Incidence of and Mortality Due to Human Prion Diseases in Taiwan: A Prospective 20-Year Nationwide Surveillance Study from 1998 to 2017
This article was published in the following Dove Press journal: Clinical Epidemiology
Yu Sun 1,2 Chih-Ching Liu3, * Ling-Yun Fan4, * Chung-Te Huang5 Ta-Fu Chen2 Chien-Jung Lu1,2 Wan-Yuo Guo 6,7 Yang-Chyuan Chang2,8 Ming-Jang Chiu 2,9–11
1 Department of Neurology, En Chu Kong Hospital, New Taipei City, Taiwan; 2 Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 3 Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan; 4 Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, QLD, Australia; 5 Center for Research, Diagnostics and Vaccine Development, Taiwan Centers for Disease Control, Taipei, Taiwan; 6 Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 7 School of Medicine, National Yang-Ming University, Taipei, Taiwan; 8 Department of Neurology, Min-Sheng General Hospital, Taoyuan, Taiwan; 9 Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; 10Graduate Institute of Psychology, College of Science, National Taiwan University, Taipei, Taiwan; 11Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
*These authors contributed equally to this work
Correspondence: Ming-Jang Chiu Tel +886-2-23123456 ext 65339 Fax +886-2-23418395 Email mjchiu@ntu.edu.tw
Introduction: Epidemiologic studies of Creutzfeldt-Jakob disease (CJD) have been undertaken worldwide since the new variant CJD outbreak in 1996 in the United Kingdom. A nationwide report system, the Creutzfeldt-Jakob Disease Surveillance Unit (CJDSU), directed by the Centers for Disease Control of Taiwan, was established in 1997 to identify human prion diseases.
Methods: From 1998 to 2017, 647 cases were referred to the committee for confirmation. The report to CJDSU included a structured questionnaire recording the clinical, demographic data, and potential iatrogenic exposure, and the results of the clinical and laboratory examination, including tests of blood and cerebrospinal fluid, electroencephalography, and brain magnetic resonance imaging.
Results: In total, 356 cases (women, n=178) were ascertained to be human prion diseases, and 97.4% (n=347) were sporadic CJD, including three definite, 314 probable, and 30 possible cases; one probable variant CJD and 8 cases of the genetic form human prion diseases. The age- and gender-specific average annual incidence were also significantly higher in the second decade (0.95/1,000,000) than in the first decade (0.63/1,000,000), with an incidence rate ratio of 1.51. The incidences increased with increasing age, reaching a peak at the age of 70–79 years. The 10-year survival curve for sCJD patients showed that the 1-, 5-, and 10-year cumulative survival rate were 52%, 5%, and 1%, respectively. PRNP polymorphisms in 170 patients showed that 98.8% were M129M and 97.6% E219E.
Discussion: The significant increase in incidence after 2008 suggests the increase in the awareness of this rare disease among physicians. The longer disease duration in patients with sCJD in Taiwan than in other countries indicates that the comprehensive support of the health care system, as well as the end-of-life care culture in Taiwan, may prolong survival time in patients with such a progressive and fatal disease.
Keywords: human prion diseases, spongiform encephalopathy, incidence, mortality, disease duration
snip...
Discussion
Our previous epidemiological research of CJD from 1998 to 2007 has been reported 10 years ago.3 In current analysis, we rechecked the information of all the ascertained cases of the first decade in the registry and found that 9 cases before 2005 should be excluded because they could not meet the diagnostic criteria with some missing data. Moreover, 2 cases that were identified in 2008 actually had their disease onset in 2007 by tracing their history again.
The overall incidence rate of CJD from 1998 to 2017 in Taiwan was 0.79 per million persons. The incidence significantly increased after 2008 to approximately 1 case per million persons per year, comparable to the worldwide incidence, typically reported to be approximately 1–2 per million person-years based on surveillance from 2005 onward.2,20 The increase in incidence for the second decade could be explained by the enhanced awareness of clinical physicians, the improved diagnostic tests, and the increase in the aging population in Taiwan, as the incidence of CJD cases, peaked in the 70- to 79-year-old age group similar distribution to the USA study.21 The incidence of CJD onset after 80 years of age was still high, without a sharp decline, which was different from other reports.6,22 Since the start of the CJDSU in 1997, several national or international symposiums focused on human transmissible spongiform encephalopathy have been held by the Taiwan Neurological Society to educate neurologists and general physicians about the updated diagnostic criteria and management of CJD patients. The Taiwan CDC has regularly revised the workbook.23 In 2008, an imported case of vCJD was reported to CJDSU.19 This first acquired case of CJD in Taiwan was a critical public health concern and might have helped raise awareness of the disease among neurologists, leading to an increase in the number of reported cases afterward. In 2009, an updated set of criteria, including MRI findings, were proposed and soon adopted by the CJDSU.17 The pattern of high signal intensity had high sensitivity and specificity for the differential diagnosis, assisting in distinguishing sCJD from other neurological diseases and helping clinicians detect suspected cases early; this, in part, resulted in the increase in the number of referrals in subsequent years.
