Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings
Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence
for Prion Type Variability Influencing Clinical Course and Laboratory Findings
Article type: Research Article
Authors: Baiardi, Simonea | Capellari, Sabinaa; b | Ladogana, Annac |
Strumia, Silviad | Santangelo, Marioe | Pocchiari, Maurizioc | Parchi, Pieroa;
b; *
Affiliations: [a] Dipartimento di Scienze Biomediche e Neuromotorie
(DiBiNeM), Università di Bologna, Bologna, Italy | [b] IRCCS Istituto delle
Scienze Neurologiche, Bologna, Italy | [c] Dipartimento di Biologica Cellulare e
Neuroscienze, Istituto Superiore di Sanità, Roma, Italy | [d] UOC di Neurologia,
Ospedale Morgagni-Pierantoni, Forlì, Italy | [e] UOC di Neurologia, Ospedale
Ramazzini, Carpi, Italy
Correspondence: [*] Correspondence to: Prof. Piero Parchi, MD, PhD, IRCCS
Istituto delle Scienze Neurologiche, Via Altura 3, 40139 Bologna, Italy. Tel.:
+39 051 4966740; Fax: +39 051 4966208; E-mail: piero.parchi@unibo.it.
Abstract: The Heidenhain variant defines a peculiar clinical presentation
of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual
disturbances at disease onset and reflecting the early targeting of prions to
the occipital cortex. Molecular and histopathological typing, thus far performed
in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To
contribute a comprehensive characterization of cases with the Heidenhain
variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients
(4.9% ) fulfilled the selection criteria. Fourteen of them belonging to sCJD
types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall
clinical disease, a high prevalence of periodic sharp-waved complexes in EEG,
and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels.
In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration
of isolated visual symptoms and overall clinical disease, non-specific EEG
findings, and cerebrospinal fluid concentration below threshold for the
diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI
disclosed an occipital cortical hyperintensity in the majority of examined cases
of both groups. While confirming the strong linkage with the methionine genotype
at the polymorphic codon 129 of the prion protein gene, our results definitely
establish that the Heidenhain variant can also be associated with the MM 2C sCJD
type in addition to the more common MM1 type. Likewise, our results highlight
the significant differences in clinical evolution and laboratory findings
between cases according to the dominant PrPSc type (type 1 versus type 2).
Keywords: Dementia, molecular typing, neurodegenerative diseases, occipital
cortex, prion diseases, prion protein
DOI: 10.3233/JAD-150668
Journal: Journal of Alzheimer's Disease, vol. Preprint, no. Preprint, pp.
1-12, 2015
Accepted 21 October 2015 | Published 1 December 2015
Heidenhain Variant Creutzfeldt Jakob Disease autopsy case report 'MOM'
DIVISION OF NEUROPATHOLOGY University of Texas Medical Branch 114
McCullough Bldg. Galveston, Texas 77555-0785
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DATE: 4-23-98
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--------------------------
Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name:
POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Admitting Race: C
Attending Dr.: Date / Time Admitted : 12/14/97 1228 Copies to:
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 Fax (409) 772-5683 Pathology Report
FINAL AUTOPSY DIAGNOSIS Autopsy' Office (409)772-2858
Autopsy NO.: AU-97-00435
AUTOPSY INFORMATION: Occupation: Unknown Birthplace: Unknown Residence:
Crystal Beach Date/Time of Death: 12/14/97 13:30 Date/Time of Autopsy: 12/15/97
15:00
Pathologist/Resident: Pencil/Fernandez Service: Private Restriction: Brain
only
FINAL AUTOPSY DIAGNOSIS
I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.
***TYPE: Anatomic(A) or Clinical(C) Diagnosis. IMPORTANCE: 1-immediate
cause of death (COD); 2.ureterlying COD; 3-contributory COD: 4.concomitant,
significant; 5-incidental ***
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date; Time: 01/30/98 - 0832
Page: 1 Continued ....
--------------
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 Fax (409) 772-5683
Pathology Report
Autopsy NO,: AU-97-00435
MICROSCOPIC DESCRIPTION: The spongiform change is evident in all areas of
neocortex, varying from mild to moderate in severity with only very mild
neuronal loss and gliosis. In the bilateral occipital lobes, there is severe
loss cortical neurons and gliosis, with a corresponding pallor of the underlying
white matter. There is only minimal, focal spongiform change in corpus striatum,
lentiform nuclei, thalamus, hippocampus, brainstem and cerebellum. There is no
significant loss of neurons from the lateral geniculate nucleus, and the optic
chiasm and tracts are well-myelinated.
SECTIONS TAKEN: N-l) Pituitary, N-2) Right frontal, N-3) Right inferior
frontal, N-4) Right caudate putamen. N-5) Right lentiform nuclei, N-6) Right
hippocampus, N-7) optic chiasm. N-8) Left inferior temporal lobe, N-9) Right
inferior occipital, N-10} Cerabellum. N-l1) Midbrain, N-12) Pons, N-13) Medulla.
FINAL DIAGNOSES: BRAIN: 1. Clinical history of rapidly progressive
dementia, clinically consistent with Creutzfeldt-Jakob Disease.
a. spongiform encephalopathy, most Severe in occipital lobes, consistent
with Heidenhain variant of Creutzfeldt-Jakob disease.
b. Ventriculer enlargement, moderate, consistent with atrophy. 1.
Communicating spherical enlargement of occipital horn of left lateral ventricle
(possible incidental congenital anomaly).
DURA; Left subdural hemorrhage, recent, minimal.
PITUITARY: Severe capillary congestion.
COMMENTS; See also western blot report from Dr. Gambetti's lab Amyloid
stains are not completed for this case as of this date. The results, which are
not essential for the diagnosis, will be reported separately in an addendum.
(this was hand written notes) no amyloid evident in the special stains. no
evidence of plaques.GAE
Gerald A. Campbell, M.D., Pathologist Division of Neuropathology
(Electronic Signature}. (Gross: 01/16/98 Final: 02/08/98
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date: Time: 02/09/98 - 1120
Page 2 END OF REPORT -------
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 fax (409) 772-5683 Pathology Report
Date/Time of Death: 12/14/97 Autopsy No.: AU-97-00435
NEUROPATHOLOGY CONSULTATION
CLINICAL HISTORY This patient was a 63-year-old white female with recent
onset of progressive dementia. She was well until September of this year, when
she noted a decrease in her visual activity and was found to have visual field
defects as well. MRI revealed no lesions in the orbits or optic pathways. She
was admitted to the hospital with the working diagnosis of bilateral optic
neuropathy for a course of intravenous methylprednisolone, but her vision
continued to deteriorate. She developed increasing memory and speech impairment,
weakness and myoclonus. She died on 12/14/97, approximately three and one-half
months after her symptoms started.
Date/Time of Death: 12/14/97 13:30 Date/Time Autopsy: 12/15/97 15:00
Pathologist Resident: PENCIL/FERNANDEZ
GROSS DESCRIPTION: Submitted are the brain, convexity dura and pituitary
gland.
The pituitary gland is very dark and almost hemorrhagic in appearance, but
has no obvious hematoma. It is submitted totally for histology.
The right convexity dura has diffuse but minimal subdura hemorrhage, and
the dura is otherwise unremarkable.
The brain is normally developed with normal size for an adult and is
symmetric externally. It does not have apparent sulcal widening. There is mild
congestion of the leptomeninges, which are transparent. There is no evidence of
inflammatory exudete. There is no evidence of internal softenings or other
lesions externally. The cerebral arteries have focal atherosclerosis, but are
without significant compromise of the vessels lumens. There is no evidence of
aneurysms or malformations.
The hemispheres are sliced coronally revealing, a ventricular system which
is mildly enlarged. The cortical ribbon is normal in thickness throughout most
of the brain, except for the inferior and medial occipital lobes bilaterally,
where the cortex is firm, thin and has a brownish discoloration, more severely
so on the left than the right. In addition there is a spherical enlargement of
the left occipital horn of the lateral ventricle which communicates with the
remainder of the lateral ventricle. The tissue of the white matter around this
enlargement is somewhat softer then in other areas. Other areas of the brain are
grossly unremarkable. The brainstem and cerebellum are sliced transversely,
revealing normal development and no evidence of gross changes or lesions.
