Creutzfeldt-Jakob disease: recent developments
REVIEW
Creutzfeldt-Jakob disease: recent developments
[version 1; referees: 2 approved]
Graeme Mackenzie https://orcid.org/0000-0002-7455-6883, Robert Will
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Abstract
Creutzfeldt-Jakob disease (CJD) is a rare prion disorder that has been the subject of both professional and public interest following the identification of variant CJD as a zoonotic disorder. There have been recent advances in diagnostic techniques, including real-time quaking-induced conversion and magnetic resonance imaging brain scan, that have allowed more accurate case recognition in all forms of CJD. Although the epidemic of variant CJD is clearly in decline, prevalence studies suggest that it may be premature to be complacent about concerns for public health.
Corresponding author: Graeme Mackenzie How to cite: Mackenzie G and Will R. Creutzfeldt-Jakob disease: recent developments [version 1; referees: 2 approved]. F1000Research 2017, 6(F1000 Faculty Rev):2053 (doi: 10.12688/f1000research.12681.1) Copyright: © 2017 Mackenzie G and Will R. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Competing interests: No competing interests were disclosed. First published: 27 Nov 2017, 6(F1000 Faculty Rev):2053 (doi: 10.12688/f1000research.12681.1) Latest published: 27 Nov 2017, 6(F1000 Faculty Rev):2053 (doi: 10.12688/f1000research.12681.1)
Introduction
Creutzfeldt-Jakob disease (CJD) belongs to a family of fatal degenerative disorders of the nervous system known as transmissible spongiform encephalopathies or prion diseases, which affect both animals and humans1. The term prion, derived from proteinaceous infectious particle, was coined by Stanley Prusiner after the identification of the disease-associated protein2. The normal prion protein, PrPC, is present in all mammalian species and is encoded by the prion gene (PRNP) on human chromosome 20. The function of prion protein has not been established. Prion diseases are characterised by the deposition of PrPSc, an abnormally misfolded isoform of the native prion protein, within the nervous system. The mechanism for triggering this conformational change is not known, but the accumulation of this abnormal prion protein leads to neuronal degeneration, astrocytic gliosis, and spongiform change, resulting in a uniformly fatal neurological disorder3.
The human prion disorders are heterogeneous with different phenotypes, epidemiology, and pathogenesis. Sporadic CJD (sCJD) is the commonest human prion disease, accounting for around 85% of cases; 10–15% are associated with mutations of PRNP and 1% are iatrogenic, most frequently associated with prior treatment with human pituitary-derived hormones or human dura mater grafts. Variant CJD (vCJD) is a novel human prion disease which occurs predominantly in the UK and has been linked to the consumption of beef products contaminated with the agent of the cattle disease, bovine spongiform encephalopathy (BSE)4–6.
sCJD has a very rapid disease course; mean survival is six months. Indeed, over 90% of patients die within a year of symptom onset. The peak incidence is in the seventh decade, and younger (20–40s) or older (>80) cases are less common7. The favoured hypothesis is that sCJD is a spontaneous neurodegenerative disease, resulting from either a somatic PRNP gene mutation or a random structural change in the PrP protein causing the formation of PrPSc2. An environmental source for the disease is not supported by epidemiological studies.
There have been recent developments in diagnostic investigations in CJD, and, although the vCJD outbreak is in decline, there are continuing concerns for public health in relation to the prevalence of infection in the normal population. These issues and the potential relevance of prion diseases to other neurodegenerative disorders are the main topics of this article.
Diagnosis
There is considerable variability in the way in which CJD can present clinically, which can make the initial diagnosis difficult. This heterogeneity of clinical presentation is linked, at least in part, to variations in the genotype at codon 129 of the prion protein gene and the type of PrPSc deposited in the brain. The genotype at codon 129 can be methionine homozygous (MM), valine homozygous (VV), or heterozygous (MV), and in the UK population, the normal codon 129 distribution has been reported as 39% MM, 50% MV, and 11% VV8. Two biochemically distinct forms of PrPSc, type 1 and type 2, can be deposited in the brain.
The classic clinical features of sCJD are rapid cognitive decline, ataxia, and myoclonus terminating in an akinetic mute state. The diagnosis of CJD is dependent upon assessment of clinical features together with specialist investigations. There has been an evolution in the diagnosis of CJD in recent years with the identification of new diagnostic tests, and this has been reflected in changes to the formal diagnostic criteria for sCJD used in the European Union (EU).
