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From: TSS ()
Subject: Colorado Surveillance Program for Chronic Wasting Disease Transmission to Humans (TWO SUSPECT CASES)
Date: March 13, 2007 at 8:15 am PST

Colorado Surveillance Program for Chronic Wasting Disease Transmission to Humans

Lessons From 2 Highly Suspicious but Negative Cases

C. Alan Anderson, MD; Patrick Bosque, MD; Christopher M. Filley, MD; David B. Arciniegas, MD; B. K. Kleinschmidt-DeMasters, MD; W. John Pape, BS; Kenneth L. Tyler, MD


Arch Neurol. 2007;64:439-441.

Objective To describe 2 patients with rapidly progressive dementia and risk factors for exposure to chronic wasting disease (CWD) in whom extensive testing negated the possible transmission of CWD.

Design/Methods We describe the evaluation of 2 young adults with initial exposure histories and clinical presentations that suggested the possibility of CWD transmission to humans.

Patients A 52-year-old woman with possible laboratory exposure to CWD and a 25-year-old man who had consumed meat from a CWD endemic area.

Interventions Clinical evaluation, neuropathological examination, and genetic testing.

Results Neuropathological and genetic assessment in the 2 patients proved the diagnoses of early-onset Alzheimer disease and a rare genetic prion disease.

Conclusion No convincing cases of CWD transmission to humans have been detected in our surveillance program.


Author Affiliations: Departments of Neurology (Drs Anderson, Bosque, Filley, Arciniegas, Kleinschmidt-DeMasters, and Tyler), Psychiatry (Drs Anderson, Filley, and Arciniegas), Pathology (Dr Kleinschmidt-DeMasters), Medicine (Dr Tyler), Microbiology (Dr Tyler), and Immunology (Dr Tyler); University of Colorado School of Medicine, Denver; Denver Veterans Affairs Medical Center, Denver (Drs Anderson, Filley, Arciniegas, and Tyler); Denver Health Medical Center, Denver (Dr Bosque); and Colorado Department of Public Health and Environment, Denver (Mr Pape).

http://archneur.ama-assn.org/cgi/content/abstract/64/3/439?ct

> Results Neuropathological and genetic assessment in the 2 patients proved the

> diagnoses of early-onset Alzheimer disease and a rare genetic prion disease

very interesting, and something to ponder here for sure ;

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

snip...

http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf

and i think this would apply to CWD to humans as well.

> rare genetic prion disease

would be interesting to know the exact genetic TSE they are speaking of. GSS, FFI, Familial/Genetic CJD, and or the sporadic FFI that is not genetic, and don't ask me why ??? does not make sense to me either. it's either genetic or not. like i have said many times, the diagnostic criteria differentiating the different human and animal TSE is missing something. but if you have a strain of genetic/familial TSE i.e. FFI, and then you classify a sub-type of that strain that use to be gentic to sporadic, then you have either gone back to sCJD, or the complete damn diagnostic criteria is wrong. you just have well named the damn thing ;

Parchi-Capellari-Chin-Schwarz-Schecter-Butts-Hudkins-Burns-Powers-Gambetti-DISEASE. ...TSS

Subject: Alzheimer-type neuropathology in a 28-year old patient with iatrogenic CJD after dural grafting
Date: March 9, 2007 at 9:15 am PST

HUMAN-04

Alzheimer-type neuropathology in a 28-year old patient with iatrogenic

Creutzfeldt-Jakob disease after dural grafting

M Preusser1, T Stroebel1, E Gelpi1, 2, M Eiler3, G Broessner4, E Schmutzhard4, H Budka1, 2

1 Institute of Neurology, Medical University Vienna, Austria; 2 Austrian Reference Centre for Human Prion Diseases

(OERPE), General Hospital Vienna, Austria; 3 Department of Neurology, LKH Rankweil, Austria; 4 Department of

Neurology, Medical University Innsbruck, Austria

We report the autopsy case of a 28-year old male patient who had received a cadaverous dura

mater graft after a traumatic open skull fracture with tearing of dura at the age of 5 years. A

clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months

prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according

to WHO criteria. Immunohistochemistry showed widespread cortical depositions of diseaseassociated

prion protein (PrPsc) in a synaptic pattern and western blot analysis identified PrPsc of

type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and

cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid

was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for

diagnosis of definite Alzheimer´s disease (AD) were met in the absence of neurofibrillar tangles

or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any

other neurological disease, and genetic analysis showed no disease-specific mutations of the

prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents 1. the

iCJD case with the longest incubation time after dural grafting reported so far, 2. the youngest

documented patient with concomitant CJD and Alzheimer-type neuropathology to date, 3. the

first description of Alzheimer type-changes in iCJD, and 4. the second case of iCJD in Austria.

Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly

related to the childhood trauma.


249 of 411 pages...tss


http://www.tse-forum.de/tse_forum/deutsch/oeffentlich/bilder/Abstract_BookFINAL_nov2.pdf

some other things to ponder ;

Alzheimer's and Transmissible Spongiform Encephalopathies

http://neurotalk.psychcentral.com/showthread.php?t=13175

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COMMENTS:
I wish to submit the following ;

HUMAN and ANIMAL TSE Classifications i.e. mad cow
disease and the UKBSEnvCJD only theory

TSEs have been rampant in the USA for decades in many
species, and they all have been rendered and fed back
to animals for human/animal consumption. I propose that
the current diagnostic criteria for human TSEs only
enhances and helps the spreading of human TSE from the
continued belief of the UKBSEnvCJD only theory in 2005.
With all the science to date refuting it, to continue
to validate this myth, will only spread this TSE agent
through a multitude of potential routes and sources
i.e. consumption, surgical, blood, medical, cosmetics
etc. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis,
Marsh, et al and many more, that the world of TSE
Tranmissible Spongiform Encephalopathy is far from an
exact science, but there is enough proven science to
date that this myth should be put to rest once and for
all, and that we move forward with a new classification
for human and animal TSE that would properly identify
the infected species, the source species, and then the
route. This would further have to be broken down to
strain of species and then the route of transmission
would further have to be broken down. Accumulation and
Transmission are key to the threshold from subclinical
to clinical disease, and of that, I even believe that
physical and or blunt trauma may play a role of onset
of clinical symptoms in some cases, but key to all
this, is to stop the amplification and transmission of
this agent, the spreading of, no matter what strain.
BUT, to continue with this myth that the U.K. strain of
BSE one strain in cows, and the nv/v CJD, one strain in
humans, and that all the rest of human TSE is one
single strain i.e. sporadic CJD (when to date there are
6 different phenotypes of sCJD), and that no other
animal TSE transmits to humans, to continue with this
masquerade will only continue to spread, expose, and
kill, who knows how many more in the years and decades
to come. ONE was enough for me, My Mom, hvCJD, DOD
12/14/97 confirmed, which is nothing more than another
mans name added to CJD, like CJD itself, Jakob and
Creutzfeldt, or Gerstmann-Straussler-Scheinker
syndrome, just another CJD or human TSE, named after
another human. WE are only kidding ourselves with the
current diagnostic criteria for human and animal TSE,
especially differentiating between the nvCJD vs the
sporadic CJD strains and then the GSS strains and also
the FFI fatal familial insomnia strains or the ones
that mimics one or the other of those TSE? Tissue
infectivity and strain typing of the many variants of
the human and animal TSEs are paramount in all variants
of all TSE. There must be a proper classification that
will differentiate between all these human TSE in order
to do this. With the CDI and other more sensitive
testing coming about, I only hope that my proposal will
some day be taken seriously.


My name is Terry S. Singeltary Sr. and I am no
scientist, no doctor and have no PhDs, but have been
independently researching human and animal TSEs since
the death of my Mother to the Heidenhain Variant of
Creutzfeldt Jakob Disease on December 14, 1997
'confirmed'. ...TSS


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518

SOURCES


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


http://jama.ama-assn.org/


Coexistence of multiple PrPSc types in individuals with

Creutzfeldt-Jakob disease


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


Summary


Background The molecular typing of sporadic
Creutzfeldt-Jakob disease (CJD) is based on the size
and glycoform

ratio of protease-resistant prion protein (PrPSc), and
on PRNP haplotype. On digestion with proteinase K, type
1 and

type 2 PrPSc display unglycosylated core fragments of
21 kDa and 19 kDa, resulting from cleavage around amino

acids 82 and 97, respectively.

Methods We generated anti-PrP monoclonal antibodies to
epitopes immediately preceding the differential proteinase

K cleavage sites. These antibodies, which were
designated POM2 and POM12, recognise type 1, but not
type 2, PrPSc.

Findings We studied 114 brain samples from 70 patients
with sporadic CJD and three patients with variant CJD.