The polymorphism at codon 129 (M129V) of PRNP is a recognized genetic marker for susceptibility to CJD in Caucasians.24 In Europe, 51% of the general population has methionine/valine (MV) heterozygosity, while 37% has methionine homozygosity (MM).25,26 In East Asia, the MM genotype was found in 94% of Koreans27 and 92% of Japanese individuals.26 Ethnic Han Chinese, who account for over 95% of the Taiwanese population, has a remarkably high frequency (98%) of methionine homozygosity in the general population.28 Methionine homozygosity is high in both healthy individuals and diseased patients, with 98.8% of CJD patients in our study having the MM genotype and less than 2% carrying the MV genotype. Prion susceptibility and protective alleles can exhibit marked geographic differences, with the effects being different in the Asian and Caucasian populations.26
Because of the short disease duration in most cases, the increase in mortality with time parallels the temporal trend in incidence, as the mortality rate was significantly higher in the second decade than in the first decade. There was no difference in the incidence and mortality rates between men and women in our study. Some countries reported a higher incidence in women than men because of the larger number of women among older populations.21 The disease duration varied based on CJD types, with a relatively chronic course in some genetic forms. The mean survival time was 56.4 (range, 35.1–67.4) months in four GSS patients (P102L), 15.4 (9.0, 21.7) months in two E196A patients, and 11.9 months in an R148H patient, while a substantially shorter disease duration of 2.4 months was noted in a patient with a 72-base pair insertion. Because of the small number of gCJD patients in our study, it is challenging to compare Taiwan with other countries regarding these patients’ survival time.
Among the patients with sCJD, women and those with younger ages at onset had longer disease durations. This finding is comparable with the results from a collaborative multi-national CJD surveillance program (EUROCJD) conducted by the European Union and allied countries. The precise mechanisms underlying the effects of age and gender effects on survival time are not known. Agerelated variations in care or resistance to terminal infections have been proposed as possible explanations.29 Whether gender-specific factors influence the disease duration needs to be studied. In this national cohort, we found some long-term survivors of sCJD, with 3-, 5- and 10-year survival rates of 13%, 5%, and 1%, respectively. The median survival time was 13.5 months (mean: 19.1 months), and 48% died within one year of onset. Our data were similar to those in the report from Japan, in which the mean survival time of sCJD patients was 15.7 (range: 1–126) months, and 46.0% of all patients with prion disease died within one year. 29 However, reports from other counties revealed a much shorter survival time. The study by the EUROCJD involving 2,451 sCJD patients showed that the median survival time was five months (range: 1–81), and 85.8% died within one year of onset.11 The median duration in a study involving 150 definite or probable sCJD cases in Argentina was 4.6 (range: 1–70) months,30 while a Swedish study involving 123 patients with prion disease found that 74.6% of patients died within one year. 31 A study from China also showed a short survival time, with a median duration of 7.1 months (range: 1.0–23.3), and 78.5% of patients died within one year of onset.10
The survival times of patients with sCJD in Taiwan and Japan were relatively longer than those reported in most of the other countries in the world. Japanese researchers explained the prolonged survival as the effects of their robust public medical insurance system and a culture allowing patients with end-stage neurological disease to receive intensive life-sustaining treatments such as tube feeding and intravenous high-calorie infusion.9,32 Taiwan adopted a single-payer National Health Insurance (NHI) system in 1995 that also provides comprehensive healthcare support.33 Patients with human prion disease do not need to pay any co-payment for outpatient or inpatient care. In addition, Taiwanese also share this end-of-life care culture.
