Friday, October 30, 2020

Analysis of Chinese patients with sporadic Creutzfeldt-Jakob disease

 . 2020; 14(1): 137–142.

Published online 2020 May 7. doi: 10.1080/19336896.2020.1761515
PMCID: PMC7219432
PMID: 32378453

Analysis of Chinese patients with sporadic Creutzfeldt-Jakob disease

Introduction

Creutzfeldt-Jakob disease (CJD) is a rare, incurable, and inevitably fatal neurodegenerative disorder [1]. The pathophysiological mechanism of CJD consists of the formation of an abnormal isoform of prion protein (PrP) called scrapie prion protein (PrPSc), and the accumulation of these abnormal proteins disrupts cell function and causes a sponge-like appearance in brain tissue [2,3]. CJD has a worldwide distribution, and the estimated incidence in the United States is 0.5 to 1 per million inhabitants per year [4,5]. There are four subtypes of CJD: sporadic (sCJD), familial (fCJD), iatrogenic (iCJD) and variant CJD (vCJD). sCJD is the most common form, accounting for ~85% of all cases. Clinical presentation of sCJD is highly variable; symptoms can range from rapidly progressive dementia to neuropsychiatric manifestations, cerebellar ataxia, visual impairment, akinetic mutism, myoclonus, and pyramidal and/or extrapyramidal signs [6]. The diagnosis of sCJD can be challenging due to the variegated symptoms and signs. To facilitate diagnosis, paraclinical tests, including electroencephalogram (EEG), cerebrospinal fluid (CSF) biomarkers, magnetic resonance imaging (MRI) of the brain, positive real-time quaking-induced conversion (RT-QuIC) and brain biopsy, can be used.

Here, we investigated the clinical characteristics and survival time of the deceased Chinese sCJD patients, including a case series in a tertiary care hospital and all the Chinese sCJD cases reported in medical journals, trying to address the associations between clinical characteristics and survival time.

Patients and methods

In the tertiary care hospital-West China Hospital of Sichuan University, the suspected CJD cases were diagnosed using the diagnostic criteria for CJD issued by the China National Health Commission [6]. The clinical data, including the general information of the patient, main clinical manifestations, the typical symptom and results of paraclinical tests were recorded in detail. The appearance of periodic sharp wave complexes (PSWC) was regarded as a specific EEG abnormality. The presence of high signal intensities in the caudate/putamen and/or cortical ribboning in diffusion-weighted imaging (DWI) was considered to be abnormal. Western blots for 14-3-3 in the CSF, and PRNP PCR and sequencing were also performed. The first presentation of neurological signs or symptoms suggestive of organic involvement was judged as disease onset. The manifestation of lacking voluntary movement and the ability to produce meaningful words were defined as akinetic mutism state [7]. All patients were followed up by telephone or face-to-face interview with an interval of 3 months. The survival time was defined as the duration from disease onset to death. All the participants gave their written informed consents; the Ethical Committee of West China Hospital approved this study. The electronic databases Chinese National Knowledge Infrastructure and Wanfang (Chinese) were utilized to search for terms including ‘Creutzfeldt-Jakob disease’ or ‘prion disease’. We also conducted a search on PubMed, restricting the search to studies conducted in China. To avoid missing literatures, we also looked through the references of relevant articles; aiming to collect all the studies regarding the Chinese sCJD cases reported within the last 10 years up until December 2018. Studies which reported the clinical data and survival time were retained for this study. Comparisons of continuous variables between two groups were made using Student’s t-test. Categorical variables were compared using Fisher’s exact test. All data were presented in the form of mean ± standard deviation, and they were analysed using SPSS 17.0. A p-value of less than 0.05 was considered to be statistically significant.

Results

General demographic features

Between 1 January 2008 and 31 December 2018, 21 patients were diagnosed as probable sCJD in Sichuan University West China Hospital according to the diagnostic criteria for sCJD; 7 were males and 14 were females, with a gender ratio of 0.5:1. The disease onset age ranged from 47 to 81 year-old (y), and the mean age of onset was 62.67 y. The highest incidence in our cohort was 60 to 69 y, and ten patients (47.62%) had an onset of illness between 60 and 69 years of age, 90.48% of cases were older than 50 years. All the patients were deceased during follow-up, and the medium survival time was 5.48 months. The clinic manifestations of these 21 sCJD patients were listed in supplementary Table 1. Between 2000 and 2018, data from articles published in China or abroad showed that 152 patients were diagnosed as probable sCJD according to the diagnostic criteria for sCJD, and the information of included studies (publish date, journal, and authors) are listed in supplementary Table 2. Out of the reported sCJD patients, 74 were males and 78 were females, with a gender ratio of 0.95:1. The disease onset age varied from 18 to 83 y, with the mean age of onset of 61.27 y. The majority of patients (63.82%) had an onset of disease between 50 and 69 years of age (52 cases were in the 60–69 y group, 45 cases were in the 50–59 y group), and 88.16% of patients were older than 50 years. The medium survival time for all these deceased patients was 7.34 months. The demographics of all included sCJD patients differentiated by gender and age of onset are listed in Table 1.