DICTATED BY: GERALD A. CAMPBELL, M.D., PATHOLOGIST 01/16/98
Page 1 Continued ....
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Patient Account: 90000014-518 Med. Rec. No,: (0160)118511Q
Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex:F Race:C
Admitting Dr.: Attending Dr: Date/Time Admitted: 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 Fax (409) 772-5683 Pathology Report
FINAL AUTOPSY REPORT Autopsy Office (409)772-2858 Autopsy No.: AU-97-00435
CLINICAL SUMMARY:
This is a 63-year-old white female with a recent onset of progressive
dementia. Her past medical history is significant for hypothyroidism. She was
well until September of this year, when she noted visual difficulty. By
mid-October, she could not read the newspaper. She was found to have a decrease
in visual acuity and visual field defects. One week after her initial
evaluation, a panel of blood tests showed no significant abnormalities and a MRI
revealed some periventricular white matter "plaque-like" areas but no lesions in
the orbits or optic pathways.
The patient had continued deterioration and distortion of her vision. The
visual field defects increased, and she was found to have paracentral scotomas
which were thought to be consistent with bilateral optic neuropathy. Early in
November, she was admitted to the hospital for a course of intravenous methyl
prednisolone.
During her hospital stay, she was noted to have short term memory and
speech impairment; her vision did not improve. She was discharged with the
diagnosis of Creutzfeldt-Jakob disease.
Later, the patient developed progressive dementia with marked impairment of
speech and memory. She had complete visual loss, increased weakness and
myoclonus. She died on December 14, 1997.
MF /AV 12/16/97
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date / Time: 01//30/98 - 0832 Page: 2 Continued .... --------------
Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name:
POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.:
Attending Dr.: Date / Time Admitted : 12/14/97 1228
UTMB University of Texas Medical Branch Galveston. Texas 77555-0543 (409)
772-1238 Fax (409) 772-5683 Pathology Report
AU-97-00435
GROSS DESCRIPTION:
EXTERNAL EXAMINATION: The body is that of a 63-year-old well-nourished,
well-developed white female. There is no rigor mortis present, and there is
unfixed dependent lividity on the posterior surface. The head is normocephalic
with a moderate amount of gray, medium length scalp hair. The irides are blue
with equal pupils measuring 0.4 mm in diameter. The nares are patent with no
exudate. Dentition is fair. Buccal membranes are normal. There is normal female
hair distribution. The chest does not have increased anterior-posterior
diameter. The abdomen is slightly protuberant. Lymph node enlargement is not
present. The extremities are unremarkable. The genitalia are those of a normal
female. Two well-healed remote scars are identified in the abdomen: one in the
right upper quadrant and another in the superpubic area.
BRAIN: The brain weighs 1450 gm. The gyri and sulci display a normal
pattern without edema or atrophy. The meninges show no abnormalities. The circle
of Willis, basilar and vertebral arteries show no significant atherosclerosis.
The brain is fixed in formalin for later examination by a neuropathologist (see
neuropathology report). No indentation of the cingulate gyri, unci or molding of
the cerebellar tonsils are noted.
SPINAL CORD: The spinal cord is not removed.
PITUITARY GLAND: The pituitary gland is removed and is fixed in formalin
for subsequent examination by a neuropathologist.
MF /AV 12/16/97
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date / Time: 01/30/98 - 0832
Page 3 Continued ....
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Patient Account : 90000014-518 Med. Rec. No.: (0160)118511Q patient Name:
POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.:
Attending Dr,: Date/Time Admitted: 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 Fax (409) 772-5683
Pathology Report AU-97-00435
MICROSCOPIC DESCRIPTION:
BRAIN: Histologic examination of multiple sampled areas of the brain showed
the characteristic features of Creutzfetdt-Jakob disease. These were present in
most sections, but were particularly prominent in the occipital cortex. The
spongiform degeneration was seen in the neuropil of the gray matter as multiple
vacuoles amoung numerous reactive astrocytes and occasional neuronal cell
bodies. These changes were most notable in the basal layer of the cortex. PAS
and amyloid stains will be performed on selected sections to asses the presence
of plaques.
MF /MF 01/28/98
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date / Time: 01/30/98 - 0832
Page: 4 Continued .... --------------
Patient Account: 90000014-518 Med. Rec. No.: (0160}118511Q Patient Name:
POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.:
Attending Dr.: Date / Time Admitted : 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 775550-0543 (409)
772-1238 Fax (409) 772-5683 Pathology Report
Autopsy office (409)772-2858 Autopsy No.: AU-97-00435
FINAL AUTOPSY REPORT
CLINICOPATHOLOGIC CORRELATION:
The clinical findings in this case strongly suggest the diagnosis of
Creutzfeldt-Jakob disease: progressive dementia, typical EEG changes, visual
disturbances and myoclonus. These characteristics indicate this is a "probable
case of CJD", according the criteria set by the EC Surveillance Group of
Creutzfeldt-Jakob Disease in Europe (1).
The definitive diagnosis of Creutzfeldt-Jakob disease, however, is
established by neuropathologic findings. There are three changes that are
classically described and considered diagnostic: spongiform change, neuronal
loss and astrocytic gliosis. The presence of these can vary significantly in
proportion and distribution and often correlate with clinical symptoms. This
permits classification of the disease into several variants.
Three variants of Creutzfeldt-Jakob disease have been proposed by Roos and
Gajdusek (2): frontopyramidal, with pyramidal or lower motor neuron involvement;
occipitoparietal {Heidenhain), characterized by disorders in higher cortical
function and vision; and diffuse, with cerebral, cortical, basal ganglia,
thalamic, cerebellar, midbrain and spinal cord involvement.
Histological examination from multiple samples of the brain in this case
revealed astrocytic gliosis, spongiform degeneration and neuronal loss. Although
these changes were seen in most sections, they were most prominent in the
occipital cortex. This correlates very well with the clinical history of visual
disturbances. Based on this finding, the present case corresponds to the
Heidenhain variant. It is not uncommon for Creutzfeldt-Jakob disease to present
with visual symptoms as the initial manifestation of the disease. Vargas et al
(3) has reported three cases with these characteristics.
There have been numerous and significant advances in our understanding of
Creutzfeldt-Jakob disease and prion diseases in general. These have been
reviewed in several papers written recently, including one by Horowich and
Weissman (4).
In summary, this 63 year old female with a history of visual disturbances
and dementia of rapid progression was found to have the neuropathologic changes
characteristic of Creutzfeldt-Jakob disease, predominantly in the occipital
cortex. The occipital tropism and consequent visual symptoms indicate this case
corresponds to the Heidenhain variant.
REFERENCES:
Patient Name: POULTER, BARBARA Patient location: AUTOPSY Room/Bed: Printed
Date / Time: 01/30/98 * 0832
Page: 5 Continued ....
--------------
Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name:
POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.:
Attending Dr.: Date / Time Admitted : 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409)
772-1238 Fax (409} 772-5683 Pathology Report
Autopsy No.: AU-97-00435
FINAL AUTOPSY REPORT
CLINICOPATHOLOGIC CORRELATION:
1. Budka H, et al: Tissue handling in suspected Creutzfeldt-Jakob disease
(CJD) and other human spongiform encephalopathies (prion diseases), Brain
Pathology. 5:319-322,1995.
2. Roos R, Gajdusek DC, Gibbs CJ Jr: The clinical characteristics of
transmissible Creutzfeldt-Jakob disease. Brain 96: 1-20, 1973.
3. Vargas ME, et al: Homonymous field defect as the first Manifestation of
Creutzfeldt-Jakob disease. American Journal of Ophthalmology. 119:497-504, 1995.
4. Horowich AL, Weissman JS: Deadly conformations - protein misfolding in
prion disease. Cell Vol.89, 499-510, 1997.