There are several limitations to the current study. First, the percentage of definite cases of human spongiform encephalopathies was relatively small. Because of the traditional ethical values among the general population in Taiwanese society, the very low autopsy rate has long been acknowledged as an unfortunate and unavoidable reality. In recent years, using the real-time quaking-induced conversion assay to detect the pathological prion protein in the CSF or other tissues has been developed and has high diagnostic accuracy. 34 However, this technique was not used by the CJDSU in Taiwan during our study period. Without obtaining tissue specimens or testing for the pathological prion protein, we are not only unable to make a definite diagnosis but also are unable to assess the various molecular subtypes of sCJD, which is useful for phenotypic classification. Second, underreporting and underestimation of CJD are inevitable. Because of the older age at onset, patients with CJD may be misdiagnosed with other diseases with the rapid progression of neurological symptoms such as stroke,35 encephalitides,36 degenerative dementia,37 and epilepsy. 38 A retrospective archival survey published in 1995 showed that only approximately 60% of prion disease patients with pathologically spongiform encephalopathy were diagnosed clinically while alive. In recent decades, diagnostic accuracy has been improved by the use of CSF biomarkers and brain MRI.17 Not infrequently, the committee recommended that the primary care physician follow-up during the clinical course and perform MRI/EEG in case of uncertainty. They were obliged to report back at the next relevant meeting.
Furthermore, due to our NHI system’s comprehensive coverage, patients with spongiform encephalopathy received complete financial support covering all necessary MRI or EEG follow-up. There is nearly a consensus in clinical practice among neurologists in Taiwan that for those patients with rapid cognitive decline, in addition to CSF studies, MRI and EEG examination, tests to exclude autoimmune encephalitis or paraneoplastic encephalopathy should usually be performed. Third, the finding of 2% (8/356) of gCJD among all CJD forms was far lower than the corresponding figures elsewhere in the world, which range from 10–14%.25,39 Although the incidence of gCJD varies considerably among countries, we speculate that the lower proportion of gCJD in our study is likely because the PRNP gene sequencing test was not routinely performed before 2009, only 170 of the 356 CJD cases tested. Approximately 60% of genetic CJD cases were reported in patients with no family history, suggesting that they could have been misclassified in the absence of the PRNP genetic analysis.39
In conclusion, this study reports the 20-year epidemiologic features of CJD in Taiwan. The second decade’s incidence rate was comparable with the corresponding figures in most other countries in the world. The significant increase in incidence after 2008 suggests the increase in awareness of this rare disease among clinical physicians and the increase in Taiwan’s aging population. The longer disease duration in patients with sCJD in Taiwan than in Western countries indicates that the healthcare system and end-of-life care culture in Taiwan may prolong survival time in patients with such a rapidly progressive and fatal disease.
***> The significant increase in incidence after 2008 suggests the increase in awareness of this rare disease among clinical physicians and the increase in Taiwan’s aging population.
that dog don't hunt no more...TSS
Conclusion: The incidence rate of CJD in Taiwan after 2007 was extremely higher than before, probably due to the physician´s sensitivity, improved reporting system, people concerning of variant CJD cases, and the high media coverage.
Prion 2016 Invited Lecture Abstracts
IL-19: Epidemiological and clinical features of human prion diseases in Japan: Prospective 17-year surveillance
Masahito Yamada Tsuyoshi Hamaguchi Kenji Sakai Ichiro Nozaki Moeko Noguchi-Shinohara Nobuo Sanjo Tadashi Tsukamoto Ryusuke Ae Yosikazu Nakamura Tetsuyuki Kitamoto Hidehiro Mizusawa
CJD Surveillance Committee, Japan Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan Department of Public Health, Jichi Medical University, Shimotsuke, Japan Department of Prion Protein Research, Division of CJD Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan
We analyzed the epidemiological and clinical features of patients with prion diseases registered by the Creutzfeldt-Jakob Disease (CJD) Surveillance Committee, Japan over the past 17 y since 1999.
Until September 2015, we obtained information on 5,041 Japanese patients suspected as having prion diseases, and judged that 2,596 patients had prion diseases.
The annual incidence rate/million of prion diseases during 1999-2013 ranged from 0.7 (1999) to 1.8 (2011/2012/2013) with an average 1.3.
The 2,596 patients with prion diseases were classified into 1,999 (77.0%) with sporadic CJD (sCJD), 501 (19.3%) with genetic prion diseases, 87 (3.4%) with acquired prion diseases, including 86 cases of dura mater graft-associated CJD (dCJD) and one case of variant CJD, and 7 cases of unclassified CJD (0.3%).