Magnetic resonance imaging
Magnetic resonance imaging in sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging (MRI) is the most useful investigation in sCJD, as it is highly sensitive and specific as well as widely available and relatively non-invasive9. The classic MRI findings in sCJD, including high signal in the caudate, putamen, or cortex (or a combination of these) on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences, are present in about 80% of cases9. DWI is more sensitive at detecting early cortical and subcortical changes (Figure 1).
9b90311d-46c9-4588-8c52-3601effe93a5_figure1.gif
Figure 1. Magnetic resonance imaging of sporadic Creutzfeldt-Jakob disease.
Diffusion-weighted image at the level of the basal ganglia demonstrates marked symmetrical hyperintensity in the caudate head and putamen with less marked affection of the thalami. Image courtesy of David Summers, Western General Hospital, Edinburgh, UK.
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Magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Symmetrical hyperintensity in the posterior thalamus, relative to the anterior putamen, on T2-weighted or FLAIR MRI is characteristic of vCJD and is known as the pulvinar sign (Figure 2)10. This finding is very rare in other types of prion disease11 and is reported to have a sensitivity of 78–90% and a specificity of 100% for vCJD in the right clinical setting5. The mediodorsal thalamic nucleus may also be involved and in combination with pulvinar hyperintensity produces an appearance coined the ‘hockey stick sign’. In 86 neuropathologically confirmed cases, involvement of the caudate nucleus on FLAIR MRI was shown in 40%, the putamen in 23.3%, and the periaqueductal grey matter in 83.3% (Figure 2)10.
9b90311d-46c9-4588-8c52-3601effe93a5_figure2.gif
Figure 2. Pulvinar sign of variant Creutzfeldt-Jakob disease. Axial fluid-attenuated inversion recovery image demonstrates symmetrical hyperintensity of the posterior thalamic nuclei. Image courtesy of David Summers, Western General Hospital, Edinburgh, UK.
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Until recently, all definite cases of vCJD have been MM at codon 129, which may account for the observed similarity of MRI findings in these cases when compared with other human prion diseases. This concept has been challenged, however, with the recent description of a neuropathologically confirmed case of vCJD with a heterozygous genotype at codon 12912. The MRI findings in this case demonstrated restricted diffusion in the basal ganglia, hypothalamus, insular cortexes, and medial thalami but not in the pulvinar nuclei.
Real-time quaking-induced conversion
A number of cerebrospinal fluid (CSF) biomarkers, including 14-3-3, S100b, and tau, have been found to be elevated in patients with CJD. These proteins have limited specificity but can be diagnostically useful in the appropriate clinical context13.
Real-time quaking-induced conversion (RT-QuIC) is a relatively new CSF test which has shown remarkably high sensitivity and specificity in recent studies (sensitivity of 85.7% and specificity of 100%) in sCJD14. The technique involves using recombinant PrP as a substrate which is then induced to aggregate by adding CSF containing PrPSc. Thioflavin T then binds to the aggregated PrPSc, causing a change in the thioflavin T emission spectrum and enabling the reaction to be monitored in real time (Figure 3). It is also a useful investigation for some genetic forms of CJD15.
9b90311d-46c9-4588-8c52-3601effe93a5_figure3.gif
Figure 3. Real-time quaking-induced conversion (RT-QuIC) responses from reactions seeded with cerebrospinal fluid (CSF) from two sporadic Creutzfeldt-Jakob disease (sCJD) cases and a positive sCJD CSF control.
The RT-QuIC from an unseeded reaction and a reaction seeded with brain homogenate from Alzheimer’s disease are also shown. Image courtesy of Neil McKenzie, University of Edinburgh, Edinburgh, UK. AD BH, Alzheimer’s disease brain homogenate; RFU, relative fluorescence units; ThT, thioflavin T.
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Real-time quaking-induced conversion olfactory mucosa and cerebrospinal fluid. The use of olfactory mucosa (OM) nasal brushings combined with RT-QuIC has been shown to improve the diagnosis of sCJD16. In a recent study17, the combined utilisation of CSF and OM RT-QuIC produced an overall specificity and sensitivity of 100% for the diagnosis of sCJD. OM RT-QuIC is limited, however, by the technical expertise required to obtain appropriate specimens. Although RT-QuIC is clearly a useful test for sCJD, the assay in its current form does not amplify the PrPSc in vCJD18.