MF /MF 01/28/98
SCOT D. PENCIL, M.D., PATHOLOGIST MARTIN FERNANDEZ, M.D. 01/29/98
(Electronic Signature)
Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed
Date / Time: 01/30/98 - 0832
Page: 6 END OF REPORT
--------------
The University of Texas Medical Branch at Galveston
Gerald A, Campbell, Ph.D., M.D, Associate Professor and Director Division
of Neuropathology Department of Pathology
February 26, 1998
Pierluigi Gambetti, M.D. Professor Institute of Pathology Case Western
Reserve University 2085 Adelbert Road Cleveland Ohio 44106
Dear Dr, Gambetti:
Enclosed please find the microscopic slides and autopsy report from our
patient, Barbara Poulter (Hosp.# 11851lQ, Autopsy # AU97-435). These slides are
being sent for consultation at the request of Mr. Singletary, Ms. Poulter's son
and next of kin. We will also send frozen tissue from the brain on dry ice next
week, and someone will call you on the day the tissue is shipped. Please return
the slides when you have finished with your examination. If you need any further
information, please do not hesitate to call me. Thanks for your assistance with
this case.
Sincerely, Gerald A. Campbell
------------------
CASE WESTERN RESERVE UNIVERSITY
February 26, 1988
Gerald Campbell, M.D,, PhD. Division of Neuropathology, G85 University TX
Medical Branch Galveston, TX 77555-0785
Dear Dr. Campbell,
As per our telephone conversation concerning a recent case of CJD, I Will
be willing to examine slides and the frozen tissue on western blotting, I will
issue a report to you about our conclusions. Below is my address, Our Fed Ex
number is XXXXXXXXXXXXXXX.
Thank your for your assistance in this matter,
Best personal regards,
Pierluigi Gambetti, M.D.
PG:In
Division of Neuropathology Pierluigi Gambetti, M.D. Director Institute Of
Neuropathology 2085 Adelbert Road Cleveland, Ohio 44106
Phone 216-368-0587 Fax 216-368-2546
------------------
CASE WESTERN RESERVE UNIVERSITY
February 27, 1998
Dr. Gerald A. Campbell The University of Texas Medical Branch at Galveston
Division of Neuropathology, G85 Galveston. TX 77555-0785
Dear Dr. Campbell,
We are in receipt of the slides you sent on Mrs. Barbara Poulter (your #:
AU97-435;our#098-28).
Best personal regards, Pierluigi Gambetti, M.D.
PG:sb
Division of Neuropathology Pierluigi Gambetti, M.D., Director
-----------------------------------
CASE WESTERN RESERVE UNIVERSITY
March 30, 1998
Dr. Gerald A, Campbell The University of Texas Medical Branch at Galveston
Division of Neuropathology Department of Pathology Galveston, Texas
Dear Dr Campbell,
We performed Western immunoblot analysis on the frozen tissue from your
case #AU97-435 (our #098-28). The Immunoblot reveals the presence of
protease-resistant prion protein (PrPres) confirming the diagnosis of prion
disease. The immunoblot pattern of PrPres is consistent with the diagnosis of
Creutzfeldt-Jakob disease.
Thank you for referring to us this interesting case.
Sincerely,
Piero Parchi, M.D.
Pierluigi Gambetti, M.D.
PP:sb
Division of Neuropathology Pierluigi Gambetti, M.D., Director Case Western
Reserve University
This Autopsy report is for the use of anyone, who is trying to understand
this hideous disease CJD. I hope it can be beneficial for some in researching
human TSE. Please remember, this was my Mom, and to use this with great respect.
thank you, kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA
-------------------------------
BARBARA FREDERICK POULTER
DIED 12-14-97
If I had one last thing I could tell you, it would be, I love you. I'm
sorry for the stupid argument we had the last few months, BEFORE this hideous
disease ROARED through your body. BUT, I PROMISE MOM, YOUR DEATH WILL NOT GO
UNANSWERED!
HEIDENHAN VARIANT CREUTZFELDT JAKOB DISEASE
We got a call from my Mother around the end of Oct. saying "the damn'est
thing has happened, I can't see, and if I'm talking to you and I don't make
sense, bare with me, I'll come back". It was a shock to all of us. It seems that
a few days before, she was crossing the ferry and became frightened because she
was having problems seeing. She explained it as looking down a tunnel or not
being able to see from the sides, and seeing brown spots.
We had NOT been talking, over something, we had NO control of, for a few
months. So I did not know she had been having these visual problems, until she
was blind. These were her first symptoms. From that point on, I was with her
most everyday. I had to cross the Galveston/Bolivar ferry, and its about 30
minutes each way, so as the disease progressed, it gave me a great deal of time
to think. When the visual problems started, it was about 2 weeks later, and she
was blind. That led to coordination, and balance problems starting. But as this
hideous disease progresses, it just GOES. You don't seem to catch up with it. It
was like a fire in a hurricane. We would go out and get her things she needed
one day, and the next day it would be obsolete, because the disease had gone to
another stage. So you started over. Her coordination and balancing led to being
in a wheel-chair. She was starting to get these trembles. I also noticed how her
hands and feet started to go inward. Her speech was nothing more than jerble at
this time, and this was probably about the 6th week, (at this point we had to
tie her to the wheel chair, to keep her from falling out). The trembles had
turned into SEVERE JERKS, that at times would take 3 of us to hold her down. I
will never forget that....About her 8th week she became comatose....She died
around the 10th week. I had spent the night, she had problems through the night,
so the nurse came. She checked her out and comforted us, (HOSPICE IS A WONDERFUL
ORGANIZATION). The nurse said she seemed to be alright and that it would
probably be alright to go home for a few hours. I was on the Ferry, going back
to Galveston, when I got the call, she was gone. What can you do, Mom was gone,
and I was stuck on the Damn Ferry, going the wrong direction.
She knew what she had. I remember, before she had lost her speech
completely. After a doctors conference, and CJD had come up. She heard us say
CJD, and she screamed, SHE knew! At that point, I didn't know what was, much
less, CREUTZFELDT JAKOB DISEASE.....I have learned a lot since. I have learned I
truly miss my Mom and I am MAD as hell that she is gone!
Terry/MADSON!!!
SYMPTOMS:
VISION - BLIND IN ABOUT 10 TO 14 DAYS
COORDINATION AND MUSCLE CONTROL SWALLOWING DIFFICULTY CONFUSION AND
DEMENTIA SPEECH PROBLEMS HALLUCINATIONS TREMBLES TOO SEVERE JERKING LOSS OF
WEIGHT HANDS AND FEET GREW INWARD UPPER TRUNK STIFFNESS, SHOULDER, UPPER ARM
Back to MANY FACES OF CJD
snip...
Saturday, December 12, 2015
CHRONIC WASTING DISEASE CWD TSE PRION REPORT DECEMBER 14, 2015
Thursday, December 17, 2015
Annual report of the Scientific Network on BSE-TSE 2015 EFSA-Q-2015-00738
10 December 2015
Saturday, December 12, 2015
BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION REPORT DECEMBER 14, 2015
Saturday, December 12, 2015
NOTICE: Environmental Impact Statement on Large Livestock Carcasses TSE
Prion REPORT December 14, 2015
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Transmission of scrapie prions to primate after an extended silent
incubation period
Authors
item Comoy, Emmanuel - item Mikol, Jacqueline - item Luccantoni-Freire,
Sophie - item Correia, Evelyne - item Lescoutra-Etchegaray, Nathalie - item
Durand, Valérie - item Dehen, Capucine - item Andreoletti, Olivier - item
Casalone, Cristina - item Richt, Juergen item Greenlee, Justin item Baron,
Thierry - item Benestad, Sylvie - item Hills, Bob - item Brown, Paul - item
Deslys, Jean-Philippe -
Submitted to: Scientific Reports Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 28, 2015 Publication Date: June 30, 2015
Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S., Correia, E.,
Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O., Casalone, C.,
Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P., Deslys, J.
2015. Transmission of scrapie prions to primate after an extended silent
incubation period. Scientific Reports. 5:11573.