In sCJD, MM1 type (Parchi's classification) is most common; among atypical sCJD cases, MM2 type appeared most common, probably related to the fact that methionine homozygosity at codon 129 polymorphism of the prion protein gene (PrP) was very common (93%) in the general Japanese population.
As for iatrogenic CJD, only dCJD cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt-Jakob disease was 149, comprising the majority of worldwide dCJD patients.
Most of the dCJD patients received cadaveric dura mater graft before or in 1987, and we still had onset of dCJD cases in recent years; the incubation period (i.e., duration from implantation of dura mater grafts to dCJD onset) was increasing to 13.2 ± 6.3 (mean ± SD) years (range, 1 to 30 years).
Regarding genetic prion diseases, the most common PrP mutation was V180I (46.7%), followed by P102L (16.6%), E200K (14.0%), and M232R (13.6%).
The distribution of the mutations was quite different from that in Europe.
The V180I and M232R mutations were quite rare worldwide. Interestingly, patients with V180I or M232R rarely had a family history of prion diseases, and our recent study with large population control cohorts indicated that such missense variants have significant effects on lifetime prion disease risk.
In conclusion, our data from the prospective 17-year surveillance revealed distinct features of human prion diseases in Japan: frequent and continuous occurrence of dCJD, and unique phenotypes of sCJD and genetic prion diseases related to the characteristic distribution of PrP mutations and polymorphisms in the Japanese population, different from those in western countries.
IL-21: Surveillance of prion diseases in Taiwan
Shun-Sheng Chen
Taiwan C. J. D. Working Group
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Taipei, Taiwan
CJD Working Group, Taiwan Neurological Society, Taipei, Taiwan
Objective: To compare the incidence rate from 1993 to 20105 and figure out the incidence increment and characteristics of CJD in Taiwan through Surveillance of prion disease in Taiwan.
Background: In Taiwan, national CJD surveillance unit (CJDSU) was setup in Taiwan Neurological Society since 1997. The incidence rates of CJD were raised up after 2007 in Taiwan and also in other industrial countries. For this reason, we try to figure out the risk factors which might be connected with this phenomenon.
Methods: Registry and Surveillance system in Taiwan: The surveillance system was a nationwide, hospital-based case report system, which was directed by the government organization, Centers for Disease Control of Taiwan, and Taiwan Neurological society since 1997. This CJDSU system performed a national survey to all the hospitals in Taiwan. In 2007, the health government announced CJD is one of the forth statutory epidemical diseases. All suspected cases are requested to registry on epidemical disease system online and notify the CJDSU for detail following and clinical tracing.
When a case is suspected, the infection control unite or neurologist will contact with CJDSU's assistant first and get a preparation note for continue work. The physician has to offer copy discs of EEG examination and MRI imagines and fill out 3 kinds of structured comprehensive questionnaire sheets. The CJD committee formed by experts of neurologists, neurosurgeons, radiologists and neuropathologists, would hold a case-identifying meeting to discuss the reported cases and determine the diagnosis of CJD.
Our criteria are based on the WHO and European CJD case definition criteria form the basis for disease classification, include EEG and MRI examination, while 'probable cases' and 'possible cases' are classified in accordance with recognized and validated clinical criteria. Also, we introduced 14-3-3 protein examination of cerebrospinal fluid as assistant criteria of CJD since 2000.
During period of 1 Jan 1997 to 31 Dec 2015, the CJDSU received more than 500 suspect TSE case notifications from 38 Neurological Training Centers in Taiwan. All cases are requested to registry online and notify the CJDSU for consensus of diagnosis, tracing and assess differences of categorical and continuous variables between 2 period groups (before and after 2007).
Results: There were more than 500 cases prospectively reported to the CJDSU. Among them, 370 cases were diagnosed with CJD; with a sex ration of M/F 1:1.09. All cases were refereed as probable or possible cases except 4 cases of GSS form and 1 probable case of new-variant CJD immigrant from UK. The incidence rates were between 0.30-1.492 per million populations, and case numbers had notified double during 2008 to 2015 with incidence raised up to 1.414, which had been fall after 2014. Between two groups, the clinical features, EEG , MRI, genetic polymorphism, and CSF 14-3-3 protein had no differences, but age-onset is earlier than before.
Conclusion: The incidence rate of CJD in Taiwan after 2007 was extremely higher than before, probably due to the physician´s sensitivity, improved reporting system, people concerning of variant CJD cases, and the high media coverage.
