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Prognostic Features of Sporadic Creutzfeldt-Jakob Disease: An Analysis of Taiwan's Nationwide Surveillance

Prognostic Features of Sporadic Creutzfeldt-Jakob Disease: An Analysis of Taiwan's Nationwide Surveillance

ORIGINAL STUDY| VOLUME 23, ISSUE 5, P845-851, MAY 01, 2022

Prognostic Features of Sporadic Creutzfeldt-Jakob Disease: An Analysis of Taiwan's Nationwide Surveillance

Yu Sun, MD, PhD Ling-Yun Fan, MD, MS Chung-Te Huang, PhD Chih-Ching Liu, PhD Ta-Fu Chen, MD, PhD Chien-Jung Lu, MD Wan-Yuo Guo, MD, PhD Yang-Chyuan Chang, MD, MBA Ming-Jang Chiu, MD, PhD 

Published: September 04, 2021DOI:https://doi.org/10.1016/j.jamda.2021.08.010

Abstract

Objectives

To study the prognostic features of Creutzfeldt-Jakob disease (CJD) and shed light on its future therapy.

Design

Retrospective cohort study of a longitudinal national cohort of the Taiwan Centers for Disease Control.

Setting and Participants

All patients with suspected CJD are reported to the CJD surveillance unit of the Taiwan Centers for Disease Control. An expert committee discussed the reported cases and designated a consensus-based diagnosis. From 1996 to 2020, a total of 809 cases were referred to the CJD surveillance unit for confirmation; of these, 441 cases (women, n = 230) were determined to be sporadic CJD.

Methods

We investigated the clinical manifestations and laboratory findings for 400 patients diagnosed with definite or probable sporadic CJD. We used Kaplan-Meier analyses and Cox proportional hazards model to identify prognostic factors.

Results

The mean age of onset was 67 ± 9.9 years. The mean survival duration was 13.3 ± 14.2 (median 10) months. The leading clinical symptoms were myoclonus (73%) and akinetic mutism (54%). For PRNP polymorphism, 99% of patients (195/197) showed a methionine homozygous genotype at codon 129 (M129M). The sensitivity of periodic sharp wave complexes (PSWCs) on electroencephalograms (EEGs) was 59.7%. The sensitivity of cerebrospinal fluid 14-3-3 protein and total tau protein (>1200 pg/mL) were 69.7% and 75.6%, respectively. Younger patients lived longer than those aged ≥65 years [hazard ratio (HR) 0.466, P < .001]. Women had a better survival probability in the first 3 years than their male counterparts (HR 0.712, P = .005). PSWCs had a persistent negative effect on survival (HR 0.788, P < .05). Although uncommon, epileptic seizures were the only clinical prognostic factor for survival time (HR 0.768, P < .05). PSWCs can be used as an EEG biomarker for prognosis. Epileptic seizures, though not common, are the only clinical prognostic factor for a short survival.

Conclusions and Implications

We found that a lower age of onset and female gender favor the survival of patients with sCJD. PSWCs are EEG biomarkers unfavorable for survival, and so are epileptic seizures.

Keywords Cortical ribbon signs periodic sharp wave complexes 14-3-3 tau epileptic seizure


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


Research Paper

Difference of geographic distributions of the Chinese patients with prion diseases in the permanent resident places and referring places

Kang Xiao, Ming-Fan Pang, Yue-Qiao Zhao, Li-Ping Gao, Yue-Zhang Wu, Yuan Wang, show all Pages 58-65 | Received 08 Nov 2021, Accepted 13 May 2022, Published online: 30 May 2022


ABSTRACT 

Human prion diseases (PrDs) are a group of transmissible neurodegenerative diseases that can be clarified as sporadic, genetic and iatrogenic forms. In this study, we have analysed the time and geographic distributions of 2011 PrD cases diagnosed by China National Surveillance for Creutzfeldt-Jakob disease (CNS-CJD) since 2006, including 1792 sporadic CJD (sCJD) cases and 219 gPrD cases. Apparently, the cases numbers of both sCJD and gPrD increased along with the surveillance years, showing a stepping up every five years. The geographic distributions of the PrDs cases based on the permanent residences were wide, distributing in 30 out of 31 provincial-level administrative divisions in Chinese mainland. However, the case numbers in the provincial level varied largely. The provinces in the eastern part of China had much more cases than those in the western part. Normalized the case numbers with the total population each province revealed higher incidences in six provinces. Further, the resident and referring places of all PrD cases were analysed, illustrating a clear concentrating pattern of referring in the large metropolises. Five provincial-level administrative divisions reported more PrD cases from other provinces than the local ones. Particularly, BJ reported not only more than one-fourth of all PrDs cases in Chinese mainland but also 3.64-fold more PrDs cases from other provinces than its local ones. We believed that good medical resources, well-trained programmes and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities. Snip...

