Thursday, February 08, 2024

A systemic analysis of Creutzfeldt Jakob disease cases in Asia

A systemic analysis of Creutzfeldt Jakob disease cases in Asia

Urwah Rasheed, Sana Khan,Minahil Khalid, Aneeqa Noor ORCID Icon & Saima Zafar

Pages 11-27 | Received 20 Oct 2023, Accepted 25 Jan 2024, Published online: 07 Feb 2024

Creutzfeldt Jakob Disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder, also known as a subacute spongiform encephalopathy. There are three major subtypes of CJD i.e. Sporadic CJD, which occurs for reasons unbeknown to science (85% of known cases), Genetic or Familial CJD which is characterized by the presence of mutations in the human prion protein (PRNP) gene (10–15% cases) and Iatrogenic CJD that occurs via accidental transmission through medical and surgical procedures (1–2% cases). CJD cases occur globally with 1 case per one million population/year. Considerable data is available related to the incidence and prevalence of CJD in Europe and America. However, the global surveillance database is yet to include Asia even though several Asian countries have their own CJD monitoring units. sCJD is the highest among all CJD cases in Asia. China (1957) and Japan (1705) have reported more cases of sCJD than any Asian country and Hong Kong (1) has reported the least. On the other hand, gCJD is highest in Japan (370) and least in India (2). Our analysis establishes the presence of all variants of CJD across Asia. However, in most Asian countries in general and Southeast Asian countries in particular, CJD cases are misdiagnosed and often underreported. Since Asia is the most populated continent in the world, the actual global prevalence of CJD cannot be estimated until and unless these countries are accounted for. Concrete and reliable surveillance networks are needed across Asia to evaluate the prevalence and incidence of CJD in the region.

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4. Incidence of sporadic CJD in Asia

4.1. China

China recorded the highest number of sCJD cases since the early cases emerged in 1982. Guo et al., published two case reports, out of which one was sporadic, whereas the other was genetic. While the source of infection for the sporadic case could not be identified, the EEG showed progressing changes aiding in the clinical diagnosis [Citation24]. Following the initial reports, the Department of Neurology, General Hospital of the People’s Liberation Army diagnosed 57 cases of sCJD, between the years 1992 and 2011. Out of these 57, 11 patients were diagnosed with sCJD, 39 were probable and 7 were possible diagnoses. Of these cases, 24 were females and 33 were males, with a gender ratio of 0.727:1. The onset age range is 36 to 75 years with 8.8% of the patients in the age group 30 to 39, 14% of the patients were in 40–49 years, 35.1% were in 50–59, 36.8% were in 60–69 and 5.3% were in above 70 age group. A follow-up study was conducted, but most patients were deceased. The time between the onset of disease and death ranged from 5 to 22 months. Among the deceased, 28 died 7 to 12 months following the onset of the disease, 17 died after a year of onset, and only 9 lived up to 6 months of onset [Citation25]. In another report published by Shi et al., 192 suspected cases of CJD were identified between the years 2006 and 2007 through surveillance systems. Fifty-one patients out of these were diagnosed as probable sCJD cases, while 30 of them were considered as possible sCJD cases, on the basis of diagnosis criteria [Citation26].

With an increase in the elderly population, more cases have emerged recently. In 2016, Shi et al., reported the surveillance data were retrieved from 15 hospitals and 12 provincial CDCs which covered Shanghai, Beijing, Chongqing, Tianjin, Hubei, Jilin, Shaanxi, Guizhou, Guangdong, Henan, Anhui, and Xinjiang. A total of 1585 cases were reported, out of which 700 were categorized as sCJD. Two out of these were definite, 560 were probable and 138 were possible [Citation27]. Overall, 5078 CJD cases have been reported between the years 2006 to 2021, out of which 1900 cases were attributed to sCJD cases. All PLADs located on the Chinese mainland experienced cases of sCJD, with the sole exception being the Xizang Autonomous Region (Tibet). It should be noted that there was no discernible correlation between the occurrence of sCJD and factors such as geographical location, season, or occupation.