Table 1.

Demographics of Chinese patients with sCJD differentiated by gender and age of onset.

  Gender
Age of onset
ItemTotalMaleFemaleP value≤50 y>50 yP value
Number1738192-21152 
Age of onset (y)61.44 ± 10.4261.63 ± 10.7361.27 ± 10.290.8223---
Survival time (m)7.34 ± 7.576.86 ± 9.547.78 ± 5.210.465311.88 ± 8.906.67 ± 7.150.0030

Clinical features

Most of the patients displayed more than one symptom at disease onset. Among the presenting symptoms, progressive memory loss and cognitive dysfunction were mostly described, which appeared in 42.28% cases. Mental and behaviour disorder, including depression, anxiety, apathy, impediment speech irritability, illusion, emotional lability and personality changes, was reported in 19.46% cases. Ataxia and gait instability were recorded in 16.11% cases, followed by visual disturbances which appeared in 10.07% cases. Nine patients showed extrapyramidal symptoms (including slowness, stiffness, tremors, and involuntary movement), and two patients exhibited pyramidal symptoms or signs. Additionally, there was one patient who was first presenting with stroke and one patient who had myoclonus as an initial symptom. However, 15 patients (8.67%) showed atypical clinical manifestations at disease onset; they only complained about dizziness at first.

With the progression of disease, more symptoms and signs were identified. Progressive dementia was noticed in 100% of patients. Extrapyramidal symptoms (77.42%) also appeared frequently, followed by myoclonus (63.64%), pyramidal symptoms (60%), cerebellar problems (54%) and akinetic mutism (48.24%). Visual disturbance was reported in 40.58% cases. The differences in the clinical major manifestations were further investigated in all included sCJD cases, who were subgrouped by gender, age of onset (≤50 y vs >50 y), DWI imaging (only cortical regions vs both cortical regions and basal ganglia), and survival time (≤6 m vs >6 m). Except for dementia, the presence of other major symptoms of sCJD was compared. No statistical differences in the presences of main manifestations were found in patients with different gender and survival time. However, the presence of myoclonus in patients with different onset age showed significantly different tendencies. The positive rate of myoclonus in sCJD patients with younger-onset (78.05%) was significantly higher than that in patients with older-onset (60.56%). Besides, pyramidal dysfunction was noted comparably in sCJD patients with different imaging manifestations on DWI; the presence of pyramidal dysfunction was more frequently in patients who had abnormalities only in cortical regions (72.22%), compared to patients who had lesions in both cortical regions and basal ganglia (46.68%). The comparison of the major symptoms among subgroups is shown in Table 2.

Table 2.

The subgroup analysis of the presence of clinical features during the course of sCJD.

 Gender
Age of onset
survival
DWI Image
ItemMaleFemaleP value≤50 y>50 yP value≤6 m>6 mP valueCortexCortex & basal gangliaP value
Myoclonus50/75
(66.67%)
48/79
(60.76%)
0.504126/33
(78.79%)
84/140
(60%)
0.046860/98
(61.22%)
38/56
(67.86%)
0.487125/40
(62.50%)
34/53
(64.15%)
1
Cerebella disturbance44/73 (60.27%)37/77 (48.05%)0.143715/26
(56.69%)
78/147
(53.06%)
0.843355/102
(53.92%)
28/50
(56%)
0.863323/36
(63.89%)
30/47
(63.83%)
1
Pyramidal dysfunction37/65
(56.92%)
38/60
(63.33%)
0.583820/34
(58.82%)
94/150
(62.67%)
0.698951/84
(60.71%)
24/41
(58.54%)
0.847526/36
(72.22%)
21/47
(44.68%)
0.0148
Extrapyramidal dysfunction49/65
(75.38%)
47/59
(79.66%)
0.668722/28
(78.57%)
115/146
(78.77%)
163/83
(75.90%)
33/41
(80.49%)
0.652127/36
(75%)
38/46
(82.61%)
0.4239
Visual disturbance30/68
(44.12%)
26/70
(37.14%)
0.488415/31
(48.39%)
58/139
(41.73%)
0.572938/92
(41.30%)
18/46
(39.13%)
0.855517/36
(47.22%)
21/47
(44.68%)
0.8281
Akinetic mutism26/56
(46.43%)
29/58
(50%)
0.712412/29
(41.38%)
75/152
(49.34%)
0.543734/74
(45.95%)
19/38
(50%)
0.694920/34
(58.82%)
20/46
(43.48%)
0.2580