Discussion As a rare disease, less than 10 Chinese PrD or CJD cases had been described in the literatures in 1990ʹs. More and more PrD cases have been identified and diagnosed since 2006 we conducted CNS-CJD, particularly in the past recent years [15,20]. Small numbers of definite sCJD cases and overnumbered probable sCJD cases in CNS-CJD are closely related with the extremely low rate of autopsy in China. Moreover, more and more provinces actively refer PrD cases to CNS-CJD along with the surveillance years. Our data here propose that about half of the provinces in Chinese mainland continually reported PrD cases in the past 10 years. It reflects that the clinical recognition capacity for PrD in Chinese mainland has been improved markedly after the implementation of CNS-CJD. We have noticed the obvious diversity in geographic distribution of the PrD cases based on their permanent addresses among the provinces. The case numbers in the provinces locating at the western part of China are much less. After normalized with the total population of each province, the geographic patterns of PrD cases has changed in a certain degree. More referred cases are concentrated in the large metropolises, such as BJ, SH TJ and CQ, with higher ratio of urban population, better medical resources and economic situation, which is most likely reflecting the wide and good knowledge of PrD among the physicians in those large cities. Our data also figure out that five provincial-level administrative divisions, including BJ, SH, GD, CQ and SN, have referred more cases of PrDs coming from other provinces than those from locals. JL province has referred the same numbers of PrD cases as the local ones. The referred case numbers of the rest provinces in Chinese mainland are less than the local ones. This scenario demonstrates excessive contributions of those five provinces to identifying and referring PrD cases. As the capital of China, BJ city has unparalleled medical resources. Ordinarily, about half of the patients in the large hospitals in BJ come from other provinces [21], particularly the patients of rare and difficult-diagnosed diseases. Previously, we had analysed the CJD surveillance activity in BJ from 2006 to 2013, proposing that the ratio of the diagnosed PrD cases from local and other provinces is 1:3.07 [21]. Such ratio maintains unchanged, even slightly increases, by June 2020 from the data in this study (1:3.65), strongly indicating the continually great role of BJ in the recognition for PrDs in CNS-CJD. On the other point, the PrD cases reported from BJ show a wide geographic distribution covering 28 different provinces, despite of large amount of cases from the neighbour provinces. It reflects that the BJ’s medical system supplies the medical services not only for BJ’s people but also for the people outside of BJ. In addition to BJ, the other four provincial-level administrative divisions (SH, GD, CQ and SH) also contribute more PrD cases from other provinces. Unlike BJ, the outside PrD cases reported from those four provinces mainly locate at the neighbour provinces. Like BJ, SH and CQ are also metropolises with high level of medical resources, making them capable of receiving hundreds of patients from the neighbour provinces. Guangzhou and Xi’an cities are the capital cities of provinces GD and SN, respectively. There are more than two medical universities and dozens of large hospitals in those two large cities. Apparently, good medical resources in the large cities are one of the major elements for identifying and referring PrDs. During the implementation of CNS-CJD, different trainings from clinical to laboratory have been conducted by China CDC almost every surveillance year. The trainees come from both the CDC sections and the department of neurology in hospitals. In some places, e.g., BJ and SH, the provincial-level CDCs have also conducted further PrD trainings to more physicians from local hospitals. We believe that those training programs have enhanced the capacity of the clinicians for PrDs. Actually, the numbers of hospitals referring PrD cases in BJ and SH are much more than the other cities (data not shown). As a huge and developing countries, the medical resources in Chinese mainland is markedly unbalance. Both numbers of referred PrD cases and referring hospitals in the western part of China are less. Further practicable training programs for the staffs in those provinces are critical. Our data here has illustrated the similar profiles in referring sCJD and gPrD cases among the provinces that BJ city has referred more than one-third of all diagnosed gPrD cases in Chinese mainland. Besides of FFI [13,22], other types of gPrDs (gCJD and GSS) usually display undistinguishable clinical manifestations as sCJD, except that the onset-ages of gPrDs are usually young [23,24]. In fact, the vast majority of gCJD and GSS were referred as sCJD before PRNP sequencing. Notably, HA province referred obviously more FFI cases than other provinces, since more than one-third of Chinese FFI cases lived in HA [22]. Good knowledge of FFI possibly makes the local neurologists more sensitive for the patients with unexplainable sleeping problem. Conclusions According to our study, the cases numbers of both sCJD and gPrD increased along with the surveillance years, with a wide geographic distribution in Chinese mainland. However, the case numbers in the eastern provinces were much more than those in the western provinces. Our study indicated that good medical resources, well training programs and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities.

KEYWORDS: Prion diseaseCreutzfeldt-Jakob diseasesurveillancecase referringgeographic difference 


Original Article

Published: 06 September 2021

Genetic Prion Disease: Insight from the Features and Experience of China National Surveillance for Creutzfeldt-Jakob Disease

Qi Shi, Cao Chen, Kang Xiao, Wei Zhou, Li-Ping Gao, Dong-Dong Chen, Yue-Zhang Wu, Yuan Wang, Chao Hu, Chen Gao & Xiao-Ping Dong Neuroscience Bulletin volume 37, pages1570–1582 (2021)Cite this article

Abstract

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50–59 year group. Gerstmann–Sträussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.