The initial indications and manifestations of sCJD cases exhibited a wide range of diversity. The prevailing symptom that was frequently cited was the gradual onset of dementia, accounting for approximately 41% of the reported cases. This was followed by impairments in cerebellar and visual functions, which constituted 18% of the cases, mental health issues at 13%, and pyramidal and extrapyramidal symptoms at 10%. As the condition progressed, a greater number of neurological abnormalities became evident. It is worth noting that all sCJD cases were accompanied by dementia, as indicated by the reports. Furthermore, the other four symptoms associated with sCJD, namely visual or cerebellar dysfunction (67%), myoclonus (76%), pyramidal or extrapyramidal symptoms (80%), and mutism (39%), were also frequently observed. A total of 19%, 40%, and 41% of the patients displayed dementia along with 4, 3, and 2 additional neurological symptoms, respectively. Small granules and the type-1 PrPSc molecule exhibited extensive dispersion throughout the cerebral tissues of a limited cohort of individuals affected by sCJD subsequent to neuropathological and molecular evaluation, whether conducted posthumously or through cerebral biopsy [Citation28].

4.2. Hong Kong

A case report of a 67-year-old was published by Chan et al., in 1987. The patient was suffering from the clinical onset of a disease for the past 6 months and was admitted to the hospital with a worsening mental state. Apart from the physical symptoms, EEG depicted irregular activities in all areas of the brain. Although the patient was reactive to painful stimuli, slight droopiness in the left central face was observed, with myoclonic jerks occurring. He was then diagnosed with CJD. The patient then slipped into coma for the next 2 months with myoclonic jerks slowly disappearing. The patient was declared deceased 4 months following his admission. His survival period from onset to death was 10 months [Citation29].

4.3. India

India is a developing country, and not many cases were reported. One of the reasons could be the lack of applicable diagnostic techniques. In the period between 1971 and 1990, 30 patients were documented which included 20 confirmed and 10 probable cases of CJD. Among them, 18 were men and 12 were women. The age of onset ranged between 34 and 76 years. The survival time ranged from 1 month to 36 months. The patients had clinical onset with psychiatric symptoms such as visual complaints, and confusion state before they were diagnosed with CJD [Citation30,Citation31].

In another case reported by Biswas et al., 10 people were categorized as probable sCJD in the year range 2011–2013 with a gender ratio of M: F = 4:6. Their ages ranged from 39 to 70 years and averaged 56.1 years. Six of them presented clinical characteristics such as behavioural abnormalities, four of them had ataxia, five presented extrapyramidal features, four complained of visual hallucination and one had cortical blindness. Within 4 months, all of them were rendered bedridden and eight died within a mean duration of 4.56 months following onset. The remaining two patients were not available for follow-up [Citation32].

4.4. Japan

After China, Japan recorded the highest number of CJD cases. From 1999 to 2009, the CJD Surveillance Committee of Japan registered 1,241 cases of prion diseases. Among them, 76.8% were sCJD cases, found mainly of MM2 genotype in thalamic and cortical forms [Citation33]. Furthermore, Iwasaki et al., reported 29 autopsied sCJD patients recorded by the Institute for Medical Science of Aging, Aichi Medical University from the year 1997 to 2009. The patients were found to be carrying the MM1 genotype of PRNP codon 129. The mean age at disease onset was 67.1 years and the mean survival time was 11.9 months. In order to diagnose, EEG was done after the onset of symptoms. Once the akinetic mutism state was reached, the period of progression to death was 9 months [Citation34].

A 2022 study by Kosami et al., reported 2440 CJD cases with sCJD attributed for 1676 (69%) cases. Patients with homozygosity for methionine may potentially face an elevated susceptibility to the development of prion disorders. The odds ratio (95% confidence interval) adjusted for sCJD was calculated to be 2.21 (1.46 to 3.34) [Citation35]. In 2023, a 72-year-old female patient arrived at the medical facility displaying visual impairment in both eyes and a duration of light sensitivity spanning two to 3 months. Her visual acuity in both eyes was recorded as 20/2000 seven days prior. Upon examination, her pupillary light reflex remained intact and fundoscopy revealed no abnormalities. However, an observation of left homonymous hemianopia and limited downward movement of the left eye was possible. Upon admission, her visual acuity was reduced to light perception. Both electroencephalography and cranial magnetic resonance imaging results exhibited no irregularities or periodic synchronous discharges. On the sixth day of hospitalization, an examination of the patient’s cerebral spinal fluid exposed the presence of tau and 14-3-3 protein, with a successful real-time quaking-induced conversion outcome. Subsequently, the patient experienced myoclonus, became mute, and eventually succumbed. Postmortem analysis revealed spongiform alteration and thinning of the right occipital lobe cerebral cortex. Deposits of irregular PrP and enlarged astrocytes were observed with immunostaining. Through the examination of brain tissue via western blot and the analysis of the PrP gene’s codon 129 polymorphism, it was subsequently established that she possessed the Heidenhain variant of sCJD characterized by the presence of both methionine/methionine type 1 and type 2 cortical form [Citation36].

