTM
cattle Casualty/
slaughter BSE
eradication Totals
Confirmations for 16-12-05 0 3 0 0 0 3

2: Details of BSE Yearly Confirmations
Year Passive Fallen OTM Casualty BSE eradication Totals
1989 15 - - - - 15
1990 14 - - - - 14
1991 17 - - - - 17
1992 18 - - - - 18
1993 16 - - - - 16
1994 19 - - - - 19
1995 16 - - - - 16
1996 73 - - - 1 74
1997 77 - - - 3 80
1998 79 - - - 4 83
1999 91 - - - 4 95
2000 138 7 - - 4 149
2001 123 81 34 4 4 246
2002 108 183 34 4 4 333
2003 40 106 31 4 1 182
2004 31 75 19 0 1 126
2005 9 47 11 1 0 59
Totals 884 499 129 13 26 1551

Ireland's targeted active surveillance programme for BSE began in the year 2000 with the testing of a proportion of fallen stock and a random survey of cattle eligible for human consumption. The initial programme was extended in the year 2001. Since January 1 2001 all cattle over 30 months being slaughtered for human consumption and all casualty animals must be tested for BSE using a so-called rapid test approved by the Scientific Steering Committee of the European Commission. Since 1July, 2001 all cattle greater than 24 months of age which die on farm (so called fallen stock) must be tested for BSE. The results of the active surveillance programme for 2004 and 2005 (January - June) are set out below.

Results for 2004 (01/01/04 to 31/12/04)
Number Final result
Category tested Positive Negative
Fallen cattle 85,300* 69* 85,230*
Casualty/Emergency slaughter 2,313 0 2,313
OTM cattle 605,408 20 605,388
BSE eradication 8,556 1 8,555
BSE suspects 275 31 244
Totals 701,852* 121* ** 701,730*

*One rapid test positive could not be confirmed. Considering other criteria, a suspicion of BSE remains and the herd has been depopulated on a precautionary basis.

**This figure differs from the number of confirmed cases because the confirmed cases total includes cases which were rapid test positive in December 2004, but were confirmed in January 2005.

Results for 2005 (01/01/05 to 31/11/05)
Number Final result
Category tested Positive Negative Pending
Fallen cattle 83,511 39* 83,471 1
Casualty/Emergency slaughter 1,876 1 1,875 0
OTM cattle 586,471 11 586,459 1
BSE eradication 3,919 0 3,919 0
BSE suspects 234 8 226 0
Totals 676,011 59 675,950 2

Definition of categories
Passive: notified to DAF as a BSE suspect
Fallen: animal greater than 24 months of age, which died on farm and was tested as per EU requirements
OTM: healthy animal greater than 30 months of age, which was slaughtered at a meat plant was tested as per EU requirements
Casualty: animals greater than 24 months of with minor injuries etc which are presented for slaughter at meat plants was tested as per EU requirements
BSE eradication: cattle greater than 30 months of age which are slaughtered for BSE reasons because they are either in a herd which is positive for BSE or are a birth cohort or the progeny of a positive animal


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