Research Article

Analysis of Chinese patients with sporadic Creutzfeldt-Jakob disease

Jing Yang,Haiyan Kuang,Qiong Wang,Jiao Liu,Xueping Chen &Huifang Shang

Pages 137-142 | Received 18 Feb 2020, Accepted 22 Apr 2020, Published online: 07 May 2020


ABSTRACT

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, incurable, and fatal neurodegenerative disorder. The objective of this study was to describe the clinical features and survival time of Chinese sCJD patients, and to explore the associations between clinical data and survival. In this study, we analysed the clinical data of 21 sCJD patients in a tertiary care hospital and used all Chinese case material available from 152 patients with sCJD in literatures between 2008 and 2018. The mean age of onset of all 173 deceased patients was 61.44 year-olds (y), with the highest incidence in the population of 60 to 69 y. The most common manifestation at disease onset was progressive dementia. With the progression of the disease, the four main clinical symptoms and signs were developed, including myoclonus, visual or cerebella disturbance, pyramidal or extrapyramidal dysfunction, and akinetic mutism. Extrapyramidal symptoms were more frequently observed. The mean survival time was 7.34 months, and 82.10% of cases died within 1 year after disease onset. The follow-up showed that the survival time was longer and the myoclonus sign was more frequently presented in younger-onset sCJD patients. Patients with abnormalities only in cortical regions had a higher frequency of pyramidal dysfunction than patients having lesions in both cortex and basal ganglia. The findings of this study might provide some insight into the clinical characteristics of sCJD patients in China, but further studies could examine the presences of clinical features and survival time in patients with early age of onset in a prospective manner.

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In summary, this study showed the clinical manifestations and survival time of Chinese sCJD patients, and the differences in the survival time between younger-onset and older-onset patients. With the development of the clinical syndrome, younger-onset patients more frequently showed myoclonus sign, and patients having abnormalities only in cortical regions had a higher frequency of pyramidal dysfunction than patients with lesions in both cortex and basal ganglia. The high frequency of myoclonus and prolonged survival time in younger-onset sCJD patients might have some implications for clinical practice, and further studies could examine the presences of clinical features and survival time in patients with different ages of onset in a prospective manner.


Letter to the Editor

Assessment of the Sensitivity and Specificity of the Established Real-time Quaking-induced Conversion (RT-QuIC) Technique in Chinese CJD Surveillance*

XIAO Kang1 , YANG Xue Hua1 , ZOU Wen Quan1 , DONG Xiao Ping1,2,3,# , and SHI Qi1,#

Real-time quaking-induced conversion (RT-QuIC) assay is a newly established PrPSc-detecting method. The development of RT-QuIC improves the diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD), showing good sensitivity and specificity in many countries when the method was used in cerebrospinal fluid (CSF) samples. However, in China, the sensitivity and specificity of RT-QuIC has yet to be determined due to the lack of definitive diagnosis samples. Recently, 30 definitive sCJD and 30 non-CJD diagnoses were evaluated by RT-QuIC assay. In the 30 sCJD CSF samples, 29 showed positive results. By contrast, all the non-CJD samples were negative. The sensitivity and specificity of our RT-QuIC assay were 96.67% and 100%, respectively, and are comparable to other published data. Results can provide a fundamental basis for the usage of RT-QuIC assay in CJD surveillance in China.

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The CSF RT-QuIC reactivities among the sCJD patients show variation[7] . On the basis of the electrophoretic patterns of PrPSc in brains and the polymorphism of codon 129, sCJD can be divided into six different subtypes[8] . Studies have already proposed that compared with MM1 patients, the MM2 subtypes usually have a longer lag time and a lower rfu intensity in CSF RT-QuIC[7] . Coincidentally, the sCJD case that was negative in RT-QuIC was an MM2 subtype. This result is meaningful for Chinese CJD surveillance because absolute majorities of Han Chinese and Chinese sCJD patients are Met/Met homozygotes at codon 129[9] . In other words, the PrPSc subtypes of Chinese sCJD patients should be MM1 and MM2 predominately. The brain PrPSc subtypes of Chinese CJD patients remain unclear due to a limited implementation of brain autopsy and biopsy in China. The PrPSc subtypes of Japanese sCJD patients have been reported to be 56.82% MM1 and 22.73% MM2[10] . Under the assumption that the profiles of PrPSc subtypes among Chinese patients are similar to those of the Japanese, 22.73% of the probable Chinese sCJD patients may display low reactivity and may even test negative in CSF RTQuIC. Combining the data of CSF RT-QuIC and that of other routine clinical and laboratory examinations may help speculate the ratio of MM2 subtypes among the probable sCJD patients in China. Ethics Approval and Consent to Participate This study was approved by the Ethical Committee of National Institute for Viral Disease Control and Prevention, China CDC under protocol 2009ZX10004- 101.