Every patient classified as CJD type 2, and all variant
CJD patients, showed POM2/POM12 reactivity in the

cerebellum and other PrPSc-rich brain areas, with a
typical PrPSc type 1 migration pattern.

Interpretation The regular coexistence of multiple
PrPSc types in patients with CJD casts doubts on the
validity of

electrophoretic PrPSc mobilities as surrogates for
prion strains, and questions the rational basis of
current CJD

classifications.


snip...


The above results set the existing CJD classifications

into debate and introduce interesting questions about

human CJD types. For example, do human prion types

exist in a dynamic equilibrium in the brains of affected

individuals? Do they coexist in most or even all CJD

cases? Is the biochemically identified PrPSc type simply

the dominant type, and not the only PrPSc species?


Published online October 31, 2005


http://neurology.thelancet.com

Detection of Type 1 Prion Protein in Variant

Creutzfeldt-Jakob Disease

Helen M. Yull,* Diane L. Ritchie,*

Jan P.M. Langeveld,? Fred G. van Zijderveld,?

Moira E. Bruce,? James W. Ironside,* and

Mark W. Head*

From the National CJD Surveillance Unit,* School of
Molecular

and Clinical Medicine, University of Edinburgh, Edinburgh,

United Kingdom; Central Institute for Animal Disease
Control

(CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute
for Animal

Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom

Molecular typing of the abnormal form of the prion

protein (PrPSc) has come to be regarded as a powerful

tool in the investigation of the prion diseases. All
evidence

thus far presented indicates a single PrPSc molecular

type in variant Creutzfeldt-Jakob disease (termed

type 2B), presumably resulting from infection with a

single strain of the agent (bovine spongiform
encephalopathy).

Here we show for the first time that the PrPSc

that accumulates in the brain in variant Creutzfeldt-

Jakob disease also contains a minority type 1 component.

This minority type 1 PrPSc was found in all 21

cases of variant Creutzfeldt-Jakob disease tested,
irrespective

of brain region examined, and was also

present in the variant Creutzfeldt-Jakob disease tonsil.

The quantitative balance between PrPSc types was maintained

when variant Creutzfeldt-Jakob disease was

transmitted to wild-type mice and was also found in

bovine spongiform encephalopathy cattle brain, indicating

that the agent rather than the host specifies their

relative representation. These results indicate that PrPSc

molecular typing is based on quantitative rather than

qualitative phenomena and point to a complex relationship

between prion protein biochemistry, disease phenotype

and agent strain. (Am J Pathol 2006, 168:151-157;

DOI: 10.2353/ajpath.2006.050766)


snip...


Discussion

In the apparent absence of a foreign nucleic acid genome

associated with the agents responsible for transmissible

spongiform encephalopathies or prion diseases,

efforts to provide a molecular definition of agent strain

have focused on biochemical differences in the abnormal,

disease-associated form of the prion protein, termed

PrPSc. Differences in PrPSc conformation and glycosylation

have been proposed to underlie disease phenotype

and form the biochemical basis of agent strain. This

proposal has found support in the observation that the

major phenotypic subtypes of sCJD appear to correlate

with the presence of either type 1 or type 2 PrPSc in

combination with the presence of either methionine or

valine at codon 129 of the prion protein gene.2 Similarly,

the PrPSc type associated with vCJD correlates with the

presence of type 2 PrPSc and is distinct from that found in

sCJD because of a characteristically high occupancy of

both N-linked glycosylation sites (type 2B).6,11 The

means by which such conformational difference is detected

is somewhat indirect; relying on the action of proteases,

primarily proteinase K, to degrade the normal

Figure 6. Type 1 PrPSc is a stable minority component
of PrPSc from the vCJD

brain. Western blot analysis of PrP in a sample of
cerebral cortex from a
case

of vCJD during digestion with proteinase K is shown.
Time points assayed

are indicated in minutes (T0, 5, 10, 30, 60, 120, 180).
Duplicate blots were

probed with 3F4, which detects both type 1 and type 2
PrPSc, and with 12B2,

which detects type 1. The insert shows a shorter
exposure of the same time

course study from a separate experiment also probed
with 3F4. Both blots

included samples of cerebral cortex from a case of
sporadic CJD MM1 (Type

1) and molecular weight markers (Markers) indicate
weights in kd.

Figure 7. A minority type 1-like PrPSc is found in vCJD
tonsil, vCJD
transmitted

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

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

of a wild-type mouse (C57BL) infected with vCJD and in
a sample of cattle

BSE brain (BSE) is shown. Tissue extracts were digested
with proteinase K.