Keywords: CJD, incidence rate, nvCJD, polymorphism, Taiwan
IL-22: Real-time quaking-induced conversion analysis for the diagnosis of sporadic Creutzfeldt-Jakob disease in Korea
Yong-Sun Kim
Ilsong Institute of Life Science, Hallym University/Department of Neurodegenerative Diseases, Korea CJD Diagnostic Center, Chuncheon-si, Korea The 14-3-3 protein is increased in the cerebrospinal fluid (CSF) of Creutzfeldt-Jakob disease (CJD) patients and has been thus used as a clinical biomarker for the pre-mortem diagnosis of human prion diseases. Nonetheless, the specificity of 14-3-3 protein is less reliable for CJD diagnosis. The newly developed assays including real-time quaking-induced conversion (RT-QuIC) made it possible to detect PrPSc-like abnormal prion isoform with a high sensitivity in animal and human specimens that might have a minute amount of PrPSc by in vitro prion replication. In this study, we performed a highly sensitive RT-QuIC assay using recombinant human PrP for the detection of PrPSc in CSF of 100 sporadic CJD (sCJD) patients in Korea. By analyzing CSF samples of 100 patients with sCJD and of 190 non-CJD patients based on the expression levels of 14-3-3, total tau and RT-QuIC assay, the positivity of RT-QuIC analysis was observed in 77 of 100 CSF samples (sensitivity 77%) but no positive in the non-CJD patients. The sensitivity of RT-QuIC in this study was similar to that in some previous reports and the specificity of RT-QuIC was higher than that of 14-3-3 in CSF, suggesting that RT-QuIC analysis can complement the weakness of the specificity of 14-3-3 for the diagnosis of sCJD. These results indicate that RT-QuIC might be of great use for rapid and specific diagnosis of sCJD and suggest a practicable novel method for the ante-mortem diagnosis of human prion diseases.
This research was supported by the National Research Foundation of Korea Grant Funded by the Korean Government (NRF-2011K3A1A1003362) and by Hallym University Specialization Fund (HRF-S-41).
Keywords. Creutzfeldt-Jakob disease, cerebrospinal fluid, RT-QuIC, 14-3-3, total tau
Prion 2015 Conference Poster Abstracts
2020 NOVEMBER
SATURDAY, SEPTEMBER 26, 2020
A nationwide trend analysis in the incidence and mortality of Creutzfeldt–Jakob disease in Japan between 2005 and 2014 with increasing trends of incidence and mortality
FRIDAY, OCTOBER 30, 2020
Analysis of Chinese patients with sporadic Creutzfeldt-Jakob disease
MONDAY, OCTOBER 05, 2020
USA, UK, JAPAN, CJD TSE PRION STATISTICS UPDATE OCTOBER 2020
MONDAY, JANUARY 20, 2020
sporadic CJD one in a million, FAKE NEWS PEOPLE!
this myth has been incorrect for decades, and had been stated as such by a few, but again, the media is too lazy to do it's job and print the facts.
human tse prion, including 85%+ of all human tse i.e. sporadic cjd, is now one in 5,000!
ZOONOSIS OF SCRAPIE TSE PRION
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.
PRION 2016 TOKYO
Saturday, April 23, 2016
SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online
Taylor & Francis
Prion 2016 Animal Prion Disease Workshop Abstracts
WS-01: Prion diseases in animals and zoonotic potential
Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,
Natalia Fernandez-Borges a. and Alba Marin-Moreno a
"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France
Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion... Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.
To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.
These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.
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.
***> why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough.
***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
Title: Transmission of scrapie prions to primate after an extended silent incubation period)
*** 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.
***> 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. <***
Transmission of scrapie prions to primate after an extended silent incubation period
Emmanuel E. Comoy, Jacqueline Mikol, Sophie Luccantoni-Freire, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Valérie Durand, Capucine Dehen, Olivier Andreoletti, Cristina Casalone, Juergen A. Richt, Justin J. Greenlee, Thierry Baron, Sylvie L. Benestad, Paul Brown & Jean-Philippe Deslys Scientific Reports volume 5, Article number: 11573 (2015) | Download Citation
Abstract
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.
SNIP...
Discussion We describe the transmission of spongiform encephalopathy in a non-human primate inoculated 10 years earlier with a strain of sheep c-scrapie. Because of this extended incubation period in a facility in which other prion diseases are under study, we are obliged to consider two alternative possibilities that might explain its occurrence. We first considered the possibility of a sporadic origin (like CJD in humans). Such an event is extremely improbable because the inoculated animal was 14 years old when the clinical signs appeared, i.e. about 40% through the expected natural lifetime of this species, compared to a peak age incidence of 60–65 years in human sporadic CJD, or about 80% through their expected lifetimes. 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.