Significant values are highlighted in bold characters.

Survival time

All included cases in the present study had died on a known date. The mean survival time of all included cases was 7.34 months, with a range of 0.5 to 72. The cumulative incidences of the survival time which was less than 3, 6, 12 and 24 months were 14.20%, 53.09%, 82.10% and 97.53%, respectively. As shown in Table 1, younger-onset patients (onset age ≤50 y) had longer survival time than patients with older-onset (onset age >50 y), but no statistical difference in survival time was found between two genders. All the included patients were examined by DWI imaging; patients with only cortical regions abnormalities had similar survival time to those patients who had both cortical regions and basal ganglia affected. The association between the survival time and the frequency of the major manifestations was analysed, and the main symptoms of progressive dementia, myoclonus, visual disturbance, cerebella disturbance, pyramidal dysfunction, extrapyramidal dysfunction, and akinetic mutism were evaluated in all the included patients. The results showed that the survival time of the patients with more than three signs (>4) were not significantly different from those with less than three signs (≤3).

Discussion

In the current study, we systematically describe the clinical features and survival time of 173 sCJD cases, among them 21 patients were from West China Hospital-a tertiary care hospital in China. Since the number of sCJD patients in a third-level hospital was too small to analyse the associations between clinical features and survival time, we did a literature search to include all the reported sCJD cases or case series from China. All the included sCJD patients were deceased, and the survival time was recorded.

There were more female than male sCJD patients in the current investigation, and the male to female ratio was 0.88/1. Similarly, a preponderance of female cases was also reported in most previous studies [814]. However, a surveillance study from China found more males in 261 sCJD patients and a male to female ratio of 1.27:1 [15]. In addition, a previous review stated that sCJD occurs equally in both sexes [16]. Furthermore, the survival time seemed to be longer in females, but the difference was not significant. Another Japanese study also found that disease duration was longer in females, but this tendency was not statistically significant [17]. Therefore, the gender differences in survival time could not reach an agreed conclusion and more reliable foreign data are required in future studies. The mean onset age was 61.44 years (range: 18–82) in the present study. Similarly, another Chinese study found a median onset age of 61 years [15], and a meta-analysis showed that the mean age of onset was 60.7 years in 3083 sCJD patients [18]. The data from our hospital and the literature both showed that the majority of cases had an onset of disease between 60 and 69 years of age, with a 25%/75% percentile value of 56/70. This finding was consistent with previous studies, which reported a peak age of onset between 60 and 69 years [15,16,19]. Only 21 sCJD patients were under 50 years old at disease onset, and we divided our sCJD patients into two groups using the cut-off value of 50 years. The results showed that patients with younger-onset (≤50 y) had a significantly longer survival time than patients with older-onset (>50 y). A similar study divided the 674 sCJD patients into four groups according to the onset age (≤39, 40–59, 60–79, ≥80 y), and they found that earlier disease onset may be associated with longer survival time, and the probabilities were 0.071 for age group [17]. A study from Germany also found that younger patients (≤50 y) with sCJD had significantly longer survival time than older patients (>50 y) [20]. Young age at disease onset was demonstrated to be one of the major factors attributing to the survival of CJD [21]. Since the clinical, pathological, and laboratory features of sCJD patients with younger-onset are quite different from those of older-onset cases [22], younger onset age could be related to a better prognosis, but this trend requires further validation by studies with larger sample size.