Duplicate blots were probed with either 3F4 or 6H4,
both of which detect

type 1 and type 2 PrPSc, and with 12B2, which detects
type 1. The blots

included samples of cerebral cortex from a case of
sporadic CJD MM1 (Type

1) and molecular weight markers (Markers) indicate
weights in kd.

Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155

AJP January 2006, Vol. 168, No. 1

cellular form of PrP and produce a protease-resistant

core fragment of PrPSc that differs in the extent of its

N-terminal truncation according to the original

conformation.

A complication has recently arisen with the finding that

both type 1 and type 2 can co-exist in the brains of

patients with sCJD.2,5-8 More recently this same phenomenon

has been demonstrated in patients with iatrogenically

acquired and familial forms of human prion disease.

9,10 The existence of this phenomenon is now

beyond doubt but its prevalence and its biological
significance

remain a matter of debate.

Conventional Western blot analysis using antibodies

that detect type 1 and type 2 PrPSc has severe quantitative

limitations for the co-detection of type 1 and type 2

PrPSc in individual samples, suggesting that the prevalence

of co-occurrence of the two types might be underestimated.

We have sought to circumvent this problem by

using an antibody that is type 1-specific and applied this

to the sole remaining human prion disease where the

phenomenon of mixed PrPSc types has not yet been

shown, namely vCJD.

These results show that even in vCJD where susceptible

individuals have been infected supposedly by a

single strain of agent, both PrPSc types co-exist: a
situation

reminiscent of that seen when similarly discriminant

antibodies were used to analyze experimental BSE in

sheep.14,17 In sporadic and familial CJD, individual

brains can show a wide range of relative amounts of the

two types in samples from different regions, but where

brains have been thoroughly investigated a predominant

type is usually evident.2,6,10 This differs from this
report

on vCJD, where type 1 is present in all samples
investigated

but always as a minor component that never

reaches a level at which it is detectable without a type

1-specific antibody. It would appear that the relative
balance

between type 1 and type 2 is controlled within

certain limits in the vCJD brain. A minority type-1-like

band is also detected by 12B2 in vCJD tonsil, in BSE

brain and in the brains of mice experimentally infected

with vCJD, suggesting that this balance of types is agent,

rather than host or tissue, specific. Interestingly the
"glycoform

signature" of the type 2 PrPSc found in vCJD (type

2B) is also seen in the type 1 PrPSc components, suggesting

that it could legitimately be termed type 1B.

PrPSc isotype analysis has proven to be extremely

useful in the differential diagnosis of CJD and is
likely to

continue to have a major role in the investigation of human

prion diseases. However, it is clear, on the basis of

these findings, that molecular typing has quantitative
limitations

and that any mechanistic explanation of prion

replication and the molecular basis of agent strain
variation

must accommodate the co-existence of multiple

prion protein conformers. Whether or not the different

conformers we describe here correlate in a simple and

direct way with agent strain remains to be determined. In

principle two interpretations present themselves: either

the two conformers can be produced by a single strain of

agent or vCJD (and, therefore, presumably BSE) results

from a mixture of strains, one of which generally
predominates.

Evidence for the isolation in mice of more than one

strain from individual isolates of BSE has been presented

previously.18,19

One practical consequence of our findings is that the

correct interpretation of transmission studies will depend

on a full examination of the balance of molecular types

present in the inoculum used to transmit disease, in
addition

to a thorough analysis of the molecular types that

arise in the recipients. Another consequence relates to

the diagnostic certainty of relying on PrPSc molecular

type alone when considering the possibility of BSE
infection

or secondary transmission in humans who have a

genotype other than methionine at codon 129 of the

PRNP gene. In this context it is interesting to note
that this

minority type 1B component resembles the type 5 PrPSc

described previously to characterize vCJD transmission

into certain humanized PRNP129VV transgenic mouse

models.12,20 This apparently abrupt change in molecular

phenotype might represent a selection process imposed

by this particular transgenic mouse model. Irrespective of

whether this proves to be the case, the results shown

here point to further complexities in the relationship
between

the physico-chemical properties of the prion protein,

human disease phenotype, and prion agent strain.

Acknowledgments


snip...


Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157

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

http://ajp.amjpathol.org/cgi/content/abstract/168/1/151maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1136646133963_237&FIRSTINDEX=0&volume=168&issue=1&journalcode=amjpathol


snip...end...TSS






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