The second possibility is a laboratory cross-contamination. Three facts make this possibility equally unlikely. First, handling of specimens in our laboratory is performed with fastidious attention to the avoidance of any such cross-contamination. Second, no laboratory cross-contamination has ever been documented in other primate laboratories, including the NIH, even between infected and uninfected animals housed in the same or adjacent cages with daily intimate contact (P. Brown, personal communication). Third, the cerebral lesion profile is different from all the other prion diseases we have studied in this model19, with a correlation between cerebellar lesions (massive spongiform change of Purkinje cells, intense PrPres staining and reactive gliosis26) and ataxia. The iron deposits present in the globus pallidus are a non specific finding that have been reported previously in neurodegenerative diseases and aging27. Conversely, the thalamic lesion was reminiscent of a metabolic disease due to thiamine deficiency28 but blood thiamine levels were within normal limits (data not shown). The preferential distribution of spongiform change in cortex associated with a limited distribution in the brainstem is reminiscent of the lesion profile in MM2c and VV1 sCJD patients29, but interspecies comparison of lesion profiles should be interpreted with caution. It is of note that the same classical scrapie isolate induced TSE in C57Bl/6 mice with similar incubation periods and lesional profiles as a sample derived from a MM1 sCJD patient30.
We are therefore confident that the illness in this cynomolgus macaque represents a true transmission of a sheep c-scrapie isolate directly to an old-world monkey, which taxonomically resides in the primate subdivision (parvorder of catarrhini) that includes humans. With an homology of its PrP protein with humans of 96.4%31, cynomolgus macaque constitutes a highly relevant model for assessing zoonotic risk of prion diseases. Since our initial aim was to show the absence of transmission of scrapie to macaques in the worst-case scenario, we obtained materials from a flock of naturally-infected sheep, affecting animals with different genotypes32. This c-scrapie isolate exhibited complete transmission in ARQ/ARQ sheep (332 ± 56 days) and Tg338 transgenic mice expressing ovine VRQ/VRQ prion protein (220 ± 5 days) (O. Andreoletti, personal communication). From the standpoint of zoonotic risk, it is important to note that sheep with c-scrapie (including the isolate used in our study) have demonstrable infectivity throughout their lymphoreticular system early in the incubation period of the disease (3 months-old for all the lymphoid organs, and as early as 2 months-old in gut-associated lymph nodes)33. In addition, scrapie infectivity has been identified in blood34, milk35 and skeletal muscle36 from asymptomatic but scrapie infected small ruminants which implies a potential dietary exposure for consumers.
Two earlier studies have reported the occurrence of clinical TSE in cynomolgus macaques after exposures to scrapie isolates. In the first study, the “Compton” scrapie isolate (derived from an English sheep) and serially propagated for 9 passages in goats did not transmit TSE in cynomolgus macaque, rhesus macaque or chimpanzee within 7 years following intracerebral challenge1; conversely, after 8 supplementary passages in conventional mice, this “Compton” isolate induced TSE in a cynomolgus macaque 5 years after intracerebral challenge, but rhesus macaques and chimpanzee remained asymptomatic 8.5 years post-exposure8. However, multiple successive passages that are classically used to select laboratory-adapted prion strains can significantly modify the initial properties of a scrapie isolate, thus questioning the relevance of zoonotic potential for the initial sheep-derived isolate. The same isolate had also induced disease into squirrel monkeys (new-world monkey)9. A second historical observation reported that a cynomolgus macaque developed TSE 6 years post-inoculation with brain homogenate from a scrapie-infected Suffolk ewe (derived from USA), whereas a rhesus macaque and a chimpanzee exposed to the same inoculum remained healthy 9 years post-exposure1. This inoculum also induced TSE in squirrel monkeys after 4 passages in mice. Other scrapie transmission attempts in macaque failed but had more shorter periods of observation in comparison to the current study. Further, it is possible that there are differences in the zoonotic potential of different scrapie strains.