4.5. Oman

Two sporadic cases were reported during the period between 1991 and 1995, in Oman [Citation37]. Aged 50 and 75, both presented clinical characteristics such as rapidly progressive dementia and myoclonic jerks. The patients were diagnosed based on the symptoms and EEG results depicting abnormalities.

4.6. Pakistan

Pakistan reported 2 probable sporadic cases in the year 2012 and 2013. The 62- and 72-years old females were diagnosed with sCJD after both presented psychiatric and behavioural symptoms along with positive EEG and MRI results. Both patients had no history of hormone therapy or grafting [Citation38]. Furthermore, one case of CJD was confirmed through biopsy [Citation39]. This 69-year-old female patient was brought into Agha Khan University Hospital, Karachi, Pakistan, with behavioural symptoms which began 5 months earlier. She was also suffering from falls and gait unsteadiness for 2 months before admission. Weeks following admission, the patient started facing myoclonus jerks, eventually leading to unresponsiveness, and was rendered bed bound. To confirm a diagnosis, multiple tests were performed. A biopsy of the frontal lobe of the brain was done which depicted spongiform changes. The biopsy sample was immune stained with 3F4 monoclonal antibody, revealing granular deposits that are specifically found in prion diseases [Citation40].

4.7. Singapore

Two sCJD cases, a 50-year-old male, and a 61-year-old female, have been reported in the years 1993 and 2002, respectively. The former was admitted to the hospital due to a deteriorating mental state. He presented behavioural changes, poor coordination, and jerky movements. An EEG was performed after several other tests, which demonstrated superimposed periodic high-voltage, sharp, and slow wave complexes in both hemispheres. A biopsy was also done from the frontal right lobe which showed degeneration of the grey matter in the cortical area, along with astrocytosis. The patient died a year later. The second patient’s EEG showed periodic lateralized epileptiform discharges (PLEDs) in the brain’s left frontal and central regions. After the confirmed diagnosis, the patient was bedridden for 10 months after onset [Citation41].

4.8. Taiwan

Taiwan CJD Surveillance Unit (CJDSU) was established in 1997 and registered CJD cases dating back to 1975. Prior to 1997, 74 cases of sCJD were reported, with 3 biopsy-proved cases only. A total of 809 cases were reported to the CJD surveillance unit from 1996 to 2020 for the purpose of confirmation. Among these cases, 441 (with 230 women) were determined to be sporadic CJD. The average age of onset was 67 years with a standard deviation of 9.9 years. The median survival period was found to be 13.3 to 14.2 months on average. The two primary clinical signs observed were myoclonus (73% of cases) and akinetic mutism (54% of cases). In terms of PRNP polymorphism, 99% of patients (195 out of 197) exhibited the methionine homozygous genotype at codon 129 (M129M). EEG demonstrated sensitivity to periodic sharp wave complexes (PSWCs) in 59.7% of cases. The sensitivity of total tau protein (>1200 pg/mL) and 14-3-3 protein (>1200 pg/mL) in cerebral fluid was determined to be 75.6% and 69.7%, respectively. It was observed that patients who were younger tended to have longer survival compared to those who were over 65 years old (hazard ratio of 0.466, P .001). In the initial triennial period, the likelihood of survival for women surpassed that of men (hazard ratio [HR] 0.712, p = .005). The presence of periodic sharp wave complexes (PSWCs) continued to exert a deleterious influence on survival (HR 0.788, p < .05). Among the various factors, only epileptic seizures emerged as a clinically significant predictor for survival duration, despite their infrequency (HR 0.768, p < .05). PSWCs represent a prognostic EEG biomarker that can be effectively capitalized upon. Although rare, epileptic seizures serve as the sole clinical prognostic marker for a brief period of survival [Citation42].