Blood and urine tests in variant Creutzfeldt-Jakob disease
In an attempt to develop a better pre-mortem test for vCJD, a number of studies have attempted to detect the abnormal PrPSc in vCJD in blood and urine by using protein misfolding cyclic amplification (PMCA). In 2014, Moda et al. successfully detected PrPSc in the urine of patients with vCJD19. The study looked at 238 urine samples from patients with vCJD, sCJD, or genetic prion diseases and healthy controls in a blinded study. Using PMCA, they were able to amplify the PrPSc to detectable amounts with a sensitivity of 93% and a specificity of 100% in vCJD. All the sCJD and control samples were negative.
Similar studies using PMCA have led to the detection of PrPSc in plasma from clinical vCJD as well as in pre-clinical blood samples taken from two vCJD patients who had donated blood prior to the onset of symptoms20,21. This is the first time that a test has successfully identified PrPSc in pre-clinical samples, and it may have the potential to be applied as a screening tool in transfusion medicine, although further validation is necessary.
Electroencephalogram
The electroencephalogram (EEG) is now a less useful investigation given the advent of MRI and CSF tests. Nonetheless, it remains an important, non-invasive surrogate marker for sCJD. The typical EEG appearances in sCJD are periodic, triphasic sharp wave complexes. These changes in the right clinical setting have a 90% specificity for CJD9 but are known to occur in other conditions, such as end-stage Alzheimer’s disease, Lewy body dementia, and metabolic encephalopathies22,23.
Diagnostic criteria for sCJD
The current diagnostic criteria used in the EU have been updated to include the cortical changes on MRI and RT-QuIC and are shown in Table 1.
1.1 DEFINITE: …
1.2 PROBABLE: …
1.3 POSSIBLE: …
I Rapidly p…
Table 1. Diagnostic criteria for surveillance of sporadic Creutzfeldt-Jakob disease from 1 January 2017. Epidemiology
The incidence of sCJD is frequently quoted as one per million population per annum. However, there has been a consistent gradual increase in mortality rates in the UK and in many other countries in which systematic surveillance is undertaken. This may relate to changes in population demographics, with an increase in the numbers of individuals in the age cohorts with a high incidence of sCJD, and improved case ascertainment as a result of increased awareness and more sensitive diagnostic investigations. Mortality rates of 1.5–2 cases per million may be more realistic on current evidence.
The vCJD epidemic is in marked decline both in the UK and internationally (Figure 4). Until recently, all tested cases of definite and probable vCJD had been MM at codon 129 of PRNP, but in 2015 a confirmed case with an MV genotype was identified12. This raises the possibility of a further outbreak, although it is likely that should this occur the number of cases will be relatively limited and probably lower than those of the primary epidemic in the MM population. The UK population were exposed to a significant level of BSE infectivity in the food chain in the 1980s and early 1990s, and the relatively small scale of the vCJD epidemic may imply a significant barrier to infection between bovines and humans24.
9b90311d-46c9-4588-8c52-3601effe93a5_figure4.gif Figure 4. Variant Creutzfeldt-Jakob disease cases by year and country. MV, methionine valine heterozygous; PRNP, prion gene.
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Secondary transmission of vCJD through blood transfusion is now established with three clinical cases of vCJD linked to the transfusion of non-leucodepleted red blood cells derived from individuals who themselves went on to develop vCJD25. In addition, a recipient of an implicated transfusion who died of a non-neurological disorder was found to have PrPSc positivity in the spleen, suggesting pre-clinical infection26. This individual was a codon 129 heterozygote, and laboratory transmission studies demonstrated prion infectivity in the spleen with characteristics similar to those of primary cases.
The prevalence of vCJD infection in the general UK population has been studied by examining routine appendicectomy samples by immunocytochemistry. Positive samples were identified in 19 out of 33,115 appendices, leading to an estimated prevalence of 1 in 4,000 in the general population27. This is a matter of concern, as there is no clinical evidence of infection prior to neuro-invasion in prion diseases and the mean incubation period in vCJD has been estimated to be 15 years. A more recent study examined appendix samples from before 1980, prior to the presumed start of the BSE epidemic, and in those born after 1996, after which human exposure to BSE was thought to be minimal. Surprisingly, 7 out of 15,959 of these samples were positive, suggesting either a more extended period of human exposure to BSE or perhaps that positivity may not imply infection with vCJD28.