Interpretive Summary:
The transmissible spongiform encephalopathies (also called prion diseases)
are fatal neurodegenerative diseases that affect animals and humans. The agent
of prion diseases is a misfolded form of the prion protein that is resistant to
breakdown by the host cells. Since all mammals express prion protein on the
surface of various cells such as neurons, all mammals are, in theory, capable of
replicating prion diseases. One example of a prion disease, bovine spongiform
encephalopathy (BSE; also called mad cow disease), has been shown to infect
cattle, sheep, exotic undulates, cats, non-human primates, and humans when the
new host is exposed to feeds or foods contaminated with the disease agent. The
purpose of this study was to test whether non-human primates (cynomologous
macaque) are susceptible to the agent of sheep scrapie. After an incubation
period of approximately 10 years a macaque developed progressive clinical signs
suggestive of neurologic disease. Upon postmortem examination and microscopic
examination of tissues, there was a widespread distribution of lesions
consistent with a transmissible spongiform encephalopathy. This information will
have a scientific impact since it is the first study that demonstrates the
transmission of scrapie to a non-human primate with a close genetic relationship
to humans. This information is especially useful to regulatory officials and
those involved with risk assessment of the potential transmission of animal
prion diseases to humans.
Technical Abstract:
Classical bovine spongiform encephalopathy (c-BSE) is an animal prion
disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the
past decades, c-BSE's zoonotic potential has been the driving force in
establishing extensive protective measures for animal and human health. In
complement to the recent demonstration that humanized mice are susceptible to
scrapie, we report here the first observation of direct transmission of a
natural classical scrapie isolate to a macaque after a 10-year incubation
period. Neuropathologic examination revealed all of the features of a prion
disease: spongiform change, neuronal loss, and accumulation of PrPres throughout
the CNS.
***This observation strengthens the questioning of the harmlessness of
scrapie to humans, at a time when protective measures for human and animal
health are being dismantled and reduced as c-BSE is considered controlled and
being eradicated. Our results underscore the importance of precautionary and
protective measures and the necessity for long-term experimental transmission
studies to assess the zoonotic potential of other animal prion strains.
*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary
Sr. Submission ***
Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats
SUMMARY: We are reopening the comment period for our proposed rule that
would revise completely the scrapie regulations, which concern the risk groups
and categories established for individual animals and for flocks, the use of
genetic testing as a means of assigning risk levels to animals, movement
restrictions for animals found to be genetically less susceptible or resistant
to scrapie, and recordkeeping requirements. This action will allow interested
persons additional time to prepare and submit comments.
DATES: The comment period for the proposed rule published on September 10,
2015 (80 FR 54660-54692) is reopened. We will consider all comments that we
receive on or before December 9, 2015. ...
COMMENT SUBMISSION TERRY S. SINGELTARY SR.
WITH regards to Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats, I
kindly submit the following ;
>>>The last major revision of the scrapie regulations
occurred on August 21, 2001, when we published in theFederal Register(66 FR
43964, Docket No. 97-093-5) a final rule amending part 79 by imposing additional
restrictions on the interstate movement of sheep and
goats.<<<
Indeed, much science has changed about the Scrapie TSE prion, including
more science linking Scrapie to humans. sadly, politics, industry, and trade,
have not changed, and those usually trump sound science, as is the case with all
Transmissible Spongiform Encephalopathy TSE Prion disease in livestock producing
animals and the OIE. we can look no further at the legal trading of the Scrapie
TSE prion both typical and atypical of all strains, and CWD all stains. With as
much science of old, and now more new science to back this up, Scrapie of all
types i.e. atypical and typical, BSE all strains, and CWD all strains, should be
regulated in trade as BSE TSE PRION. In fact, I urge APHIS et al and the OIE,
and all trading partners to take heed to the latest science on the TSE prion
disease, all of them, and seriously reconsider the blatant disregards for human
and animal health, all in the name of trade, with the continued relaxing of TSE
Prion trade regulations through the ‘NEGLIGIBLE BSE RISK’ PROGRAM, which was set
up to fail in the first place. If the world does not go back to the ‘BSE RISK
ASSESSMENTS’, enhance, and or change that assessment process to include all TSE
prion disease, i.e. ‘TSE RISK ASSESSMENT’, if we do not do this and if we
continue this farce with OIE and the USDA et al, and the ‘NEGLIGIBLE BSE RISK’
PROGRAM, we will never eradicate the TSE prion aka mad cow type disease, they
will continue to mutate and spread among species of human and animal origin, and
they will continue to kill. ...
please see ;
O.05: Transmission of prions to primates after extended silent incubation
periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni,
Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys
Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies
reputed to be transmissible under field conditions since decades. The
transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that
an animal PD might be zoonotic under appropriate conditions. Contrarily, in the
absence of obvious (epidemiological or experimental) elements supporting a
transmission or genetic predispositions, PD, like the other proteinopathies, are
reputed to occur spontaneously (atpical animal prion strains, sporadic CJD
summing 80% of human prion cases). Non-human primate models provided the first
evidences supporting the transmissibiity of human prion strains and the zoonotic
potential of BSE. Among them, cynomolgus macaques brought major information for
BSE risk assessment for human health (Chen, 2014), according to their
phylogenetic proximity to humans and extended lifetime. We used this model to
assess the zoonotic potential of other animal PD from bovine, ovine and cervid
origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical
scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD,
albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked
in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases. We will present an
updated panorama of our different transmission studies and discuss the
implications of such extended incubation periods on risk assessment of animal PD
for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
***This information will have a scientific impact since it is the first
study that demonstrates the transmission of scrapie to a non-human primate with
a close genetic relationship to humans. This information is especially useful to
regulatory officials and those involved with risk assessment of the potential
transmission of animal prion diseases to humans.
***This observation strengthens the questioning of the harmlessness of
scrapie to humans, at a time when protective measures for human and animal
health are being dismantled and reduced as c-BSE is considered controlled and
being eradicated. Our results underscore the importance of precautionary and
protective measures and the necessity for long-term experimental transmission
studies to assess the zoonotic potential of other animal prion strains.
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Evaluation of the zoonotic potential of transmissible mink
encephalopathy
Authors
item Comoy, Emmanuel - item Mikol, Jacqueline - item Ruchoux,
Marie-Madeleine - item Durand, Valerie - item Luccantoni-Freire, Sophie - item
Dehen, Capucine - item Correia, Evelyne - item Casalone, Cristina - item Richt,
Juergen item Greenlee, Justin item Torres, Juan Maria - item Brown, Paul - item
Deslys, Jean-Philippe -
Submitted to: Pathogens Publication Type: Peer Reviewed Journal Publication
Acceptance Date: July 30, 2013 Publication Date: July 30, 2013 Citation: Comoy,
E.E., Mikol, J., Ruchoux, M., Durand, V., Luccantoni-Freire, S., Dehen, C.,
Correia, E., Casalone, C., Richt, J.A., Greenlee, J.J., Torres, J.M., Brown, P.,
Deslys, J. 2013. Evaluation of the zoonotic potential of transmissible mink
encephalopathy. Pathogens. 2:(3)520-532.
Interpretive Summary: Cases of bovine spongiform encephalopathy (BSE) or
mad cow disease can be subclassified into at least 3 distinct disease forms with
the predominate form known as classical BSE and the others collectively referred
to as atypical BSE. Atypical BSE can be further subdivided into H-type and
L-type cases that are distinct from classical BSE and from each other. Both of
the atypical BSE subtypes are believed to occur spontaneously, whereas classical
BSE is spread through feeding contaminated meat and bone meal to cattle.