4.9. Thailand

While there are no official surveillance or statistics on CJd in Thailand, 2 probable and 1 possible case between the year 2012 and 2014 were reported from Thammasat University Hospital. A 42-year-old Thai woman exhibited an irregular walking pattern and subacute dizziness. After 2 weeks, she began experiencing cognitive decline, including memory loss and difficulty concentrating. Her level of enjoyment and interest in activities significantly diminished. Eventually, she became uncommunicative and developed rigid muscles as her overall health worsened. Subsequently, her limbs exhibited spontaneous myoclonus movements. T2-weighted and diffusion-weighted imaging revealed heightened signal intensity in the bilateral caudate nuclei, putamen, and left frontotemporal cortex. Electroencephalography detected generalized and synchronous periodic sharp wave complexes occurring at intervals of 0.6–0.8 seconds. Further analysis with back-averaging EEG confirmed multifocal myoclonus originating from the brain. Unfortunately, 32 weeks after the initial onset of symptoms, she passed away. The patient’s clinical history, physical manifestations, EEG findings, and brain MRI results all align with a probable diagnosis of sCJD.

In another case, a 76-year-old Thai male patient sought medical attention due to a three-week history of mental confusion, hallucinations, difficulties in speech articulation, and slight weakness on his left side. He denied ever experiencing a headache or a fever. The analysis of his CSF and the general blood chemistry were both consistent with acceptable values. On fluid-attenuated inversion recovery (FLAIR) MRI sequences, his bilateral caudate nuclei, putamen, and bilateral fronto-temporo-parietal cortices demonstrated symmetrical hypersignal intensity, with restricted diffusion on diffusion-weighted imaging (DWI). His electroencephalogram (EEG) detected periodic generalized sharp wave complexes. As time progressed, his clinical condition deteriorated, and he began to experience involuntary muscular contractions throughout his body. Sadly, he developed aspiration pneumonia, and after a duration of 8 months from the initial onset of symptoms, he tragically passed away. The patient’s condition was identified as being consistent with sCJD, with a high probability.

In the same period, a female Thai teacher, aged 53, who had previously suffered from exhaustion, insomnia, and vertigo, presented with symptoms. These symptoms included memory impairment, reduced motor coordination, and withdrawal from social interactions 1 month later. Upon physical examination, the patient displayed alertness but a significant decline in her ability to produce speech. We observed general stiffness and occasional spontaneous muscle contractions. Following an initial diagnosis of akinetic-rigid syndrome, comprehensive blood tests and cerebrospinal fluid investigations were conducted. A CT scan of the brain revealed no abnormalities. EEG detected intermittent delta slow waves superimposed on a characteristic alpha background. The patient’s condition rapidly deteriorated, resulting in muteness and confinement to bed. Spontaneous muscle contractions in the limbs were observed. Four months after the onset of symptoms, the patient passed away. Based on the clinical history, disease progression, and physical examination findings, a potential diagnosis of sCJD was indicated [Citation43].

5. Incidence of genetic CJD in Asia

5.1. China

CJD was hardly diagnosed in China till the end of the 1980s. According to the data provided by Chinese National Surveillance for CJD, a total of 5,078 cases of CJD were reported of which 243 cases accounted for different types of Genetic Prion Diseases (gPRDs) including gCJD. Of all the prion disease (PrD) cases diagnosed between 2006 and 2021, 11.1% were gPrD cases of which 167 were confirmed as gCJD [Citation44]. Overall, 19 different subtypes of PRNP mutations were identified in Chinese patients [Citation45]. CJD cases were diagnosed according to the criteria provided by the Chinese National Health Commission and World Health Organization. Clinical examinations including MRI, EEG, CSF 14-3-3, CSF tau, and CSF biochemistry analysis was done followed by PRNP PCR and sequencing. The results were clinically correlated by the expert neurologists and epidemiologists.