The Features of Genetic Prion Diseases Based on Chinese Surveillance Program

Qi Shi,Wei Zhou,Cao Chen,Bao-Yun Zhang,Kang Xiao,Xiu-Chun Zhang,Xiao-Jing Shen,Qing Li,Li-Quan Deng,Jian-Hua Dong,Wen-Qing Lin,Pu Huang,Wei-Jia Jiang, [ ... ],Xiao-Ping Dong [ view all ]

Published: October 21, 2015


Abstract

Objective

To identify the features of Chinese genetic prion diseases.

Methods

Suspected Creutzfeldt-Jakob disease (CJD) cases that were reported under CJD surveillance were diagnosed and subtyped using the diagnostic criteria issued by the WHO. The general information concerning the patient, their clinical, MRI and EEG data, and the results of CSF 14-3-3 and PRNP sequencing were carefully collected from the database of the national CJD surveillance program and analyzed using the SPSS 11.5 statistical software program.

Results

Since 2006, 69 patients were diagnosed with genetic prion diseases and as having 15 different mutations. The median age of the 69 patients at disease onset was 53.5 years, varying from 19 to 80 years. The majority of patients displaying clinical symptoms were in the 50–59 years of age. FFI, T188K gCJD and E200K were the three most common subtypes. The disease appeared in the family histories of 43.48% of the patients. The clinical manifestations varied considerably among the various diseases. Patients who carried mutations in the N-terminus displayed a younger age of onset, were CSF 14-3-3 negative, had a family history of the condition, and experienced a longer duration of the condition. The clinical courses of T188K were significantly shorter than those of FFI and E200K gCJD, while the symptoms in the FFI group appeared at a younger age and for a longer duration. Moreover, the time intervals between the initial neurologist visit to the final diagnosis were similar among patients with FFI, T188K gCJD, E200K gCJD and other diseases.

Conclusion

The features of Chinese genetic prion diseases are different from those seen in Europe and other Asian countries.


CASE REPORT article

Front. Neurol., 28 July 2020 | https://doi.org/10.3389/fneur.2020.00763

Could Sporadic Creutzfeldt-Jakob Disease Be Underdiagnosed in China? Experience From Four Cases

Yi-Liu Zhang1, Xiao-Mei Wu1, Yang Chen1, Wen-Ping Gu2* and Wei Lu1*

1Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Background: Creutzfeldt-Jakob Disease (CJD) is a rapidly progressive neurodegenerative disease caused by the misfolded version of the cellular prion protein. Here we report four cases of sporadic CJD (sCJD) and describe the diagnostic methods available in order avoid missed or delayed recognition of CJD in China.

Case presentation: We report four patients diagnosed with sCJD between March 2018 and December 2019 at Xiangya Hospital and the Second Xiangya Hospital of Central South University. All patients were admitted to the hospital because of a progressive cognitive decline. Although their routine tests and biochemical indicators in the cerebrospinal fluid (CSF), as well as computed tomography (CT) imaging, did not reveal any apparent abnormalities, the presence of “cortical ribboning” was incidentally found on diffusion-weighted imaging (DWI). The patients were subsequently diagnosed with CJD based on positive testing for 14-3-3 protein in their CSF, and the presence of periodic sharp and slow wave complexes (PSWCs) on their electroencephalograms (EEG). Additionally, two of patients was confirmed pathological examination of cerebral biopsies demonstrating neuronal loss, gliosis, and spongiform changes.

Conclusions: CJD is a rare disease and is easily misdiagnosed by clinician in China due to a lack of recognition and awareness of CJD. Based on our experience described in this report, enhanced vigilance for CJD is required for patients with rapidly progressive dementia in China and other developing countries. DWI, EEG and detection of 14-3-3 protein in CSF should be performed in order to achieve a timely diagnosis of CJD.

snip...

Conclusion

CJD is a rare disease, but the limited availability of more advance diagnostic methods combined with a lack of awareness about CJD in China and other developing countries may be leading to a missed diagnoses, misdiagnoses and low diagnostic rate. New, less invasive and more accessible diagnostic techniques as an alternative to brain biopsy, including EEG, DWI, RT-QuIC, 14-3-3 protein, and other biomarkers, could improve the accuracy of diagnosing prion diseases. We diagnosed four cases within a <2-year period, which alerts us to CJD being a public health concern that requires greater attention. In China, awareness should be generated for patients with rapidly progressive dementia in clinical practice, and patients should be examined by methods such as DWI, testing for 14-3-3 proteins in the CSF, RT-QuIC, and so on, in order to ensure a correct diagnosis.


Published: 18 October 2008

Surveillance for Creutzfeldt-Jakob disease in China from 2006 to 2007

Qi Shi, Chen Gao, Wei Zhou, Bao-Yun Zhang, Jian-Ming Chen, Chan Tian, Hui-Ying Jiang, Jun Han, Ni-Juan Xiang, Xiao-Fang Wang, Yong-Jun Gao & Xiao-Ping Dong 

BMC Public Health volume 8, Article number: 360 (2008) Cite this article

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Abstract

Background

Human transmissible spongiform encephalopathies (HTSE), or Creutzfeldt-Jakob disease (CJD), is a group of rare and fatal diseases in central nervous system. Since outbreak of bovine spongiform encephalopathy (BSE) and variant CJD, a worldwide CJD surveillance network has been established under the proposition of WHO. In China, a national CJD surveillance system has started since 2002. The data of CJD surveillance from 2006 to 2007 was analyzed.