Other misfolding protein disorders
In addition to prion diseases, there are a number of diseases associated with protein misfolding. These conditions are associated with the accumulation of oligomers of A-beta, tau, and alpha-synuclein and include Alzheimer’s disease, Parkinson’s disease (PD), and Huntington’s29. The identification of alpha-synuclein deposits in a foetal graft in patients with PD30,31 led to the hypothesis that there may be the potential of seeding of protein from abnormal to normal tissue and subsequently there have been extensive studies in laboratory animals that suggest that this may occur in many protein misfolding disorders32. The presence of beta-amyloid deposits in the brains of human growth hormone recipients and not in age-matched controls has added to concerns about parallels between prion diseases and other neurodegenerative diseases33,34. Whether this is an important issue for public health is uncertain and there may be a difference between seeding of protein and the actual transmission of a disease. One epidemiological study, for example, has shown no evidence of transfusion transmission of a number of neurodegenerative disorders, including Alzheimer’s disease35.
Conclusions
The diagnosis of CJD has improved in recent years with the advent of improved brain imaging and the development of specific CSF tests in sCJD and the potential for diagnostic tests in plasma and urine in vCJD. The public health concerns raised by the BSE epidemic have clearly decreased as new cases of vCJD have become a rarity in both the UK and other countries. However, the potential prevalence of infection in the general population remains a matter of concern and the parallels between prion diseases and other protein misfolding disorders are an area of active and continued research.
Tuesday, December 12, 2017
Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology
WEDNESDAY, NOVEMBER 1, 2017
Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies
MONDAY, NOVEMBER 06, 2017
Experimental transfusion of variant CJD-infected blood reveals previously uncharacterised prion disorder in mice and macaque
''On secondary and tertiary transmissions, however, the proportion of PrPres positive animals gradually increased to almost 100%.
''Recent communications suggest that a similar situation might exist in other models of experimental exposure to prions involving swine32 and cattle33.''
''Experimental transfusion of variant CJD-infected blood reveals previously uncharacterised prion disorder in mice and macaque''
SATURDAY, DECEMBER 02, 2017
Public health risks from subclinical variant CJD
MONDAY, OCTOBER 02, 2017
Creutzfeldt Jakob Disease United States of America USA and United Kingdom UK Increasing and Zoonotic Pontential From Different Species
THURSDAY, AUGUST 17, 2017
*** Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States revisited 2017
Singeltary et al
THURSDAY, JULY 13, 2017
TEXAS CREUTZFELDT JAKOB DISEASE CJD TSE PRION
SUNDAY, NOVEMBER 23, 2014
Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas in June 2014 confirmed as USA case NOT European
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
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***
===============
***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.
==============
Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
SPONTANEOUS ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***
1st, this is an old document, but thought you should have it for your files...
Chronic wasting disease AND TISSUES THAT MIGHT CARRY A RISK FOR HUMAN FOOD AND ANIMAL FEED CHAINS REPORT
Detection of Prions in Blood of Cervids at the Asymptomatic Stage of Chronic Wasting Disease
Carlos Kramm, Sandra Pritzkow, Adam Lyon, Tracy Nichols, Rodrigo Morales & Claudio Soto
Scientific Reports 7, Article number: 17241 (2017) doi:10.1038/s41598-017-17090-x
Download Citation NeurodegenerationPathogens
Received: 21 August 2017
Accepted: 21 November 2017
Published online: 08 December 2017
Abstract
Chronic wasting disease (CWD) is a rapidly spreading prion disorder affecting captive and free-ranging cervids. The zoonotic potential of CWD is unknown, as well as the mechanism for its highly efficient transmission. A top priority to minimize further spreading of this disease and its potential impact on environmental prion contamination is the development of a non-invasive, sensitive, and specific test for ante-mortem detection of infected animals. Here, we optimized the protein misfolding cyclic amplification (PMCA) assay for highly efficient detection of CWD prions in blood samples. Studies were done using a blind panel of 98 field-collected samples of whole blood from codon 96 glycine/glycine, captive white-tailed deer that were analyzed for prion infection post-mortem by immunohistochemistry (IHC). The results showed a sensitivity of 100% in animals with very poor body condition that were IHC-positive in both brain and lymph nodes, 96% in asymptomatic deer IHC-positive in brain and lymph nodes and 53% in animals at early stages of infection that were IHC-positive only in lymph nodes. The overall mean diagnostic sensitivity was 79.3% with 100% specificity. These findings show that PMCA might be useful as a blood test for routine, live animal diagnosis of CWD.
snip...