The most common mutation in China is T188K with 65 cases i.e., 29.8% of all the gPRD cases. T188K cases have been identified in 20 provinces across China, with largest number of cases in Shandong. First case of T188K mutation in China was identified in 2009. Median age at the onset of gCJD with T188K mutation is 61 years and the average survival time of the patient is 4 months. MRI of 78% of the T188K patients showed special abnormalities [Citation46,Citation47]. Only a single instance of the eight CJD T188K cases documented in one study exhibited a positive familial background of the ailment. The affected individuals ranged in age from 39 to 76 years old. The initial symptoms are reportedly inconsistent. The predominant clinical presentation in most patients (63%) was rapidly progressive dementia, followed by walking instability (50%), in that particular sequence. Each individual experienced dementia, as well as pyramidal or extrapyramidal complications, during the later stages of the condition. Moreover, cerebellar dysfunctions and myoclonus were also frequently observed, akinetic mutism was also recorded [Citation47]. Another study that analysed 30 patients with the T188K mutation concluded that progressive dementia observed among these patients was quite prevalent, with a prevalence rate of 66%. Additional early markers included extrapyramidal symptoms, mental dysfunction, and cerebellar problems at a rate of 30%, 33%, and 40%, respectively. Visual abnormalities and akinetic mutism were also observed in the later stages of the illness among the patients. Approximately 27.9% of T188K mutation cases showed periodic sharp wave complexes (PSWC) on EEG [Citation48].

The second most common mutation to have been diagnosed in China is E200K with 41 cases in total and constituting 19.8% of the total gPRD cases [Citation44,Citation49]. Only 6 out of 41 E200K patients showed family history. Increased proportion of CSF tau protein was observed in these patients. The first Chinese case of E200K mutation was diagnosed in 2010 which displayed missense mutation in codon 200 (E200K) and methionine homozygous genotype at codon 129 of PRNP gene [Citation50]. In a study, 30 patients with E200K mutation were analysed, showed that 14-3-3 marker was detected in a majority of the patients. The EEG pattern exhibited an anomalous nature characterized by a decrease in the rate of background activity and the presence of periodicity, accompanied by triphasic sharp waves. In nearly half (48%) of the gCJD cases pertaining to the E200K mutation, the presence of PSWC on EEG recordings were identified [Citation48]E200K cases are more prevalent in Northern China and are identified in 16 provinces. The average age at the onset of E200K mutation gCJD is 57 years and survival time is 6 months [Citation44].

The third most common mutation in gCJD patients is E196A with a total of 16 cases till date and 7.3% of the entire gPRDs [Citation48,Citation51]. None of the patients with E196A reported any family history of CJD. A total of 73% of the patients with E196A mutation displayed special abnormalities on MRI. The average age at the onset of gCJD in patients with E196A mutation is 61 years and the survival time is six and half months [Citation44]. E196A patients show similarities with sCJD phenotypically with slight differences in a few clinical features [Citation52]. In a study, it was reported that an elderly Chinese male, aged 76, who was diagnosed with CJD, exhibited a unique mutation in the PRNP gene. The presence of the 14-3-3 protein was detected in the cerebrospinal fluid, while diffusion-weighted MRI scans revealed the existence of a ribbon-like high signal intensity in both cortices. Furthermore, electroencephalography demonstrated a typical periodic synchronous discharge. The diagnosis of CJD was established based on the manifestation of distinct clinical symptoms. Remarkably, the identification of a point mutation at codon 196 (E196A: GAG→GCG) within the PRNP gene was made [Citation53].

Other mutations with less than 5 cases throughout China are E196K, V2031, R208H, V210I, G114I, R148H, V180I, T183A and E200G with 5, 3, 3, 3, 2, 2, 1, 1, and 1 case identified respectively [Citation54–57].