Transmissible mink encephalopathy (TME) is another prion disease that transmits
to cattle and show similarities to L-type BSE when subjected to laboratory
testing. The purpose of this study was to use non-human primates (cynomologous
macaque) and transgenic mice expressing the human prion protein to determine if
TME could represent a potential risk to human health. TME from two sources
(cattle and raccoons) was able to infect non-human primates and transgenic mice
after exposure by the intracranial route. This result suggest that humans may be
able to replicate TME prions after an exposure that allows infectious material
access to brain tissue. At this time, it is unknown whether non-human primates
or transgenic mice would be susceptible to TME prions after oral exposure. The
results obtained in these animal models were similar to those obtained for
L-type BSE. Although rare, the existence of TME and that it transmits to cattle,
non-human primates, and transgenic mice suggest that feed bans preventing the
feeding of mammalian tissues to cattle should stay in place and that regular
prion surveillance during the slaughter should remain in place. Parties with
interest in the cattle and beef industries and regulatory officials responsible
for safe feeding practices of cattle will be interested in this work. Technical
Abstract: Successful transmission of Transmissible Mink Encephalopathy (TME) to
cattle supports the bovine hypothesis to the still controversial origin of TME
outbreaks. Human and primate susceptibility to classical Bovine Spongiform
Encephalopathy (c-BSE) and the transmissibility of L-type BSE to macaques assume
a low cattle-to-primate species barrier: we therefore evaluated the zoonotic
potential of cattle-adapted TME. In less than two years, this strain induced in
cynomolgus macaques a neurological disease similar to L-BSE and distinct from
c-BSE. TME derived from another donor species (raccoon) induced a similar
disease with shorter incubation periods.
*** L-BSE and cattle-adapted TME were also transmissible to transgenic mice
expressing human PrP. Interestingly, secondary transmissions to transgenic mice
expressing bovine PrP showed the maintenance of prion strain features for the
three tested bovine prion strains (cattle TME, c-BSE and L-BSE) regardless of
intermediate host.
*** Thus, TME is the third animal prion strain transmissible to both
macaques and humanized transgenic mice, suggesting zoonotic potentials that
should be considered in the risk analysis of animal prion diseases for human
health.
*** Moreover, the similarities between TME and L-BSE are highly suggestive
of a link between those strains, and of the presence of L-BSE decades prior to
its identification in USA and Europe.
Research Project: Transmission, Differentiation, and Pathobiology of
Transmissible Spongiform Encephalopathies
2014 Annual Report
1a.Objectives (from AD-416): 1. Investigate the pathobiology of atypical
transmissible spongiform encephalopathies (TSEs) in natural hosts. A.
Investigate the pathobiology of atypical scrapie. B. Investigate the
pathobiology of atypical bovine spongiform encephalopathy (BSE). 2. Investigate
the horizontal transmission of TSEs. A. Assess the horizontal transmission of
sheep scrapie in the absence of lambing. B. Determine routes of transmission in
chronic wasting disease (CWD) infected premises. C. Assess oral transmission of
CWD in reindeer. 3. Investigate determinants of CWD persistence. A. Determine
CWD host range using natural routes of transmission. B. Investigate the
pathobiology of CWD.
1b.Approach (from AD-416): The studies will focus on three animal
transmissible spongiform encephalopathy (TSE) agents found in the United States:
bovine spongiform encephalopathy (BSE); scrapie of sheep and goats; and chronic
wasting disease (CWD) of deer, elk, and moose. The research will address sites
of accumulation, routes of infection, environmental persistence, and ante mortem
diagnostics with an emphasis on controlled conditions and natural routes of
infection. Techniques used will include clinical exams, histopathology,
immunohistochemistry and biochemical analysis of proteins. The enhanced
knowledge gained from this work will help mitigate the potential for
unrecognized epidemic expansions of these diseases in populations of animals
that could either directly or indirectly affect food animals.
3.Progress Report: Research efforts directed toward meeting objective 1 of
our project plan, Investigate the pathobiology of atypical transmissible
spongiform encephalopathies (TSEs) in natural hosts, include work in previous
years starting with the inoculation of animals for studies designed to address
the pathobiology of atypical scrapie, atypical bovine spongiform encephalopathy
(BSE), as well as a genetic version of BSE. Animals inoculated with atypical
scrapie have not yet developed disease. Atypical BSE animals have developed
disease and evaluation of the samples is currently underway. Animals inoculated
with a genetic version of BSE have developed disease and the manuscript has been
published (2012). In addition, we have investigated the possibility that
atypical scrapie was present earlier than previously detected in the national
flock by analyzing archived field isolates using methods that were unavailable
at the time of original diagnosis. Sample quality was sufficiently degraded that
modern methods were not suitable for evaluation. In research pertaining to
objective 2, Investigate the horizontal transmission of TSEs, we have initiated
a study to determine if cohousing non-lambing scrapie inoculated sheep is
sufficient to transmit scrapie to neonatal lambs. At this time, scrapie free
ewes have lambed in the presence of scrapie inoculated animals and the lambs are
cohoused with these inoculated animals.
4.Accomplishments 1. Evaluated enzyme immunoassay for rapid identification
of prion disease in livestock. Scrapie of sheep and bovine spongiform
encephalopathy of cattle are diseases that cause damage to the central nervous
system including the retina in the eye. The infectious agent is an abnormal
protein called a prion that has misfolded from its normal state and is resistant
to breakdown by the host cells. Current diagnostic methods require the testing
of brain material, which can be difficult to collect and may lead to
contamination of the environment and exposure of personnel to the infectious
agent. Eyes can be readily collected without opening the skull. ARS researchers
at Ames, Iowa demonstrated that the enzyme immunoassay results using eyes of
negative controls or samples collected from sheep or cattle with clinical signs
were in agreement with approved confirmatory assays (western blot or
immunohistochemistry). These results indicate the retina is a useful tissue for
rapid diagnosis of prion disease in clinically ill sheep and cattle and could be
considered to greatly increase the number of samples submitted for prion disease
diagnosis with a minimal investment of time and limited exposure of personnel to
prion agents.
2. Evaluated E211K cattle as a model for inherited human prion disease.
Prion diseases cause damage to the central nervous system of animals and humans.
The infectious agent is an abnormal protein called a prion that has misfolded
from its normal state and is resistant to breakdown by the host cells and thus
accumulates and damages those cells. Some forms of prion disease are genetic and
can be inherited. Current models of genetic prion disease in humans rely on
mouse models expressing either the human prion protein (E200K) or a combination
of both mouse and human sequences. In addition to being an entirely artificial
system these mouse models have a short lifespan making them a less than ideal
system to study a naturally occurring genetic disorder with a long incubation
time and late onset of disease. Cattle, however, exhibit a number of
similarities to humans with regard to prion disease and perhaps most notable is
the late onset of genetic prion disease. ARS researchers at Ames, Iowa have
produced cattle containing both 1 and 2 chromosome copies of the cattle prion
gene (E211K) and evaluated many aspects of this prion protein from cattle
including protein stability, protein expression levels and ratios, as well as
evidence of oxidative stress. Taken together, these results highlight the
differences between mouse models of genetic prion disease and a naturally
occurring prion disease system in cattle and suggest that cattle will provide a
more relevant understanding of genetic prion disease in humans than do current
rodent models.
Review Publications Smith, J.D., Greenlee, J.J. 2014. Detection of
misfolded prion protein in retina samples of sheep and cattle by use of a
commercially available enzyme immunoassay. American Journal of Veterinary
Research. 75(3):268-272. Haldar, S., Beveridge, A.J., Wong, J., Singh, A.J.,
Galimberti, D., Borroni, D., Zhu, X., Blevins, J., Greenlee, J., Perry, G.,
Mukhopadhyay, C.K., Schmotzer, C., Singh, N. 2014. A low-molecular-weight
ferroxidase is increased in the CSF of sCJD Cases: CSF ferroxidase and
transferrin as diagnostic biomarkers for sCJD. Antioxidants & Redox
Signaling. 19(14):1662-1675.