Progressive memory loss and cognitive dysfunction were most detectable presenting symptoms, followed by mental disorder, cerebellum symptoms. The frequencies of presenting symptoms in our sCJD patients were similar to those reported in a previous study [15]. We also noticed that 8.67% of sCJD patients experienced dizziness as the presenting symptom, and this kind of symptoms is non-specific and easily misdiagnosed. Dizziness presentation is not frequent in sCJD, which was reported to be present as an initial symptom in 2.6% of CJD patients [18]. Studies also reported that the initial symptoms of CJD could mimic benign peripheral vestibulopathy, leading to a misdiagnosis or a delayed diagnosis [2326]. The relatively high percentage of dizziness as an initial manifestation in Chinese sCJD patients may due to the lack of a thorough knowledge of early deficits of sCJD, and it is important to raise awareness of the clinical symptoms and presentations of this rare disease. As the disease progressed to a more advanced stage, more symptoms had been observed. There was no significant difference in terms of the main symptoms, when our sCJD patients were divided into two groups by gender and survival time. However, when they were grouped by onset age, myoclonus was more frequently released in our patients with younger-onset (≤50 y), compared to those patients with older-onset (>50 y). Relatively high frequency of myoclonus sign (90%) in young sCJD patients during disease course had been reported previously [20]. The frequency of visual or cerebellar disturbance in young sCJD patients was reported to be lower than that of total sCJD [22], but we did not find such pattern. In the present study, the positive rate of visual and cerebellar disturbance was 48.57% and 56.67% in sCJD patients with young-onset, comparable with the results from all sCJD patients (43.15% and 53.69%, respectively). In addition, the frequency pyramidal dysfunction was higher in patients with abnormalities only in cortical regions compared to those patients who had lesions in both cortical regions and basal ganglia. Pathologically in sCJD, the most severely affected region is neocortex, and the severity of lesion is related to the disease duration [27,28]. The previous study found that abnormalities of the only cortical regions were found in 24% of sCJD patients, while the alterations in the basal ganglia region and the presence of cortical ribboning were present in 68% [29]. Therefore, along with the progression of disease, pyramidal dysfunction is observed, and the combination with the hyperintensity in the cerebral cortex in DWI image may indicate the diagnosis of the sCJD, even though there is no DWI hyperintensity in basal ganglia region. However, we should be concerned about the bias produced by the limited sample size; further study with more case numbers is required. We also analysed the association of survival time with the appearance of the main manifestations in our sCJD patients during disease progression and found that patients who had more than three signs had similar survival time with those patients who had less than three neurological manifestations. A large portion of sCJD patients had more than three manifestations during the disease progression, but no matter how many main manifestations were present, there were no statistical differences in the survival time. It is possible that when more than three manifestations are presented, an extended neuropathologic damage has already occurred in sCJD patients.

The mean survival time of the present study was 7.34 months, with a range of 0.5–72; and 82.10% of patients died within 1 year after onset. Similarly, the Chinese surveillance data from 2008 to 2011 showed a mean survival time of 6.1 months and a 1-year mortality of 74% [30]. The data from China are comparable to that of Western countries. The European CJD Surveillance Network (EuroCJD) included 2,451 deceased sCJD patients from 31 December 1992 to 31 December 2002 and found a median survival time of 5 months (range: 1–81) and a 1-year mortality of 85.8% [14]. The surveillance of CJD in Argentina (1997–2008) also revealed that the mean survival time was 4.6 months (range: 1–70) in sCJD patients [31]. However, the Japanese CJD surveillance programme from 1 April 1999 through 4 September 2008 reported a longer survival time of 17.4 months in patients with prion diseases, and 46.0% patients died within 1 year after disease onset. The inconsistent findings from Japanese study are likely resulted from the country’s healthcare system [17]. An observational study indicated that sCJD patients from North American and European died shortly after reaching the akinetic mutism state [32]. This phenomenon was probably due to financial and ethical concerns. In Western countries and China, patients with fatal neurological disorders normally did not receive the intensive life-sustaining treatments, but the tube-feeding and mechanical ventilation therapy were commonly implemented for Japanese sCJD patients even they had reached the akinetic mutism state [33].

There are several limitations to this study. Only 21 sCJD patients were from our hospital, a large portion of patients was gleaned from the literature, and the quality of the study was relying on the data of the literature. Some case reports may specifically report the atypical sCJD patients, which would cause bias. Additionally, some studies did not conduct the PRNP analysis; it is possible that some cases could actually be fCJD cases.

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.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed here.

Supplemental Material:

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Chinese Specific Characteristics of Sporadic Creutzfeldt-Jakob Disease: A Retrospective Analysis of 57 Cases 

Wei Zhao,Jia-Tang Zhang ,Xiao-Wei Xing,De-Hui Huang,Cheng-Lin Tian,Wei-Quan Jia,Xu-Sheng Huang,Wei-Ping Wu,Chuan-Qiang Pu,Sen-Yang Lang,Sheng-Yuan Yu


Abstract Objective Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and transmissible neurodegenerative disorder. However, no studies have reported Chinese specific characteristics of sCJD. We aimed to identify differences in sCJD between Chinese patients and patients from other countries.