Methods

Total 12 provinces are included in CJD surveillance system. The surveillance unit in each province consists of one or two sentinel hospitals and the provincial CDC. All suspected CJD cases reported from CJD surveillance were diagnosed and subtyped based on the diagnostic criteria for CJD issued by WHO.

Results

Total 192 suspected CJD cases were reported and 5 genetic CJD, 51 probable and 30 possible sporadic CJD (sCJD) cases were diagnosed. The collected sCJD cases distribute sporadically without geographical clustering and seasonal relativity and the highest incidences in both probable and possible sCJD cases appeared in the group of 60–69 year. The most common three foremost symptoms were progressive dementia, cerebellum and mental-related symptoms. The probable sCJD patients owning both typical EEG alteration and CSF protein 14-3-3 positive have more characteristic clinical syndromes than the ones having only one positive. The polymorphisms of codon 129 of all tested reported cases shows typical patterns of Han Chinese as previous reports, that M129M are predominant whereas M129V are seldom.

Conclusion

Chinese CJD patients possessed similar epidemiological and clinical characteristics as worldwide.


RESOLUTION No. 17

Recognition of the Bovine Spongiform Encephalopathy Risk Status of Members

3. The Director General publish the following List of Members with zones18 recognised as having a negligible BSE risk in accordance with Chapter 11.4. of the Terrestrial Code: China (People’s Rep. of): a zone designated by the Delegate of China (People’s Rep. of) in a document addressed to the Director General in November 2013, consisting of the People’s Republic of China with the exclusion of Hong Kong and Macau.


Chinese scientist elected chairman of OIE Regional Commission for Asia, the Far East and Oceania Source：MARA Date：2021-05-31 Dr. Huang Baoxu, World Organization for Animal Health (OIE) Delegate from China and a researcher with the China Animal Health and Epidemiology Center (CAHEC), was elected chairman of OIE Regional Commission for Asia, the Far East and Oceania (AFEO) on May 28, 2021.

The 88th General Session of the World Assembly of National Delegates to the OIE was held virtually on May 24–28. The Assembly unanimously approved maintaining the recognition of a negligible bovine spongiform encephalopathy (BES) risk status, and rinderpest-free, contagious bovine pleuropneumonia-free, and African horse sickness-free status for China. The Exotic Disease Watch and Research Center of CAHEC was designated as an OIE African Swine Fever Reference Laboratory. All these signify China’s achievements in animal diseases control are well received by the international community, and China’s research and diagnostic capabilities are up to globally advanced level. 

The OIE’s recognition is of great significance in increasing China’s voice in animal health and enabling China’s leading role in the region. It will also boost the process of standard-setting and sound development of veterinary service in China. 

The OIE, an intergovernmental organization, plays an important role in global animal health and food safety. Its animal health standards are recognized as international standards or guidelines by the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS measures) of the World Trade Organization. The OIE has set up five regional commissions to coordinate and promote cooperation among its members, and address policy and technical issues related with animal diseases control in respective region. 

No.11 Nongzhanguan Nanli,Chaoyang District,Beijing China (100125)


PEOPLE’S REPUBLIC OF CHINA ("CHINA")

Questions from the United States to China 

concerning Sanitary and Phytosanitary Measures 

 The following communication, dated 2 October 2009, is being circulated at the request of the Delegation of the United States. _______________

Restrictions on trade in beef

1. China continues to impose bovine spongiform encephalopathy (BSE) related restrictions on imports of beef and beef products from the United States, contrary to the guidelines of the World Organization for Animal Health (OIE) . The OIE classified the United States as "controlled risk" for BSE in May 2007. The OIE Code provides for conditions under which beef and beef products can be safely traded from all countries. In the case of "controlled risk" countries, the OIE recognizes that trade in beef and beef products and cattle of all ages from a "controlled risk" country is safe, provided that certain slaughter and beef processing conditions are met, including the removal of appropriate specified risk materials (SRMs) in a manner that avoids cross-contamination of meat. The United States has satisfied these conditions by taking the following steps to mitigate BSE risk: (a) appropriate removal of SRMs; (b) implementation of an appropriate feed ban that has been effectively enforced; (c) an active surveillance program that has exceeded OIE requirements, and (d) thorough epidemiological investigations of all BSE cases. Since the May 2007 OIE classification of the United States as a "controlled risk" country, the governments of Canada, the Philippines, Indonesia, Malaysia, Ghana, Costa Rica and Belize, among others, have opened their markets to the full range of US beef and beef products consistent with OIE guidelines, recognizing that US BSE measures are effective. To date, however, China has only offered to accept products from animals that are under 30 months of age.