Discussion
A safe, non-invasive, sensitive and specific live animal test to identify cervids infected with CWD prions is a top priority to control further spreading of this emerging infectious disease. Availability of such a test could have many important applications, including: (i) screening of deer farms to remove infected animals before they can spread substantial amounts of prions into the environment; (ii) monitoring the efficacy of prion decontamination procedures; (iii) monitoring the extent of environmental prion contamination; and (iv) whole herd screenings for determination of CWD status.
Currently, the only definitive way to diagnose CWD is by post-mortem examination of brain and lymphoid tissues for the presence of PrPSc by IHC, the current gold standard for prion detection. Various attempts have been made to develop a test for ante-mortem detection of prions during the long, silent period between prion infection and the onset of clinical signs of the disease, which can encompass several months or years. One strategy that has been evaluated is palatine tonsil biopsy followed by IHC analysis48. However, this method is invasive and time consuming, and requires anesthesia that may lead to complications. An alternative possibility for ante-mortem CWD detection, is rectal biopsy followed by IHC analysis for protease resistant PrPSc. Various independent studies have shown the efficacy of this procedure for pre-clinical detection of prions in CWD-infected animals24,25,26. In a collaborative study between the Canadian Food Inspection Agency and the USDA, a detailed analysis was done for the sensitivity and specificity of IHC detection of PrPSc in rectal biopsy samples25. For this study, samples were collected post-mortem from white-tailed deer in four CWD-infected herds. PrPSc detection was compared to the CWD infection rate estimated by IHC analysis of the obex and MRPLN. The overall diagnostic sensitivity of this assay was estimated at 68%, including all stages of the disease and all polymorphic variants analyzed25. The study also showed a clear correlation between disease progression, genotype at codon 96 and the presence of PrPSc signal in rectal biopsy samples. Disease progression was estimated from the presence and degree of PrPSc signal in obex as well as prion detection in MRPLN. In early disease progression (low obex grades), the diagnostic sensitivity of the rectal biopsy assay was 36% in samples from animals that did not have PrPSc in brain, but were positive in MRPLN25. The genotype at codon 96 also strongly influenced the outcome of the rectal biopsy IHC, with GG animals having a higher detection rate than GS and SS animals25. Sensitivity was slightly increased by using RT-QuIC instead of IHC, reaching an overall diagnostic sensitivity (including all disease stages and polymorphisms) of 70% in samples obtained by rectal biopsy36. In this study, sensitivity for RT-QuIC in rectal samples from animals negative in the obex was 25%, compared to only 8% using IHC. However, several false positives were found using this technique, decreasing specificity to 94%36. The same authors also analyzed the efficacy of RT-QuIC using nasal brushing as a less invasive sample collection compared to rectal biopsy. The results showed a diagnostic sensitivity of only 34%49, suggesting that this strategy is significantly less effective for cervid samples than human sCJD samples50.
In our blind study using field collected blood samples from white-tailed deer, we found a mean overall diagnostic sensitivity of 79.3%, with 100% specificity. Sensitivity for blood samples from CWD-infected animals at the pre-clinical stage of the disease was 96%, when were IHC positive in both the obex and the MRPLN. For similar samples in which only the MRPLN was IHC positive, sensitivity was reduced to 53%. Provided that the infection status of these animals was correctly determined by IHC and because of the extremely high sensitivity of PMCA, which is able to detect few particles of PrPSc aggregates45,46, these results suggest that at some stages of the pre-clinical disease, infected animals may not have PrPSc in blood. Since obtaining blood samples is relatively non-invasive, a much more accurate ante-mortem laboratory diagnosis of CWD could be done by repeating the PMCA test multiple times in live animals. This scheme is useful because sensitivity approaches 100% as the disease progress. Nevertheless, further studies need to be done employing larger number of samples in which the status of prion infection has been confirmed by IHC and a biochemical procedure (western blot or ELISA), as well as analyzing the efficacy of the test in animals harboring the less frequent Prnp genotypes (such as GS and SS at position 96). Studies should also be done in blood samples longitudinally collected from experimentally infected deer to determine the earliest time in which PrPSc can be detected by PMCA and the dynamic changes on the PrPSc levels present in blood during the incubation period. Our results suggest that PMCA may provide a suitable platform for rapid prion diagnosis in farmed and wild cervids. Early and non-invasive CWD prion detection could not only help to control severely affected premises, but also be useful for surveillance of areas where CWD cases are not yet known to occur.