http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=421870&fy=2014
http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=421870
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Scrapie transmits to white-tailed deer by the oral route and has a
molecular profile similar to chronic wasting disease
Authors
item Greenlee, Justin item Moore, S - item Smith, Jodi - item Kunkle,
Robert item West Greenlee, M -
Submitted to: American College of Veterinary Pathologists Meeting
Publication Type: Abstract Only Publication Acceptance Date: August 12, 2015
Publication Date: N/A Technical Abstract: The purpose of this work was to
determine susceptibility of white-tailed deer (WTD) to the agent of sheep
scrapie and to compare the resultant PrPSc to that of the original inoculum and
chronic wasting disease (CWD). We inoculated WTD by a natural route of exposure
(concurrent oral and intranasal (IN); n=5) with a US scrapie isolate. All
scrapie-inoculated deer had evidence of PrPSc accumulation. PrPSc was detected
in lymphoid tissues at preclinical time points, and deer necropsied after 28
months post-inoculation had clinical signs, spongiform encephalopathy, and
widespread distribution of PrPSc in neural and lymphoid tissues. Western
blotting (WB) revealed PrPSc with 2 distinct molecular profiles. WB on cerebral
cortex had a profile similar to the original scrapie inoculum, whereas WB of
brainstem, cerebellum, or lymph nodes revealed PrPSc with a higher profile
resembling CWD. Homogenates with the 2 distinct profiles from WTD with clinical
scrapie were further passaged to mice expressing cervid prion protein and
intranasally to sheep and WTD. In cervidized mice, the two inocula have distinct
incubation times. Sheep inoculated intranasally with WTD derived scrapie
developed disease, but only after inoculation with the inoculum that had a
scrapie-like profile. The WTD study is ongoing, but deer in both inoculation
groups are positive for PrPSc by rectal mucosal biopsy. In summary, this work
demonstrates that WTD are susceptible to the agent of scrapie, two distinct
molecular profiles of PrPSc are present in the tissues of affected deer, and
inoculum of either profile readily passes to deer.
Monday, November 16, 2015
*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary
Sr. Submission ***
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Transmission of the agent of sheep scrapie to deer results in PrPSc
with two distinct molecular profiles Authors
item Greenlee, Justin item Moore, Sarah - item Smith, Jodi item West
Greenlee, Mary - item Kunkle, Robert
Submitted to: Prion Publication Type: Abstract Only Publication Acceptance
Date: March 31, 2015 Publication Date: May 25, 2015 Citation: Greenlee, J.,
Moore, S.J., Smith, J.., West Greenlee, M.H., Kunkle, R. 2015.
Scrapie transmits to white-tailed deer by the oral route and has a
molecular profile similar to chronic wasting disease and distinct from the
scrapie inoculum. Prion 2015. p. S62. Technical Abstract: The purpose of this
work was to determine susceptibility of white-tailed deer (WTD) to the agent of
sheep scrapie and to compare the resultant PrPSc to that of the original
inoculum and chronic wasting disease (CWD). We inoculated WTD by a natural route
of exposure (concurrent oral and intranasal (IN); n=5) with a US scrapie
isolate. All scrapie-inoculated deer had evidence of PrPSc accumulation. PrPSc
was detected in lymphoid tissues at preclinical time points, and deer necropsied
after 28 months post-inoculation had clinical signs, spongiform encephalopathy,
and widespread distribution of PrPSc in neural and lymphoid tissues. Western
blotting (WB) revealed PrPSc with 2 distinct molecular profiles. WB on cerebral
cortex had a profile similar to the original scrapie inoculum, whereas WB of
brainstem, cerebellum, or lymph nodes reveal PrPSc with a higher profile
resembling CWD. Homogenates with the 2 distinct profiles from WTD with clinical
scrapie were further passaged to mice expressing cervid prion protein and
intranasally to sheep and WTD. In cervidized mice, the two inocula have distinct
incubation times. Sheep inoculated intranasally with WTD derived scrapie
developed disease, but only after inoculation with the inoculum that had a
scrapie-like profile. The WTD study is ongoing, but deer in both inoculation
groups are positive for PrPSc by rectal mucosal biopsy. In summary, this work
demonstrates that WTD are susceptible to the agent of scrapie, two distinct
molecular profiles of PrPSc are present in the tissues of affected deer, and
inoculum of either profile type readily passes to deer.
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Scrapie transmits to white-tailed deer by the oral route and has a
molecular profile similar to chronic wasting disease Authors
item Greenlee, Justin item Moore, S - item Smith, Jodi - item Kunkle,
Robert item West Greenlee, M -
Submitted to: American College of Veterinary Pathologists Meeting
Publication Type: Abstract Only Publication Acceptance Date: August 12, 2015
Publication Date: N/A
Technical Abstract: The purpose of this work was to determine
susceptibility of white-tailed deer (WTD) to the agent of sheep scrapie and to
compare the resultant PrPSc to that of the original inoculum and chronic wasting
disease (CWD). We inoculated WTD by a natural route of exposure (concurrent oral
and intranasal (IN); n=5) with a US scrapie isolate. All scrapie-inoculated deer
had evidence of PrPSc accumulation. PrPSc was detected in lymphoid tissues at
preclinical time points, and deer necropsied after 28 months post-inoculation
had clinical signs, spongiform encephalopathy, and widespread distribution of
PrPSc in neural and lymphoid tissues. Western blotting (WB) revealed PrPSc with
2 distinct molecular profiles. WB on cerebral cortex had a profile similar to
the original scrapie inoculum, whereas WB of brainstem, cerebellum, or lymph
nodes revealed PrPSc with a higher profile resembling CWD. Homogenates with the
2 distinct profiles from WTD with clinical scrapie were further passaged to mice
expressing cervid prion protein and intranasally to sheep and WTD. In cervidized
mice, the two inocula have distinct incubation times. Sheep inoculated
intranasally with WTD derived scrapie developed disease, but only after
inoculation with the inoculum that had a scrapie-like profile. The WTD study is
ongoing, but deer in both inoculation groups are positive for PrPSc by rectal
mucosal biopsy. In summary, this work demonstrates that WTD are susceptible to
the agent of scrapie, two distinct molecular profiles of PrPSc are present in
the tissues of affected deer, and inoculum of either profile readily passes to
deer.
PO-039: A comparison of scrapie and chronic wasting disease in white-tailed
deer
Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture;
Agricultural Research Service, National Animal Disease Center; Ames, IA USA
2012
PO-039: A comparison of scrapie and chronic wasting disease in white-tailed
deer
Justin Greenlee, Jodi Smith, Eric Nicholson US Dept. Agriculture;
Agricultural Research Service, National Animal Disease Center; Ames, IA USA
snip...
The results of this study suggest that there are many similarities in the
manifestation of CWD and scrapie in WTD after IC inoculation including early and
widespread presence of PrPSc in lymphoid tissues, clinical signs of depression
and weight loss progressing to wasting, and an incubation time of 21-23 months.
Moreover, western blots (WB) done on brain material from the obex region have a
molecular profile similar to CWD and distinct from tissues of the cerebrum or
the scrapie inoculum. However, results of microscopic and IHC examination
indicate that there are differences between the lesions expected in CWD and
those that occur in deer with scrapie: amyloid plaques were not noted in any
sections of brain examined from these deer and the pattern of immunoreactivity
by IHC was diffuse rather than plaque-like.
*** After a natural route of exposure, 100% of WTD were susceptible to
scrapie.
Deer developed clinical signs of wasting and mental depression and were
necropsied from 28 to 33 months PI. Tissues from these deer were positive for
PrPSc by IHC and WB. Similar to IC inoculated deer, samples from these deer
exhibited two different molecular profiles: samples from obex resembled CWD
whereas those from cerebrum were similar to the original scrapie inoculum. On
further examination by WB using a panel of antibodies, the tissues from deer
with scrapie exhibit properties differing from tissues either from sheep with
scrapie or WTD with CWD. Samples from WTD with CWD or sheep with scrapie are
strongly immunoreactive when probed with mAb P4, however, samples from WTD with
scrapie are only weakly immunoreactive. In contrast, when probed with mAb’s 6H4
or SAF 84, samples from sheep with scrapie and WTD with CWD are weakly
immunoreactive and samples from WTD with scrapie are strongly positive. This
work demonstrates that WTD are highly susceptible to sheep scrapie, but on first
passage, scrapie in WTD is differentiable from CWD.
White-tailed deer are susceptible to the agent of sheep scrapie by
intracerebral inoculation
snip...