5.2. India

Due to the lack of genetic testing facilities, reports regarding gCJD from India are limited [Citation58]. Only two studies identifying genetic or familial CJD have been carried out so far. First familial CJD case with D178N from South-East Asian region was reported in India. A 42-year-old male patient exhibited a history of dementia, behavioural problems, and difficulty in walking. Over the course of 3 months his symptoms exacerbated rapidly, and he developed myoclonus. He also had a family history on his maternal side of the family where his family members developed similar symptoms. Genetic testing revealed D178N mutation in the PRNP gene. CSF 14-3-3 turned out to be negative which is in accordance with the previous studies which discovered that CSF 14-3-3 is negative in patients with D178N mutation. Neuroimaging and clinical evaluation also indicated CJD. All the symptomatic members of his family died within 3 to 15 months of the onset of the disease. Two more family members were also tested positive for D178N mutation and V/V polymorphism was identified at 129th amino acid but they were asymptomatic [Citation59].

In another case report in India, a man presented a history of short-term memory loss, behavioural changes, mood swings, deterioration in communication, hand tremor, lost control of urination. Neuropathological analysis showed major neuronal loss along with the shrinkage of cortex. Rare small plaques were seen in PrP immunostaining. Genetic analysis showed D178N mutation in PRNP. Genetic testing on 27 members of his was performed, the results showed that two of his family members were positive for D178N mutation [Citation60].

5.3. Japan

In 1996, three gCJD patients were identified with M232R mutation in Japan. The patients exhibited rapidly progressive dementia, abnormal EEG results and myoclonus. All three patients suffered akinetic mutism within 2 to 6 months of developing the disease and died within 4 to 24 months. Diffused grey matter was seen in immune PrP staining. Loss of neurons could be seen in histopathological analysis. Plaque formation in the brain wasn’t observed. Healthy controls did not have the M232R mutation indicating that the disease in those three patients was indeed caused by M232R [Citation61].

In another report, two brothers were reported to have familial CJD, both patients presented rapidly progressive dementia, abnormal EEG, and myoclonus. One brother was 62 years old and died within 6 months of developing the disease. The second brother was 58-year-old when he developed the disease and died within 13 months. Genetic analysis identified point mutation in PrP gene at codon 200 of one of the first brother. Heterogenous phenotype of CJD200 was identified in Europe and America whereas in Japan the phenotype was homogenous [Citation62]. In 1997, another family was reported to have familial CJD with codon 200 and codon 219 mutation [Citation63]. In 1999, Japan established its national surveillance system to identify prion diseases in humans. This program collected clinical, neurological, and genetic information of patients suffering from CJD from 1999 to 2014. Of 2,394 cases identified, 365 were of gCJD. The overall prevalence was 1.2 cases/million per year. According to the genetic testing, the most prevalent mutation was V180I with a total of 211 cases followed by M232R and E200K with 63 and 61 cases respectively. Currently, there are numerous reports indicating that the V180I mutation in PRNP is responsible for distinct clinical and pathological findings. Due to the rarity of a familial history of the disease among patients with V180I, the question of whether this mutation is the cause of prion disease persists. Conversely, patients with V180I exhibit various specific clinical features that differentiate them from those diagnosed with Scjd or other genetic prion diseases (gPrDs). Patients with V180I can be easily distinguished from those with other forms of dementia due to the presence of specific hyperintensity observed in the cerebral cortex during diffusion-weighted MRI [Citation64] Five cases of D179N were also identified [Citation59]. Five cases of D179N were also identified [Citation65].

5.4. South Korea

Due to the close proximity of the Republic of Korea and Japan, similar patterns of mutations were identified, however data related to mutations and polymorphisms associated with gCJD is scarce in Korea. A surveillance study was carried out from 2001 to 2019 in Korea, during this period 33 were familial or genetic. The mutations that were prevalent in South Korea include E200K, V1801, M232R, D178N, and V203I [Citation66].

In a study, in addition to MRI and EEG, genetic analysis was carried out which revealed gCJD patients had three mutations at codon D178N, E200K, and M232R. The D178N mutation (with homozygous M/M at codon 129) was initially identified in 2009 in a male patient of age 67 who suffered from atypical CJD, without any familial background. The observed symptoms consisted of gradual disruption of gait and speech difficulties accompanied by extrapyramidal indicators, but not insomnia. Additionally, the patient displayed rigidity and bradykinesia, yet there was an absence of myoclonus, visual impairment, cognitive decline, or pyramidal symptoms. Over the course of a few months, the patient’s condition rapidly deteriorated into akinetic mutism, although the duration of the disease was relatively extended, exceeding 2 years. EEG results were within the normal range, with positive findings for the 14-3-3 CSF marker. MRI scans exhibited elevated signal intensities in both the parietal and occipital gyri [Citation67].