The most striking observation in our study is the extended incubation period of scrapie in the macaque model, which has several implications. Firstly, our observations constitute experimental evidence in favor of the zoonotic potential of c-scrapie, at least for this isolate that has been extensively studied32,33,34,35,36. The cross-species zoonotic ability of this isolate should be confirmed by performing duplicate intracerebral exposures and assessing the transmissibility by the oral route (a successful transmission of prion strains through the intracerebral route may not necessarily indicate the potential for oral transmission37). However, such confirmatory experiments may require more than one decade, which is hardly compatible with current general management and support of scientific projects; thus this study should be rather considered as a case report.
Secondly, transmission of c-BSE to primates occurred within 8 years post exposure for the lowest doses able to transmit the disease (the survival period after inoculation is inversely proportional to the initial amount of infectious inoculum). The occurrence of scrapie 10 years after exposure to a high dose (25 mg) of scrapie-infected sheep brain suggests that the macaque has a higher species barrier for sheep c-scrapie than c-BSE, although it is notable that previous studies based on in vitro conversion of PrP suggested that BSE and scrapie prions would have a similar conversion potential for human PrP38.
Thirdly, prion diseases typically have longer incubation periods after oral exposure than after intracerebral inoculations: since humans can develop Kuru 47 years after oral exposure39, an incubation time of several decades after oral exposure to scrapie would therefore be expected, leading the disease to occur in older adults, i.e. the peak age for cases considered to be sporadic disease, and making a distinction between scrapie-associated and truly sporadic disease extremely difficult to appreciate.
Fourthly, epidemiologic evidence is necessary to confirm the zoonotic potential of an animal disease suggested by experimental studies. A relatively short incubation period and a peculiar epidemiological situation (e.g., all the first vCJD cases occurring in the country with the most important ongoing c-BSE epizootic) led to a high degree of suspicion that c-BSE was the cause of vCJD. Sporadic CJD are considered spontaneous diseases with an almost stable and constant worldwide prevalence (0.5–2 cases per million inhabitants per year), and previous epidemiological studies were unable to draw a link between sCJD and classical scrapie6,7,40,41, even though external causes were hypothesized to explain the occurrence of some sCJD clusters42,43,44. However, extended incubation periods exceeding several decades would impair the predictive values of epidemiological surveillance for prion diseases, already weakened by a limited prevalence of prion diseases and the multiplicity of isolates gathered under the phenotypes of “scrapie” and “sporadic CJD”.
Fifthly, considering this 10 year-long incubation period, together with both laboratory and epidemiological evidence of decade or longer intervals between infection and clinical onset of disease, no premature conclusions should be drawn from negative transmission studies in cynomolgus macaques with less than a decade of observation, as in the aforementioned historical transmission studies of scrapie to primates1,8,9. Our observations and those of others45,46 to date are unable to provide definitive evidence regarding the zoonotic potential of CWD, atypical/Nor98 scrapie or H-type BSE. The extended incubation period of the scrapie-affected macaque in the current study also underscores the limitations of rodent models expressing human PrP for assessing the zoonotic potential of some prion diseases since their lifespan remains limited to approximately two years21,47,48. This point is illustrated by the fact that the recently reported transmission of scrapie to humanized mice was not associated with clinical signs for up to 750 days and occurred in an extreme minority of mice with only a marginal increase in attack rate upon second passage13. The low attack rate in these studies is certainly linked to the limited lifespan of mice compared to the very long periods of observation necessary to demonstrate the development of scrapie. Alternatively, one could estimate that a successful second passage is the result of strain adaptation to the species barrier, thus poorly relevant of the real zoonotic potential of the original scrapie isolate of sheep origin49. The development of scrapie in this primate after an incubation period compatible with its lifespan complements the study conducted in transgenic (humanized) mice; taken together these studies suggest that some isolates of sheep scrapie can promote misfolding of the human prion protein and that scrapie can develop within the lifespan of some primate species.
In addition to previous studies on scrapie transmission to primate1,8,9 and the recently published study on transgenic humanized mice13, our results constitute new evidence for recommending that the potential risk of scrapie for human health should not be dismissed. Indeed, human PrP transgenic mice and primates are the most relevant models for investigating the human transmission barrier. To what extent such models are informative for measuring the zoonotic potential of an animal TSE under field exposure conditions is unknown. During the past decades, many protective measures have been successfully implemented to protect cattle from the spread of c-BSE, and some of these measures have been extended to sheep and goats to protect from scrapie according to the principle of precaution. Since cases of c-BSE have greatly reduced in number, those protective measures are currently being challenged and relaxed in the absence of other known zoonotic animal prion disease. We recommend that risk managers should be aware of the long term potential risk to human health of at least certain scrapie isolates, notably for lymphotropic strains like the classical scrapie strain used in the current study. Relatively high amounts of infectivity in peripheral lymphoid organs in animals infected with these strains could lead to contamination of food products produced for human consumption. Efforts should also be maintained to further assess the zoonotic potential of other animal prion strains in long-term studies, notably lymphotropic strains with high prevalence like CWD, which is spreading across North America, and atypical/Nor98 scrapie (Nor98)50 that was first detected in the past two decades and now represents approximately half of all reported cases of prion diseases in small ruminants worldwide, including territories previously considered as scrapie free... Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.