It is unlikely that CWD will be eradicated from free-ranging cervids, and
the disease is likely to continue to spread geographically [10]. However, the
potential that white-tailed deer may be susceptible to sheep scrapie by a
natural route presents an additional confounding factor to halting the spread of
CWD. This leads to the additional speculations that
1) infected deer could serve as a reservoir to infect sheep with scrapie
offering challenges to scrapie eradication efforts and
2) CWD spread need not remain geographically confined to current endemic
areas, but could occur anywhere that sheep with scrapie and susceptible cervids
cohabitate.
This work demonstrates for the first time that white-tailed deer are
susceptible to sheep scrapie by intracerebral inoculation with a high attack
rate and that the disease that results has similarities to CWD. These
experiments will be repeated with a more natural route of inoculation to
determine the likelihood of the potential transmission of sheep scrapie to
white-tailed deer. If scrapie were to occur in white-tailed deer, results of
this study indicate that it would be detected as a TSE, but may be difficult to
differentiate from CWD without in-depth biochemical analysis.
2011
*** After a natural route of exposure, 100% of white-tailed deer were
susceptible to scrapie.
White-tailed Deer are Susceptible to Scrapie by Natural Route of Infection
Jodi D. Smith, Justin J. Greenlee, and Robert A. Kunkle; Virus and Prion
Research Unit, National Animal Disease Center, USDA-ARS
Interspecies transmission studies afford the opportunity to better
understand the potential host range and origins of prion diseases. Previous
experiments demonstrated that white-tailed deer are susceptible to sheep-derived
scrapie by intracranial inoculation. The purpose of this study was to determine
susceptibility of white-tailed deer to scrapie after a natural route of
exposure. Deer (n=5) were inoculated by concurrent oral (30 ml) and intranasal
(1 ml) instillation of a 10% (wt/vol) brain homogenate derived from a sheep
clinically affected with scrapie. Non-inoculated deer were maintained as
negative controls. All deer were observed daily for clinical signs. Deer were
euthanized and necropsied when neurologic disease was evident, and tissues were
examined for abnormal prion protein (PrPSc) by immunohistochemistry (IHC) and
western blot (WB). One animal was euthanized 15 months post-inoculation (MPI)
due to an injury. At that time, examination of obex and lymphoid tissues by IHC
was positive, but WB of obex and colliculus were negative. Remaining deer
developed clinical signs of wasting and mental depression and were necropsied
from 28 to 33 MPI. Tissues from these deer were positive for scrapie by IHC and
WB. Tissues with PrPSc immunoreactivity included brain, tonsil, retropharyngeal
and mesenteric lymph nodes, hemal node, Peyer’s patches, and spleen. This work
demonstrates for the first time that white-tailed deer are susceptible to sheep
scrapie by potential natural routes of inoculation. In-depth analysis of tissues
will be done to determine similarities between scrapie in deer after
intracranial and oral/intranasal inoculation and chronic wasting disease
resulting from similar routes of inoculation.
see full text ;
==========================================
***our findings suggest that possible transmission risk of H-type BSE to
sheep and human. Bioassay will be required to determine whether the PMCA
products are infectious to these animals.
==========================================
PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS
*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***
O18
Zoonotic Potential of CWD Prions
Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1,
Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve
University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy,
3Encore Health Resources, Houston, Texas, USA
*** These results indicate that the CWD prion has the potential to infect
human CNS and peripheral lymphoid tissues and that there might be asymptomatic
human carriers of CWD infection.
==================
***These results indicate that the CWD prion has the potential to infect
human CNS and peripheral lymphoid tissues and that there might be asymptomatic
human carriers of CWD infection.***
==================
P.105: RT-QuIC models trans-species prion transmission
Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover
Prion Research Center; Colorado State University; Fort Collins, CO USA
Conversely, FSE maintained sufficient BSE characteristics to more
efficiently convert bovine rPrP than feline rPrP. Additionally, human rPrP was
competent for conversion by CWD and fCWD.
***This insinuates that, at the level of protein:protein interactions, the
barrier preventing transmission of CWD to humans is less robust than previously
estimated.
================
***This insinuates that, at the level of protein:protein interactions, the
barrier preventing transmission of CWD to humans is less robust than previously
estimated.***
================
BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION REPORT DECEMBER 14, 2015
***********OCTOBER 2015*************
*** PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS ***
THANK YOU PRION 2015 TAYLOR & FRANCIS, Professor Chernoff, and
Professor Aguzzi et al, for making these PRION 2015 Congressional Poster and
Oral Abstracts available freely to the public. ...Terry S. Singeltary Sr.
P.108: Successful oral challenge of adult cattle with classical BSE
Sandor Dudas1,*, Kristina Santiago-Mateo1, Tammy Pickles1, Catherine
Graham2, and Stefanie Czub1 1Canadian Food Inspection Agency; NCAD Lethbridge;
Lethbridge, Alberta, Canada; 2Nova Scotia Department of Agriculture; Pathology
Laboratory; Truro, Nova Scotia, Canada
Classical Bovine spongiform encephalopathy (C-type BSE) is a feed- and
food-borne fatal neurological disease which can be orally transmitted to cattle
and humans. Due to the presence of contaminated milk replacer, it is generally
assumed that cattle become infected early in life as calves and then succumb to
disease as adults. Here we challenged three 14 months old cattle per-orally with
100 grams of C-type BSE brain to investigate age-related susceptibility or
resistance. During incubation, the animals were sampled monthly for blood and
feces and subjected to standardized testing to identify changes related to
neurological disease. At 53 months post exposure, progressive signs of central
nervous system disease were observed in these 3 animals, and they were
euthanized. Two of the C-BSE animals tested strongly positive using standard BSE
rapid tests, however in 1 C-type challenged animal, Prion 2015 Poster Abstracts
S67 PrPsc was not detected using rapid tests for BSE. Subsequent testing
resulted in the detection of pathologic lesion in unusual brain location and
PrPsc detection by PMCA only. Our study demonstrates susceptibility of adult
cattle to oral transmission of classical BSE. We are further examining
explanations for the unusual disease presentation in the third challenged
animal.
***Our study demonstrates susceptibility of adult cattle to oral
transmission of classical BSE. ***
***our findings suggest that possible transmission risk of H-type BSE to
sheep and human. ***
P.86: Estimating the risk of transmission of BSE and scrapie to ruminants
and humans by protein misfolding cyclic amplification
Morikazu Imamura, Naoko Tabeta, Yoshifumi Iwamaru, and Yuichi Murayama
National Institute of Animal Health; Tsukuba, Japan
To assess the risk of the transmission of ruminant prions to ruminants and
humans at the molecular level, we investigated the ability of abnormal prion
protein (PrPSc) of typical and atypical BSEs (L-type and H-type) and typical
scrapie to convert normal prion protein (PrPC) from bovine, ovine, and human to
proteinase K-resistant PrPSc-like form (PrPres) using serial protein misfolding
cyclic amplification (PMCA).
Six rounds of serial PMCA was performed using 10% brain homogenates from
transgenic mice expressing bovine, ovine or human PrPC in combination with PrPSc
seed from typical and atypical BSE- or typical scrapie-infected brain
homogenates from native host species. In the conventional PMCA, the conversion
of PrPC to PrPres was observed only when the species of PrPC source and PrPSc
seed matched. However, in the PMCA with supplements (digitonin, synthetic polyA
and heparin), both bovine and ovine PrPC were converted by PrPSc from all tested
prion strains. On the other hand, human PrPC was converted by PrPSc from typical
and H-type BSE in this PMCA condition.
Although these results were not compatible with the previous reports
describing the lack of transmissibility of H-type BSE to ovine and human
transgenic mice, ***our findings suggest that possible transmission risk of
H-type BSE to sheep and human. Bioassay will be required to determine whether
the PMCA products are infectious to these animals.
================
==========================================
***our findings suggest that possible transmission risk of H-type BSE to
sheep and human. Bioassay will be required to determine whether the PMCA
products are infectious to these animals.