CHRONIC WASTING DISEASE CWD TSE PRION ZOONOTIC ZOONOSIS
PRICE OF TSE PRION POKER GOES UP!
2017
Subject: ***CDC Now Recommends Strongly consider having the deer or elk tested for CWD before you eat the meat
CDC Now Recommends Strongly consider having the deer or elk tested for CWD before you eat the meat
Chronic Wasting Disease (CWD)
Prevention
If CWD could spread to people, it would most likely be through eating of infected deer and elk. In a 2006-2007 CDC survey of U.S. residents, nearly 20 percent of those surveyed said they had hunted deer or elk and more than two-thirds said they had eaten venison or elk meat. However, to date, no CWD infections have been reported in people.
Hunters must consider many factors when determining whether to eat meat from deer and elk harvested from areas with CWD, including the level of risk they are willing to accept. Hunters harvesting wild deer and elk from areas with reported CWD should check state wildlife and public health guidance to see whether testing of animals is recommended or required in a given state or region. In areas where CWD is known to be present, CDC recommends that hunters strongly consider having those animals tested before eating the meat.
Tests for CWD are monitoring tools that some state wildlife officials use to look at the rates of CWD in certain animal populations. Testing may not be available in every state, and states may use these tests in different ways. A negative test result does not guarantee that an individual animal is not infected with CWD, but it does make it considerably less likely and may reduce your risk of exposure to CWD.
To be as safe as possible and decrease their potential risk of exposure to CWD, hunters should take the following steps when hunting in areas with CWD:
Do not shoot, handle or eat meat from deer and elk that look sick or are acting strangely or are found dead (road-kill). When field-dressing a deer: Wear latex or rubber gloves when dressing the animal or handling the meat. Minimize how much you handle the organs of the animal, particularly the brain or spinal cord tissues. Do not use household knives or other kitchen utensils for field dressing. Check state wildlife and public health guidance to see whether testing of animals is recommended or required. Recommendations vary by state, but information about testing is available from many state wildlife agencies. Strongly consider having the deer or elk tested for CWD before you eat the meat. If you have your deer or elk commercially processed, consider asking that your animal be processed individually to avoid mixing meat from multiple animals. If your animal tests positive for CWD, do not eat meat from that animal. The U.S. Department of Agriculture’s Animal and Plant Health Inspection Service regulates commercially farmed deer and elk. The agency operates a national CWD herd certification program. As part of the voluntary program, states and individual herd owners agree to meet requirements meant to decrease the risk of CWD in their herds. Privately owned herds that do not participate in the herd certification program may be at increased risk for CWD.
Page last reviewed: August 17, 2017 Page last updated: August 17, 2017 Content source: Centers for Disease Control and Prevention National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Division of High-Consequence Pathogens and Pathology (DHCPP)
> However, to date, no CWD infections have been reported in people.
key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry
LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$
*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***
Molecular Barriers to Zoonotic Transmission of Prions
*** chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.
*** Furthermore, the form of human PrPres produced in this in vitro assay when seeded with CWD, resembles that found in the most common human prion disease, namely sCJD of the MM1 subtype.
TUESDAY, SEPTEMBER 12, 2017
CDC Now Recommends Strongly consider having the deer or elk tested for CWD before you eat the meat
Prion 2017 Conference Abstracts CWD
https://ec.europa.eu/food/sites/food/files/safety/docs/sci-com_ssc_out324_en.pdf
2017 PRION CONFERENCE
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen
This is a progress report of a project which started in 2009. 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves.
Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice.
At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation.