The 58-year-old patient with E200K mutation displayed swift disease progression, impaired gait, cognitive disarray, and myoclonus. Subsequently, dysarthria, diminished gait, decreased attention, and restlessness manifested. During the neuropsychological assessment, the patient exhibited signs of confusion and disorientation. The patient succumbed to the illness 3 months after the initial onset of symptoms. MRI unveiled heightened signal intensity in various regions of the brain, encompassing both the bilateral frontal temporoparietal area and the caudate nucleus. EEG revealed the presence of sharp spikes and slow waves, and CSF tested positive for the 14-3-3 signal [Citation67]. Another case of gCJD with E200k mutation was documented in Korea, the patient, displayed the onset of progressive dysarthria and visual hallucinations at the age of 63. Subsequently, within a brief period, the patient also encountered impairments in gait, myoclonus, and behavioural abnormalities. The DWI examination revealed significant elevation in signal intensity within the basal ganglia and occipitoparietal cortex regions. A patient who was 65-year-old with M232R mutation exhibited rapidly progressive dementia and walking disability, MRI displayed heightened signal intensities in the parieto-occipital cortex and temporal lobes and CSF exhibited positivity for 14-3-3 protein. The patient died within 16 months of developing the disease [Citation67].

In another case, a 75-year-old woman was reported to have fCJD with V180I mutation. This is the first case of a point mutation at codon 180 in South Korea. The EEG examination of the patient revealed the presence of delayed oscillations in the right cerebral hemisphere, whereas the CSF analysis showed a positive outcome for the 14-3-3 protein. In addition, MRI showed elevated intensities of signal in the frontal, parietal, temporal, and occipital regions, bilaterally. The woman did not have any family history of dementia [Citation68]. One study documented the admission of an elderly patient that had V180I mutation with serious neurological symptoms to the hospital. The patient had intense lesions in the thalamus, right frontal cortex, and temporal cortex. Analysis of brain tissue showed changes in the tissue, empty spaces, scarring, and loss of neurons in most parts of the brain [Citation69]. Another study documented the case of five patients with V180I mutation, The onset of the disease occurred between the ages of 72 and 77 in four of the subjects, while one patient experienced the onset at the age of 57. All five patients exhibiting the V180I mutation displayed either positive or slightly positive results for the presence of 14-3-3 protein in their CSF. The symptoms consisted of cognitive impairment, coordination difficulties, mood disorder, or brain dysfunction [Citation70].

5.5 Taiwan

According to the surveillance study conducted by CJDSU from 1998 to 2017, eight cases of gCJD were identified in Taiwan. Of the eight cases identified, two cases consisted of E196A-129 M and one case of R148H-129 M mutation [Citation71]. The age range of the onset of disease was 29–67 years and the mean survival time was 2.5 to 5.5 years [Citation72]. Table 1 summarizes the PRNP mutations that are prevalent in Asian countries.

6. Incidence of iatrogenic CJD in Asia

6.1 Japan

Iatrogenic cases increased significantly during the 1990s in Asia, mostly due to the transplantation of dura mater grafts which corresponds to 95% of the cases [Citation73]. The CJD surveillance committee of Japan performed a comparative analysis among Japan and other counties and revealed that the prevalence of iCJD was significantly higher than in other counties, the reason being the frequent use of lyodura in 2012 [Citation74]. Most iCJD cases were those of dura mater graft-associated CJD (dCJD) i.e., 0.05% to 0.02% [Citation67,Citation75]. In Japan, 1,241 patients have been identified as definite and probable cases of CJD from 1975 to 2009 among which 77 cases were iCJD [Citation74]. According to Japan’s monitoring system, 2003 showed a significant decline in iCJD cases but in 2017, one case was recorded which was attributed to the long incubation period of this disease [Citation76,Citation77].

