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From: TSS ()
Subject: Clinical features and diagnosis of dura mater graft–associated Creutzfeldt–Jakob disease
Date: July 26, 2007 at 8:44 am PST

NEUROLOGY 2007;69:360-367
© 2007 American Academy of Neurology

Clinical features and diagnosis of dura mater graft–associated
Creutzfeldt–Jakob disease

M. Noguchi-Shinohara, MD, T. Hamaguchi, MD, PhD, T. Kitamoto, MD, PhD, T.
Sato, MD, PhD, Y. Nakamura, MD, MPH, FFPH, H. Mizusawa, MD, PhD and M.
Yamada, MD, PhD
From the Department of Neurology and Neurobiology of Aging (M.N.-S., T.H.,
M.Y.), Kanazawa University Graduate School of Medical Science, Kanazawa;
Department of Prion Protein Research, Division of CJD Science and Technology
(T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of
Neurology (T.S.), Higashi-Yamato Hospital, Higashiyamato; Department of
Public Health (Y.N.), Jichi Medical University, Shimotsuke; Department of
Neurology and Neurological Science (H.M.), Graduate School, Tokyo Medical
and Dental University, Tokyo; and the Creutzfeldt–Jakob Disease Surveillance
Committee (T.K., T.S., Y.N., H.M., M.Y.), Japan.

Address correspondence and reprint requests to Professor Masahito Yamada,
Department of Neurology and Neurobiology of Aging, Kanazawa University
Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8640,

Background: A subset of patients with dura mater graft–associated
Creutzfeldt–Jakob disease (dCJD) demonstrates atypical clinical features and
plaque formation in the brain (plaque type).

Objective: To elucidate the frequency and clinical features of plaque type
dCJD in comparison with the non-plaque type.

Methods: We analyzed clinicopathologic findings of 66 patients who had been
registered as having dCJD by the Creutzfeldt–Jakob Disease Surveillance
Committee, Japan, between April 1999 and February 2006.

Results: 1) Analysis of pathologically confirmed dCJD patients (n = 23)
demonstrated plaque type dCJD in 11 patients (48%). In contrast to the
non-plaque type with classic CJD features, the plaque type commonly
presented with ataxic gait as an initial manifestation, relatively slow
progression of neurologic symptoms, and no or late occurrence of periodic
sharp-wave complexes (PSWCs) on EEG. MRI, especially diffusion-weighted
images, and CSF 14-3-3 protein and neuron specific enolase (NSE) showed high
diagnostic sensitivities for plaque as well as non-plaque types. 2) Analysis
of clinically diagnosed dCJD patients (n = 34) demonstrated that 7 patients
(21%) had atypical clinical features without PSWCs, probably corresponding
to plaque type dCJD.

Conclusion: The frequency of the plaque type in dura mater graft–associated
Creutzfeldt–Jakob disease is apparently higher than previously recognized.
For the clinical diagnosis of the plaque type dura mater graft–associated
Creutzfeldt–Jakob disease, MRI and CSF markers would be useful, in addition
to the core features, i.e., onset with ataxic gait disturbance, relatively
slow progression, and no or late occurrence of periodic sharp-wave complexes
on EEG.


Disclosure: The authors report no conflicts of interest.

Received October 20, 2006. Accepted in final form February 27, 2007.

Human Prion Protein V129 Prevents Expression of Variant CJD Phenotype
Jonathan D.F.Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan
Joiner, Ian Gowland, JulieWelch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,
* Sebastian Brandner, John
MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National
Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
*Present address: Department of Biochemistry and Molecular Biology and Department of Pathology, University of Melbourne,
Parkville, Victoria 3010, Australia.
†To whom correspondence should be addressed. E-mail:
Variant CJD (vCJD) is a unique and highly distinctive
clinicopathological and molecular phenotype of human
prion disease associated with infection with BSE-like
prions. Here we found that generation of this phenotype
in transgenic mice required expression of human PrP 129
methionine. Expression of human PrP 129 valine resulted
in a distinct phenotype and, remarkably, persistence of a
barrier to transmission of BSE-derived prions on subpassage.
Polymorphic residue 129 of human prion protein
dictated propagation of distinct prion strains following
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


While caution must be exercised extrapolating from
animal models, even where, as here, faithful recapitulation of
molecular and pathological phenotypes is possible, our
findings argue that primary human BSE prion infection, and
secondary infection with vCJD prions by iatrogenic routes,
may not be restricted to a single disease phenotype. These
data, together with the recent recognition of probable
iatrogenic transmission of vCJD prions to recipients of blood
(21, 22), including a PRNP codon 129 MV heterozygote
individual (22), reiterate the need to stratify all human prion
disease patients by PrPSc type. This surveillance will facilitate
rapid recognition of novel PrPSc types and any change in
relative frequencies of particular PrPSc sub-types in relation to
either BSE exposure patterns or iatrogenic sources of vCJD

The EMBO Journal (2002) 21, 6358–6366, doi: 10.1093/emboj/cdf653

BSE prions propagate as either variant CJD-like or sporadic CJD-like prion
strains in transgenic mice expressing human prion protein

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 Collinge

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of
Neurology, University College, Queen Square, London WC1N 3BG, UK

To whom correspondence should be addressed
John Collinge,

Received 1 August 2002; Revised 24 September 2002; Accepted 17 October 2002.