==========================================
Thursday, December 17, 2015
Annual report of the Scientific Network on BSE-TSE 2015 EFSA-Q-2015-00738
10 December 2015
Saturday, December 12, 2015
BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION REPORT DECEMBER 14, 2015
Saturday, December 12, 2015
NOTICE: Environmental Impact Statement on Large Livestock Carcasses TSE
Prion REPORT December 14, 2015
Thursday, December 24, 2015
Infectious disease spread is fueled by international trade
Objects in contact with classical scrapie sheep act as a reservoir for
scrapie transmission
Timm Konold1*, Stephen A. C. Hawkins2, Lisa C. Thurston3, Ben C. Maddison4,
Kevin C. Gough5, Anthony Duarte1 and Hugh A. Simmons1
1 Animal Sciences Unit, Animal and Plant Health Agency Weybridge,
Addlestone, UK, 2 Pathology Department, Animal and Plant Health Agency
Weybridge, Addlestone, UK, 3 Surveillance and Laboratory Services, Animal and
Plant Health Agency Penrith, Penrith, UK, 4 ADAS UK, School of Veterinary
Medicine and Science, University of Nottingham, Sutton Bonington, UK, 5 School
of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington,
UK
Classical scrapie is an environmentally transmissible prion disease of
sheep and goats. Prions can persist and remain potentially infectious in the
environment for many years and thus pose a risk of infecting animals after
re-stocking. In vitro studies using serial protein misfolding cyclic
amplification (sPMCA) have suggested that objects on a scrapie affected sheep
farm could contribute to disease transmission. This in vivo study aimed to
determine the role of field furniture (water troughs, feeding troughs, fencing,
and other objects that sheep may rub against) used by a scrapie-infected sheep
flock as a vector for disease transmission to scrapie-free lambs with the prion
protein genotype VRQ/VRQ, which is associated with high susceptibility to
classical scrapie. When the field furniture was placed in clean accommodation,
sheep became infected when exposed to either a water trough (four out of five)
or to objects used for rubbing (four out of seven). This field furniture had
been used by the scrapie-infected flock 8 weeks earlier and had previously been
shown to harbor scrapie prions by sPMCA. Sheep also became infected (20 out of
23) through exposure to contaminated field furniture placed within pasture not
used by scrapie-infected sheep for 40 months, even though swabs from this
furniture tested negative by PMCA. This infection rate decreased (1 out of 12)
on the same paddock after replacement with clean field furniture. Twelve grazing
sheep exposed to field furniture not in contact with scrapie-infected sheep for
18 months remained scrapie free. The findings of this study highlight the role
of field furniture used by scrapie-infected sheep to act as a reservoir for
disease re-introduction although infectivity declines considerably if the field
furniture has not been in contact with scrapie-infected sheep for several
months. PMCA may not be as sensitive as VRQ/VRQ sheep to test for environmental
contamination.
snip...see more here ;
Wednesday, December 16, 2015
*** Objects in contact with classical scrapie sheep act as a reservoir for
scrapie transmission
Tuesday, December 15, 2015
Chronic Wasting Disease will cause a Wyoming deer herd to go virtually
extinct in 41 years, a five-year study predicts
Study: Chronic Wasting Disease kills 19% of deer herd annually
Chronic Wasting Disease will cause a Wyoming deer herd to go virtually
extinct in 41 years, a five-year study predicts.
The investigation, which relied on the capture of 143 deer, examined the
dynamics in the Southern Converse County Mule Deer Herd that lives southwest of
Douglas near Laramie Peak. There, a population that once numbered some 14,000 in
the early 2000s dwindled to half that size in about a decade.
The Chronic Wasting Disease study is one of only three that have been
conducted on wild deer, elk or moose herds, none of which have yet seen print.
While wildlife managers have long suspected CWD as a principle agent in the
ravaged Converse herd, the study puts numbers on the problem, calculating a 19
percent decline annually.
University of Wyoming doctoral student Melia DeVivo spent four years of
fieldwork and another year crunching numbers before defending her PhD thesis on
the herd. She calculated the herd would go extinct in 41 years, without taking
into account genetic differences that make some deer more resistant to CWD, or
accounting for deer migration into the area. Even when taking in those factors,
the herd will decline dramatically, she said.
“I estimated that CWD was causing a 19 percent annual reduction in the
population, which is pretty significant,” she said. “Potentially, in 41 years,
it would be locally extinct.”
snip...see full text ;
Saturday, December 05, 2015
CWD Prions Remain Infectious after Passage Through the Digestive System of
Coyotes (Canis latrans)
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
Tuesday, June 30, 2015
visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant
Creutzfeldt Jakob Disease hvCJD
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26
April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated
online 11 September 2015 Erratum (October, 2015)
*** Evidence for human transmission of amyloid-β pathology and cerebral
amyloid angiopathy
07 02:27 AM
re-Evidence for human transmission of amyloid-? pathology and cerebral
amyloid angiopathy
*** Terry S. Singeltary Sr. said:
I would kindly like to comment on the Nature Paper, the Lancet reply, and
the newspaper articles.
snip...see full text ;
Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO
PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
BSE101/1 0136
IN CONFIDENCE
CMO
From: . Dr J S Metiers DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
snip...
4. The other dimension to consider is the public reaction. To some extent
the GSS case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral injection. If other prion diseases can be transmitted in this way
it is little surprise that some pathological findings observed in GSS were also
transmissible to a marmoset. But the transmission of features of Alzheimer's
pathology is a different matter, given the much greater frequency of this
disease and raises the unanswered question whether some cases are the result of
a transmissible prion. The only tenable public line will be that "more research
is required’’ before that hypothesis could be evaluated. The possibility on a
transmissible prion remains open. In the meantime MRC needs carefully to
consider the range and sequence of studies needed to follow through from the
preliminary observations in these two cases. Not a particularly comfortable
message, but until we know more about the causation of Alzheimer's disease the
total reassurance is not practical.
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH
832 llllYc!eS 2 92/11.4/1.2
>>> The only tenable public line will be that "more
research is required’’ <<<
>>> possibility on a transmissible prion remains
open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is
"more research is required’’ enough time for evaluation ?
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14,
2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1
reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD)
has been stable since 1985. These estimates, however, are based only on reported
cases, and do not include misdiagnosed or preclinical cases. It seems to me that
misdiagnosis alone would drastically change these figures. An unknown number of
persons with a diagnosis of Alzheimer disease in fact may have CJD, although
only a small number of these patients receive the postmortem examination
necessary to make this diagnosis. Furthermore, only a few states have made CJD
reportable. Human and animal transmissible spongiform encephalopathies should be
reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
26 March 2003
Terry S. Singeltary, retired (medically) CJD WATCH
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?
2 January 2000
British Medical Journal
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
15 November 1999
British Medical Journal
vCJD in the USA * BSE in U.S.
The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003
doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI
Tracking spongiform encephalopathies in North America
Original
Xavier Bosch
“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.” 49-year—old Singeltary is
one of a number of people who have remained largely unsatisfied after being told
that a close relative died from a rapidly progressive dementia compatible with
spontaneous Creutzfeldt—Jakob ...
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number of
campaigners who say that some sCJD, like the variant CJD related to BSE, is
caused by eating meat from infected animals. Their suspicions have focused on
sheep carrying scrapie, a BSE-like disease that is widespread in flocks across
Europe and North America. Now scientists in France have stumbled across new
evidence that adds weight to the campaigners' fears. To their complete surprise,
the researchers found that one strain of scrapie causes the same brain damage in
mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb...
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 – 2009
The Pathological Protein:
Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases
Philip Yam
''Answering critics like Terry Singeltary, who feels that the US
undercounts CJD, Schonberger _conceded_ that the current surveillance system has
errors but stated that most of the errors will be confined to the older
population''....end
RIP MOM DOD December 14, 1997 confirmed Heidenhain Variant of Creutzfeldt
Jakob Disease hvCJD...I’m still here mom!
these blogs are for educational use. I do not advertise or make money from
them.
MOM DOD 12/14/97 confirmed hvCJD, just made a promise to mom, never forget,
and never let them forget...
Merry Christmas !
kindest regards, terry
Terry S. Singeltary Sr. Bacliff, Texas USA 77518 flounder9@verizon.net
posted by Terry S. Singeltary Sr. at
12:15 PM