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS
Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO
PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS
*** PRION 2017 CONFERENCE VIDEO
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
TUESDAY, JULY 04, 2017
*** PRION 2017 CONFERENCE ABSTRACTS ON CHRONIC WASTING DISEASE CWD TSE PRION ***
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT Chronic Wasting Disease in European moose is associated with PrPSc features different from North American CWD
Wednesday, May 24, 2017
PRION2017 CONFERENCE VIDEO UPDATE 23 – 26 May 2017 Edinburgh UPDATE 1
SATURDAY, JULY 29, 2017
Risk Advisory Opinion: Potential Human Health Risks from Chronic Wasting Disease CFIA, PHAC, HC (HPFB and FNIHB), INAC, Parks Canada, ECCC and AAFC
Prion Infectivity in Fat of Deer with Chronic Wasting Disease▿
Brent Race#, Kimberly Meade-White#, Richard Race and Bruce Chesebro* + Author Affiliations
In mice, prion infectivity was recently detected in fat. Since ruminant fat is consumed by humans and fed to animals, we determined infectivity titers in fat from two CWD-infected deer. Deer fat devoid of muscle contained low levels of CWD infectivity and might be a risk factor for prion infection of other species.
Prions in Skeletal Muscles of Deer with Chronic Wasting Disease
Here bioassays in transgenic mice expressing cervid prion protein revealed the presence of infectious prions in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk to prion exposure.
*** WDA 2016 NEW YORK ***
We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions.
Wildlife Disease Risk Communication Research Contributes to Wildlife Trust Administration Exploring perceptions about chronic wasting disease risks among wildlife and agriculture professionals and stakeholders
Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo Zoonotic Potential of CWD Prions: An Update
Ignazio Cali1, Liuting Qing1, Jue Yuan1, Shenghai Huang2, Diane Kofskey1,3, Nicholas Maurer1, Debbie McKenzie4, Jiri Safar1,3,5, Wenquan Zou1,3,5,6, Pierluigi Gambetti1, Qingzhong Kong1,5,6
1Department of Pathology, 3National Prion Disease Pathology Surveillance Center, 5Department of Neurology, 6National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
4Department of Biological Sciences and Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada,
2Encore Health Resources, 1331 Lamar St, Houston, TX 77010
Chronic wasting disease (CWD) is a widespread and highly transmissible prion disease in free-ranging and captive cervid species in North America. The zoonotic potential of CWD prions is a serious public health concern, but the susceptibility of human CNS and peripheral organs to CWD prions remains largely unresolved. We reported earlier that peripheral and CNS infections were detected in transgenic mice expressing human PrP129M or PrP129V. Here we will present an update on this project, including evidence for strain dependence and influence of cervid PrP polymorphisms on CWD zoonosis as well as the characteristics of experimental human CWD prions.
PRION 2016 TOKYO
In Conjunction with Asia Pacific Prion Symposium 2016
PRION 2016 Tokyo
Prion 2016
Cervid to human prion transmission
Kong, Qingzhong
Case Western Reserve University, Cleveland, OH, United States
Abstract
Prion disease is transmissible and invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting deer, elk and moose, and it is a widespread and expanding epidemic affecting 22 US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic prion transmission risks in North America because of huge venison consumption (>6 million deer/elk hunted and consumed annually in the USA alone), significant prion infectivity in muscles and other tissues/fluids from CWD-affected cervids, and usually high levels of individual exposure to CWD resulting from consumption of the affected animal among often just family and friends. However, we still do not know whether CWD prions can infect humans in the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis has already occurred, and we have no essays to reliably detect CWD infection in humans. We hypothesize that:
(1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;
(2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;
(3) Reliable essays can be established to detect CWD infection in humans;and
(4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.
Aim 1 will prove that the classical CWD strain may infect humans in brain or peripheral lymphoid tissues at low levels by conducting systemic bioassays in a set of "humanized" Tg mouse lines expressing common human PrP variants using a number of CWD isolates at varying doses and routes. Experimental "human CWD" samples will also be generated for Aim 3.
Aim 2 will test the hypothesis that the cervid-to-human prion transmission barrier is dependent on prion strain and influenced by the host (human) PrP sequence by examining and comparing the transmission efficiency and phenotypes of several atypical/unusual CWD isolates/strains as well as a few prion strains from other species that have adapted to cervid PrP sequence, utilizing the same panel of humanized Tg mouse lines as in Aim 1.
Aim 3 will establish reliable essays for detection and surveillance of CWD infection in humans by examining in details the clinical, pathological, biochemical and in vitro seeding properties of existing and future experimental "human CWD" samples generated from Aims 1-2 and compare them with those of common sporadic human Creutzfeldt-Jakob disease (sCJD) prions.