(a) In connection with last year’s transitional review before this Committee, the United States asked China whether it had performed a risk assessment relevant to its BSE-related restrictions on imports of beef and beef products from the United States. China stated that it had "conducted the necessary risk assessments on beef imported from the United States and there had been many technical communications on numerous occasions". However, no additional information was provided. Please provide additional information on the risk assessment, including an explanation of how that risk assessment supports the measures that China is applying to US-origin beef and beef products. 

(b) Please explain China’s plans for opening its market to the full range of US beef and beef products consistent with OIE guidelines.

BSE-related restrictions on other products

2. China continues to impose additional BSE-related import restrictions on protein-free tallow. The OIE’s BSE chapter specifies that protein-free tallow should be traded regardless of the BSE status of the exporting country without BSE-related restrictions. However, China continues to insist that the United States certify that the tallow not be processed from certain SRMs, and that certain tallow processing methods commonly used in the United States be prohibited. Additionally, China insists that the United States certify that materials used to produce tallow were not sourced from farms where a BSE-positive animal has been detected. China’s position is not aligned with OIE guidelines and has effectively blocked imports of US-origin protein-free tallow. The United States has provided China with several quantitative risk assessments that demonstrate that any BSE-related risks associated with protein-free tallow are too small to calculate. 

(a) In connection with last year’s transitional review before this Committee, the United States asked China whether it had performed a risk assessment relevant to its BSE-related restrictions on imports of protein-free tallow from the United States. At last year’s transitional review before this Committee, China stated that it had "conducted the necessary risk assessments on beef imported from the United States and there had been many technical communications on numerous occasions". However, no additional information was provided, and China’s response was unclear as to whether it has also conducted a risk assessment relevant to protein-free tallow. Please provide additional information on any risk assessment that China has conducted which is relevant to its BSE-related restrictions on imports of US-origin protein-free tallow. 



2.2.2. Maintenance of a negligible BSE risk status The OIE Status Department reviewed all annual reconfirmations for negligible BSE risk status including those in section 2.1. and reported the outcome of its analysis to the Commission.

11 A zone designated by the Delegate of China in a document addressed to the Director General in November 2013, consisting of the People’s Republic of China with the exclusion of Hong Kong and Macau.


Scrapie, CWD, TSE, Prion, China ???

ORIGINAL ARTICLE

Open Access

Concordance of CSF RT-QuIC across the European Creutzfeldt-Jakob Disease surveillance network

Neil McKenzie,Gabriele Piconi,Audrey Culeux,Anna-Lena Hammarin,Christos Stergiou,Socrates Tzartos,Alexandra A. M. Versleijen,Jacqueline van de Geer,Patrick Cras,Franco Cardone,Anna Ladogana,Angela Mammana,Marcello Rossi,Matilde Bongianni,Daniela Perra,Guenther Regelsberger,Sigrid Klotz,Simone Horneman,Adriano Aguzzi,Schmitz Matthias,Mary Andrews,Kimberley Burns,Stéphane Haïk,Raquel Ruiz-García,Jenny Verner-Carlsson,John Tzartos,Marcel M. Verbeek,Bart De Vil,Anna Poleggi,Piero Parchi,Gianluigi Zanusso,Ellen Gelpi,Karl Frontzek,Regina Reiman,Peter Hermann,Inga Zerr,Suvankar Pal,Alison Green … 

First published: 07 May 2022 https://doi.org/10.1111/ene.15387

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/ene.15387

Background

Cerebrospinal fluid (CSF) Real Time-Quaking Induced Conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD) and this has led to it being included in revised European CJD Surveillance network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC.

Methods

Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative.

Results

All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories; one had a disease duration greater than 26 months with a negative 14-3-3, whilst the remaining case had a 4 month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study.

Conclusions

This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, rPrP substrates and CSF volumes. We recommend the adoption of CSF RT-QuIC by all CJD surveillance centres.

snip...

Conclusions:

CSF RT-QuIC has been incorporated in the diagnostic criteria since Jan 2017 but has not been uniformly adopted by all surveillance centres . Many studies have shown that CSF RT-QuIC is a very accurate test for sCJD with a high degree of sensitivity and specificity. This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, different rPrP substrates and a range of CSF volumes to seed the reaction. We recommend the adoption of CSF RT-QuIC by all CJD surveillance centres. 

References: snip...see full text;


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


Sunday, November 1, 2020 

Taiwan Incidence of and Mortality Due to Human TSE Prion Diseases Sees Significant Increase In Incidence After 2008 


***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.***

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.

https://www.nature.com/articles/srep11573 

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. 

============== 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf 

***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. 

http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20 

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

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. 

http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20

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. 

http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160

GAME FARM INDUSTRY WANTS TO COVER UP FINDINGS OF INCREASE RISK TO CJD FROM CERVID

BSE INQUIRY

CJD9/10022

October 1994

Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge Spencers Lane 

BerksWell Coventry CV7 7BZ

Dear Mr Elmhirst,

CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT

Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.

The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended.. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.

The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.

The statistical results regarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.

I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all. 

http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf

Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize the human dementias"

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the scrapie problem urgent if the sheep industry is not to suffer grievously.

snip...