Methods The data from 57 Chinese sCJD patients were retrospectively analyzed, including demographic data, clinical manifestations, laboratory examinations, electroencephalograms (EEGs), diffusion-weighted imaging (DWI) scans, positron emission tomography (PET) scans, and pathological results.

Result The disease was pathologically confirmed in 11 patients. 39 cases were diagnosed as probable sCJD, and 7 were possible. Of the total cases, 33 were male, and 24 were female. The onset age ranged from 36 to 75 years (mean: 55.5, median: 57). Disease onset before the age of 60 occurred in 57.9% of patients. The disease duration from onset to death ranged 5–22 months (mean: 11.6, median: 11), and 51.9% of patients died 7 to 12 months after disease onset. The majority of patients presented with sub-acute onset with progressive dementia. 3 of the 9 patients who took 14-3-3 protein analysis had positive results (33.3%). The sensitivity of EEG was 79.6% (43/54). For DWI and PET examinations, the sensitivities were 94% (47/50) and 94.1% (16/17), respectively. In seven patients who did not show typical hyper-intensities on the first DWI examination, abnormalities of hypo-metabolism in the cerebral cortex were clearly detected by PET. In 13 out of the 17 patients, PET detected extra abnormal regions in addition to the hyper-intense areas observed in DWI.

Conclusion This is the first study to indicate that Chinese sCJD patients have a much earlier onset age and a longer disease duration than other populations, which is most likely related to racial differences. The longer disease duration may also be a probable characteristic of Asian populations. PET had high sensitivity for the diagnosis of sCJD.

snip...

In conclusion, this is the first report to detail specific disease characteristics of Chinese sCJD patients. In China, the onset age of sCJD was much earlier and the disease duration was much longer compared with other countries, and these characteristics are most likely related to racial differences. The longer disease duration was not only a special feature of Chinese patients but most likely represents a difference between patients in Asian countries and in Western countries. The sensitivity of the EEG in our study was slightly higher than observed in other studies. Regarding onset style, clinical manifestations, and DWI findings, Chinese patients were similar to other patient populations. PET has high sensitivity for the early diagnosis of sCJD.

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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 

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.

snip...

Conclusion

The results of the present study revealed the general epidemiology status of CJD in China from 2006 to 2007. Foremost clinical manifestations were different among the CJD patients, but along with the progression of the disease, progressive dementia was observed sooner or later in all cases. EEG examination, CSF protein 14-3-3 test and PRNP gene analyses were the main laboratory tools for the suspected patients without postmortem. M129M were the predominant genotype in Han Chinese. The morbidity of CJD in China still remained unsettled for the short-term surveillance. Due to the lower rate of postmortem, enhancing follow-up will improve the quality of the CJD surveillance system.

see full text ;



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


MONDAY, OCTOBER 05, 2020 

USA, UK, JAPAN, CJD TSE PRION STATISTICS UPDATE OCTOBER 2020


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 





2.3.2. New evidence on the zoonotic potential of atypical BSE and atypical scrapie prion strains

PLEASE NOTE;

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 

Bovine adapted transmissible mink encephalopathy is similar to L-BSE after passage through sheep with the VRQ/VRQ genotype but not VRQ/ARQ 





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!


SUNDAY, OCTOBER 4, 2020 

Cattle Meat and Offal Imported from the United States of America, Canada and Ireland to Japan (Prions) Food Safety Commission of Japan


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 

Assessing the aggregated probability of entry of a novel prion disease agent into the United Kingdom


Tuesday, September 15, 2020 

Mad Camel Disease CPD TSE Prion dromedary camels (Camelus dromedarius) is spreading


FRIDAY, SEPTEMBER 11, 2020 

Norway Skrantesjuke CWD TSE Prion detected on reindeer buck from Hardangervidda


THURSDAY, SEPTEMBER 10, 2020 

Saskatchewan, Canada, Chronic Wasting Disease CWD TSE Prion


MONDAY, AUGUST 24, 2020 

Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease


THURSDAY, AUGUST 20, 2020 

Why is USDA "only" BSE TSE Prion testing 25,000 samples a year?


Terry S. Singeltary Sr.