Aim 4 will attempt to detect clinical CWD-affected human cases by examining a significant number of brain samples from prion-affected human subjects in the USA and Canada who have consumed venison from CWD-endemic areas utilizing the criteria and essays established in Aim 3. The findings from this proposal will greatly advance our understandings on the potential and characteristics of cervid prion transmission in humans, establish reliable essays for CWD zoonosis and potentially discover the first case(s) of CWD infection in humans.
Public Health Relevance There are significant and increasing human exposure to cervid prions because chronic wasting disease (CWD, a widespread and highly infectious prion disease among deer and elk in North America) continues spreading and consumption of venison remains popular, but our understanding on cervid-to-human prion transmission is still very limited, raising public health concerns. This proposal aims to define the zoonotic risks of cervid prions and set up and apply essays to detect CWD zoonosis using mouse models and in vitro methods. The findings will greatly expand our knowledge on the potentials and characteristics of cervid prion transmission in humans, establish reliable essays for such infections and may discover the first case(s) of CWD infection in humans.
Funding Agency Agency National Institute of Health (NIH)
Institute National Institute of Neurological Disorders and Stroke (NINDS)
Type Research Project (R01)
Project # 1R01NS088604-01A1
Application # 9037884
Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer Wong, May
Project Start 2015-09-30
Project End 2019-07-31
Budget Start 2015-09-30
Budget End 2016-07-31
Support Year 1
Fiscal Year 2015
Total Cost $337,507
Indirect Cost $118,756
Institution
Name Case Western Reserve University
Department Pathology
Type Schools of Medicine
DUNS # 077758407
City Cleveland
State OH
Country United States
Zip Code 44106
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To: Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD. That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From: Sent: Sunday, September 29, 2002 10:15 AM
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease 2008 1: Vet Res. 2008 Apr 3;39(4):41 A prion disease of cervids: Chronic wasting disease Sigurdson CJ.
snip...
*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,
snip... full text ;
I urge everyone to watch this video closely...terry
*** you can see video here and interview with Jeff's Mom, and scientist telling you to test everything and potential risk factors for humans ***
*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. These circumstances represent a potential threat to blood, blood products, and plasma supplies.
BSE INQUIRY
*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). ***
*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). ***
*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).
*** There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).
The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).
snip...
It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).
snip...
In conclusion, an analysis of dietary histories revealed statistical associations between various meats/animal products and INCREASED RISK OF CJD. When some account was taken of possible confounding, the association between VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS STATISTICALLY. ...
snip...
***In the study in the USA, a range of foodstuffs were associated with an increased risk of CJD, including liver consumption which was associated with an apparent SIX-FOLD INCREASE IN THE RISK OF CJD.
By comparing the data from 3 studies in relation to this particular dietary factor, the risk of liver consumption became non-significant with an odds ratio of 1.2 (PERSONAL COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)
snip...see full report ;
you can see more evidence here ;
Chronic wasting disease AND TISSUES THAT MIGHT CARRY A RISK FOR HUMAN FOOD AND ANIMAL FEED CHAINS REPORT
WEDNESDAY, NOVEMBER 22, 2017
NIH scientists and collaborators find infectious prion protein in skin of CJD patients
http://creutzfeldt-jakob-disease.blogspot.com/2017/11/nih-scientists-and-collaborators-find.html
http://creutzfeldt-jakob-disease.blogspot.com/2017/11/nih-scientists-and-collaborators-find.html
WEDNESDAY, NOVEMBER 22, 2017
Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
http://creutzfeldt-jakob-disease.blogspot.com/2017/11/prion-seeding-activity-and-infectivity.html
Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
http://creutzfeldt-jakob-disease.blogspot.com/2017/11/prion-seeding-activity-and-infectivity.html
*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
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.
http://synucleinopathy.blogspot.com/ (no post yet...tss)
DECEMBER 14, 2017, 20 YEARS POST DOD MOM HEIDENHAIN VARIANT CREUTZFELDT JAKOB DISEASE HVCJD DECEMBER 14, 1997, JUST MADE A PROMISE TO MOM, AND YOU DON'T BREAK PROMISES WITH YOUR MOM, NEVER FORGET, AND NEVER LET THEM FORGET...TERRY S. SINGELTARY SR.
posted by Terry S. Singeltary Sr. at
12:31 PM
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