76/10.12/4.6

http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf

IN CONFIDENCE

SCRAPIE TRANSMISSION TO CHIMPANZEES

IN CONFIDENCE

reference...

RB3.20

TRANSMISSION TO CHIMPANZEES

1. Kuru and CJD have been successfully transmitted to chimpanzees but scrapie and TME have not.

2. We cannot say that scrapie will not transmit to chimpanzees. There are several scrapie strains and I am not aware that all have been tried (that would have to be from mouse passaged material). Nor has a wide enough range of field isolates subsequently strain typed in mice been inoculated by the appropriate routes (i/c, ilp and i/v) :

3. I believe the proposed experiment to determine transmissibility, if conducted, would only show the susceptibility or resistance of the chimpanzee to infection/disease by the routes used and the result could not be interpreted for the predictability of the susceptibility for man. Proposals for prolonged oral exposure of chimpanzees to milk from cattle were suggested a long while ago and rejected.

4. In view of Dr Gibbs' probable use of chimpazees Mr Wells' comments (enclosed) are pertinent. I have yet to receive a direct communication from Dr Schellekers but before any collaboration or provision of material we should identify the Gibbs' proposals and objectives.

5. A positive result from a chimpanzee challenged severely 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.

6. A negative result would take a lifetime to determine but that would be a shorter period than might be available for human exposure and it would still not answer the question regarding mans' susceptibility. In the meantime no doubt the negativity would be used defensively. It would however be counterproductive if the experiment finally became positive. We may learn more about public reactions following next Monday' s meeting.

R. Bradley

23 September 1990

CVO (+Mr Wells' comments)

Dr T W A Little

Dr B J Shreeve

90/9.23/1.1.

http://web.archive.org/web/20090506041740/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf

IN CONFIDENCE CHIMPANZEES

CODE 18-77 Reference RB3.46

Some further information that may assist in decision making has been gained by discussion with Dr Rosalind Ridley.

She says that careful study of Gajdusek's work shows no increased susceptibility of chimpanzees over New World Monkeys such as Squirrel Monkeys. She does not think it would tell you anything about the susceptibility to man. Also Gajdusek did not, she believes, challenge chimpanzees with scrapie as severely as we did pigs and we know little of that source of scrapie. Comparisons would be difficult. She also would not expect the Home Office to sanction such experiments here unless there was a very clear and important objective that would be important for human health protection. She doubted such a case could be made. If this is the case she thought it would be unethical to do an experiment abroad because we could not do it in our own country.

Retrospectively she feels they should have put up more marmosets than they did. They all remain healthy. They would normally regard the transmission as negative if no disease resulted in five years.

We are not being asked for a decision but I think that before we made one we should gain as much knowledge as we can. If we decided to proceed we would have to bear any criticisms for many years if there was an adverse view by scientists or ­media. This should not be undertaken lightly. There is already some adverse comment here, I gather, on the pig experiment though that will subside.

The Gibbs' (as' distinct from Schellekers') study is somewhat different. We are merely supplying material for comparative studies in a laboratory with the greatest experience of human SEs in the world and it has been sanctioned by USDA (though we do not know for certain yet if chimpanzees specifically will be used). This would keep it at a lower profile than if we conducted such an experiment in the UK or Europe.

I consider we must have very powerful and defendable objectives to go beyond Gibbs' proposed experiments and should not initiate others just because an offer has been made.

Scientists have a responsibility to seek other methods of investigative research other than animal experimentation. At present no objective has convinced me we need to do research using Chimpanzees - a species in need of protection. Resisting such proposals would enable us to communicate that information to the scientist and the public should the need arise. A line would have been drawn.

CVO cc Dr T Dr B W A Little Dr B J Shreeve

R Bradley

26 September 1990

90/9.26/3.2

http://web.archive.org/web/20090506041605/http://www.bseinquiry.gov.uk/files/yb/1990/09/26003001.pdf

this is tse prion political theater here, i.e. what i call TSE PRION POKER...tss

http://web.archive.org/web/20031028205208/www.bseinquiry.gov.uk/files/yb/1990/08/28002001.pdf

http://web.archive.org/web/20030822170317/www.bseinquiry.gov.uk/files/yb/1990/11/01005001.pdf

3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs.

snip...

PAGE 26

Transmission Studies

Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}....TSS

resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret.

The occurrence of CWD must be viewed against the contest of the locations in which it occurred. It was an incidental and unwelcome complication of the respective wildlife research programmes. Despite its subsequent recognition as a new disease of cervids, therefore justifying direct investigation, no specific research funding was forthcoming. The USDA viewed it as a wildlife problem and consequently not their province! ...page 26. 

snip...see;

IN CONFIDENCE

PERCEPTIONS OF UNCONVENTIONAL SLOW VIRUS DISEASE OF ANIMALS IN THE USA

GAH WELLS

REPORT OF A VISIT TO THE USA

APRIL-MAY 1989

http://web.archive.org/web/20090506002237/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf

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...

https://web.archive.org/web/20090506041740/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf

Sunday, January 10, 2021 
APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087] Singeltary Submission June 17, 2019

APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087] Singeltary Submission

Greetings APHIS et al, 

I would kindly like to comment on APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087], and my comments are as follows, with the latest peer review and transmission studies as references of evidence.