Like lambs to the slaughter
* 31 March 2001 *
Debora MacKenzie *
Magazine issue 2284
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
Exclusive from New Scientist magazine
Four years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious.
The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Photo: Murdo McLeod
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.
Brain damage Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health.
But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD.
They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three.
Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.
As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain.
As expected, they all affected the brain in a different way from BSE and vCJD.
But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology. Multiple strains "The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys.
"You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie," she says.
In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar. But there are more than 20 strains of scrapie, and six of sCJD.
"You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys.
Bruce is cautious about the mouse results, but agrees they require further investigation.
Other trials of scrapie and sCJD in mice, she says, are in progress.
Deformed proteins People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways.
Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD. But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD.
"If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere.
Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain.
Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.
Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE.
And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.
More at: Proceedings of the National Academy of Sciences (vol 98, p 4142)
Correspondence about this story should be directed to letters@newscientist.com 1900 GMT, 28 March 2001
* New Scientist
http://www.newscientist.com/dailynews/news.jsp?id=ns9999560
http://www.newscientist.com/article.ns?id=mg16922840.300
http://www.newscientist.com/article.ns?id=mg16922840.300
2.3.2. New evidence on the zoonotic potential of atypical BSE and atypical scrapie prion strains
2.3.2. New evidence on the zoonotic potential of atypical BSE and atypical scrapie prion strains
Olivier Andreoletti, INRA Research Director, Institut National de la Recherche Agronomique (INRA) – École Nationale Vétérinaire de Toulouse (ENVT), invited speaker, presented the results of two recently published scientific articles of interest, of which he is co-author: ‘Radical Change in Zoonotic Abilities of Atypical BSE Prion Strains as Evidenced by Crossing of Sheep Species Barrier in Transgenic Mice’ (MarinMoreno et al., 2020) and ‘The emergence of classical BSE from atypical/Nor98 scrapie’ (Huor et al., 2019).
In the first experimental study, H-type and L-type BSE were inoculated into transgenic mice expressing all three genotypes of the human PRNP at codon 129 and into adapted into ARQ and VRQ transgenic sheep mice. The results showed the alterations of the capacities to cross the human barrier species (mouse model) and emergence of sporadic CJD agents in Hu PrP expressing mice: type 2 sCJD in homozygous TgVal129 VRQ-passaged L-BSE, and type 1 sCJD in homozygous TgVal 129 and TgMet129 VRQ-passaged H-BSE.
WEDNESDAY, OCTOBER 28, 2020
EFSA Annual report of the Scientific Network on BSE-TSE 2020 Singeltary Submission
SUNDAY, OCTOBER 11, 2020
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FRIDAY, OCTOBER 23, 2020
Scrapie TSE Prion Zoonosis Zoonotic, what if?
SUNDAY, OCTOBER 11, 2020
Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ
WEDNESDAY, OCTOBER 28, 2020
EFSA Annual report of the Scientific Network on BSE-TSE 2020 Singeltary Submission
TUESDAY, SEPTEMBER 29, 2020
ISO's Updated 22442 Animal Tissue Standards — What Changed? TSE Prion!
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THURSDAY, SEPTEMBER 24, 2020
The emergence of classical BSE from atypical/ Nor98 scrapie
TUESDAY, SEPTEMBER 22, 2020
APHIS USDA MORE SCRAPIE ATYPICAL Nor-98 Confirmed USA September 15 2020
Monday, September 14, 2020
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MONDAY, AUGUST 24, 2020
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Why is USDA "only" BSE TSE Prion testing 25,000 samples a year?
Friday, January 17, 2014
Taiwan Opening to Canadian beef conditional: Health Ministry BSE CJD UPDATE
Terry Singeltary, Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis
Terry S. Singeltary Sr.