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 BSE-derived 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.

Keywords: BSE, Creutzfeldt-Jakob disease, prion, transgenic



Prion propagation involves recruitment and conversion of host PrPC into
PrPSc, and the degree of primary structural similarity between inoculated
PrPSc and host PrPC is thought to be a key component of intermammalian
transmission barriers (Prusiner et al., 1990). It is clear, however, that
prion strain type can also be crucial, as clearly demonstrated by the very
distinctive transmission properties of sporadic CJD 129MM and vCJD 129MM
prions (of identical PrP primary structure) in either 129VV Tg152 (Hill et
al., 1997; Collinge, 1999) or 129MM Tg35 mice. Prion strain type may also
affect transmission barriers via an effect on PrPSc tertiary structure and
state of aggregation (Hill et al., 1997; Collinge, 1999).

These 129MM Tg35 mice, in which human PrPSc types can be propagated, have
been used to study the BSE-to-human species barrier. The frequent presence
of sub-clinical prion disease in vCJD- and BSE-inoculated 129MM Tg35 mice
further argues for the need to reassess current definitions of 'species' or
transmission barriers that limit prion transmission between different hosts
(Hill et al., 2000). Such barriers have hitherto been quantitated on the
basis of either comparative end-point titrations in the two respective
hosts, or by measuring the fall in incubation period between primary and
subsequent passage as the prion strain adapts to the new host. Both methods
rely on measurement of time to onset of a clinical syndrome. Modelling the
BSE-to-human barrier in 129MM Tg35 mice would lead to the conclusion, on the
basis of induced clinical disease, that a substantial barrier existed. How
ever, it is clear that human PrPSc propagation can be efficiently induced by
inoculation with BSE or vCJD prions, suggesting a smaller barrier to
infection (but not to clinical disease) than hitherto thought (Collinge et
al., 1995) in humans of the PRNP 129MM genotype. Humans infected with BSE
prions, but who became asymptomatic carriers, may nevertheless pose a threat
of iatrogenic transmission via medical and surgical procedures.
Alternatively, it is possible that the lifespan of the laboratory mouse is
insufficient to allow expression of clinical disease in most inoculated
mice, whereas a higher proportion of infected humans might survive the
incubation period to develop clinical signs of disease. Serial passage
studies and titration of prions in these mice are in progress to study this

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 florid PrP plaques, can be recapitulated
on BSE or vCJD transmission to these mice. However, the most surprising
aspect of the studies was the finding 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 sub-type of sporadic
CJD. This finding 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 stratification 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 sub-types in both BSE-affected and unaffected countries in the
light of these findings. If human BSE prion infection can result in
propagation of type 2 PrPSc, it would be expected that such cases would be
indistinguishable on clinical, pathological and molecular criteria from
classical CJD. It may also be expected that such prions would behave
biologically like those isolated from humans with sporadic CJD with type 2
PrPSc. The transmission properties of prions associated with type 2 PrPSc
from BSE-inoculated 129MM Tg35 mice are being investigated by serial

We consider these data inconsistent with contamination of some of the 129MM
Tg35 mice with sporadic CJD prions. These transmission studies were
performed according to rigorous biosafety protocols for preparation of
inocula and both the inoculation and care of mice, which are all uniquely
identified 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 findings 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 flocks. 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.


We describe a 47 year old patient who developed pathology proven CJD 38 years after hGH injections. The patient was never treated with hGH but received a small dose as part of a diagnostic procedure. The onset of CJD was signalled by prodromal symptoms of paraesthesia followed by a rapidly progressive ataxia. The disease presentation and course with predominantly cerebellar and eye movement disorders are compatible with iatrogenic CJD caused by hGH treatment.6 8

spontaneous, or sourced ?

Date: July 22, 2007

By Terry S. Singeltary Sr.



1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.





MARCH 26, 2003

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?

Copyright © 2003 Published by Elsevier Ltd.

Tracking spongiform encephalopathies in North America

Xavier Bosch

Available online 29 July 2003.

Volume 3, Issue 8, August 2003, Page 463

“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my
mom to hvCJD (Heidenhain variant CJD)
and have been searching for answers ever since. What I have found is that we
have not been told the truth. CWD
in deer and elk is a small portion of a much bigger problem.”


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