THE OIE/USDA BSE Minimal Risk Region MRR is nothing more than free pass to import and export the Transmissible Spongiform Encephalopathy TSE Prion disease. December 2003, when the USDA et al lost it's supposedly 'GOLD CARD' ie BSE FREE STATUS (that was based on nothing more than not looking and not finding BSE), once the USA lost it's gold card BSE Free status, the USDA OIE et al worked hard and fast to change the BSE Geographical Risk Statuses i.e. the BSE GBR's, and replaced it with the BSE MRR policy, the legal tool to trade mad cow type disease TSE Prion Globally. The USA is doing just what the UK did, when they shipped mad cow disease around the world, except with the BSE MRR policy, it's now legal. 

Also, the whole concept of the BSE MRR policy is based on a false pretense, that atypical BSE is not transmissible, and that only typical c-BSE is transmissible via feed. This notion that atypical BSE TSE Prion is an old age cow disease that is not infectious is absolutely false, there is NO science to show this, and on the contrary, we now know that atypical BSE will transmit by ORAL ROUTES, but even much more concerning now, recent science has shown that Chronic Wasting Disease CWD TSE Prion in deer and elk which is rampant with no stopping is sight in the USA, and Scrapie TSE Prion in sheep and goat, will transmit to PIGS by oral routes, this is our worst nightmare, showing even more risk factors for the USA FDA PART 589 TSE PRION FEED ban. 

The FDA PART 589 TSE PRION FEED ban has failed terribly bad, and is still failing, since August 1997. there is tonnage and tonnage of banned potential mad cow feed that went into commerce, and still is, with one decade, 10 YEARS, post August 1997 FDA PART 589 TSE PRION FEED ban, 2007, with 10,000,000 POUNDS, with REASON, Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement. you can see all these feed ban warning letters and tonnage of mad cow feed in commerce, year after year, that is not accessible on the internet anymore like it use to be, you can see history of the FDA failure August 1997 FDA PART 589 TSE PRION FEED ban here, but remember this, we have a new outbreak of TSE Prion disease in a new livestock species, the camel, and this too is very worrisome.

WITH the OIE and the USDA et al weakening the global TSE prion surveillance, by not classifying the atypical Scrapie as TSE Prion disease, and the notion that they want to do the same thing with typical scrapie and atypical BSE, it's just not scientific.

WE MUST abolish the BSE MRR policy, go back to the BSE GBR risk assessments by country, and enhance them to include all strains of TSE Prion disease in all species. With Chronic Wasting CWD TSE Prion disease spreading in Europe, now including, Norway, Finland, Sweden, also in Korea, Canada and the USA, and the TSE Prion in Camels, the fact the the USA is feeding potentially CWD, Scrapie, BSE, typical and atypical, to other animals, and shipping both this feed and or live animals or even grains around the globe, potentially exposed or infected with the TSE Prion. this APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087], under it's present definition, does NOT show the true risk of the TSE Prion in any country. as i said, it's nothing more than a legal tool to trade the TSE Prion around the globe, nothing but ink on paper.

AS long as the BSE MRR policy stays in effect, TSE Prion disease will continued to be bought and sold as food for both humans and animals around the globe, and the future ramifications from friendly fire there from, i.e. iatrogenic exposure and transmission there from from all of the above, should not be underestimated. ... 





Control of Chronic Wasting Disease OMB Control Number: 0579-0189 APHIS-2021-0004 Singeltary Submission



Docket No. APHIS-2018-0011 Chronic Wasting Disease Herd Certification



*** 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.

http://cdmrp.army.mil/prevfunded/nprp/NPRP_Summit_Final_Report.pdf

Published: 06 September 2021

***> Chronic wasting disease: a cervid prion infection looming to spillover

Alicia Otero, Camilo Duque Velásquez, Judd Aiken & Debbie McKenzie 

Veterinary Research volume 52, Article number: 115 (2021) 



SUNDAY, MAY 08, 2022 

 

USA National Prion Disease Pathology Surveillance Center Surveillance Update April 11th, 2022

 

https://creutzfeldt-jakob-disease.blogspot.com/2022/05/usa-national-prion-disease-pathology.html

 

TUESDAY, APRIL 05, 2022 

 

Incidence of Creutzfeldt-Jakob Disease in the United States 1993-2014

 

https://creutzfeldt-jakob-disease.blogspot.com/2022/04/incidence-of-creutzfeldt-jakob-disease_5.html


TUESDAY, MAY 24, 2022 

Texas Creutzfeldt Jakob Disease CJD TSE Prion Update Singeltary FOIA Request Received May 23, 2022


Terry Singeltary, Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis


Aug 7, 2011







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. 

Terry S. Singeltary Sr.
at