Other than dCJD, iCJD can also be caused due to corneal transplant. CJD cases recorded from 1990 to 2006 also included patients who got corneal transplants 1.5 years earlier. But unfortunately, the origin couldn’t be detected as eye banks denied that any donors were infected with prion disease. No patients of iCJD have been reported in Asia who previously received gonadotrophin and human growth hormone (hGH), and this trend can correlate with the careful preparation of human growth hormone through chromatographic purification in Japan [Citation78]. Similarly, since the 1980s no cases of iCJD have been reported to occur via EEG needles and surgical instruments.

6.2. Taiwan

A hospital-based nationwide study performed under the Taiwan CJD surveillance unit from 1996 onwards identified 123 patients of CJD but no patients of iCJD [Citation42]. Epidemiological studies in Taiwan indicated that the annual incidence of CJD is lesser compared to other countries. Specifically, iCJD cases are non-existent in Taiwan despite their full-scale tracking system [Citation71,Citation79].

6.3. India

Unfortunately, India, like many other countries have not developed any nationwide surveillance unit, hence we are unable to detect the actual number of CJD in general and specifically iCJD patients. Contrary to these induvial studies have shown that there are probable cases of iatrogenic origin in India. For example, a case study conducted from 1971 to 1990 which depicted 3 out of 20 CJD patients had undergone an invasive medical procedure in past [Citation31].

7. Comparison to US and Europe

Different countries in Asia exhibit varying rates of sCJD, with certain regions reporting lower incidences compared to others. Among the Asian nations, Japan stands out with the highest reported rates of sCJD. In comparison to numerous Asian nations, the US displays a relatively lower prevalence of sCJD. Approximately 1 out of every 1 million individuals are annually affected by this condition. Significant regional disparities in sCJD surveillance and reporting can be observed in Asia, potentially leading to underreporting in certain areas. The US employs a more centralized and standardized approach to monitor and report rare diseases like sCJD, resulting in more accurate statistical data. The prevalence rates in Europe exhibit substantial variation, with specific Western European countries documenting elevated frequencies of sCJD compared to other Eastern European countries. sCJD has emerged as the central area of interest for multiple extensively financed research networks and institutions throughout Europe, demonstrating noteworthy advancements in the examination and management of this condition [Citation80].

The mutation pattern observed in Japan differed from that observed in the European countries. Among the mutations associated with CJD, the occurrence of V180I (0.2% in the EuroCJD population) and M232R (not detected in the EuroCJD population) was found to be significantly higher in Japan compared to Europe. Among the mutations associated with gCJD, the V180I mutation was found to occur at a rate of 0.2% in the EuroCJD population, while the M232R mutation was not detected in EuroCJD. Interestingly, these mutations were observed to be significantly more common in Japan compared to Europe. On the other hand, the E200K mutation was found to be present in 17.1% of Japanese CJD cases and 41.2% of European cases. Similarly, the V210I mutation was absent in Japanese patients but had a prevalence of 16.2% in European patients. Additionally, the occurrence of the octapeptide insertion was found to be 1.4% in Japan and 9.9% in Europe, while the D178N mutation with either the 129 M/M or V/V genotype was less frequent in Japan compared to European patients [Citation81].

T188K has been documented in two legal instances within the European region, specifically in Austria and Germany. Furthermore, there is a lack of available data regarding the presence of T188K within Asian populations, namely Korean or Japanese, with the exception of Chinese individuals [Citation45]. On the other hand, E196K appears to be more prevalent among European patients, as it has solely been observed in a solitary Chinese case [Citation82]. The occurrence of M129V and E219K showed dissimilarities in East Asia and Europe as well. In the overall population of Koreans and Japanese, a majority of individuals possess the MM allele for M129, whereas the MV allele (approximately 6–7%) and the VV allele (less than 1%) may be infrequent. Conversely, in the general populations of Europe, the MV and VV alleles are rather prevalent (35–51% and 8–12% respectively). Heterozygous E219K was observed in around 7–8% of healthy Koreans and Japanese, while it is likely to be exceedingly rare among the general European population [Citation83].

Studies have shown the frequency of individuals acquiring iCJD after Hgh transplant was higher in European countries (especially in France (119 cases) & UK (65 cases) whereas US reported 29 cases and Asian countries (specifically Japan) reported 77 cases. Analysis of patients with Dura graft transmission showed that Japan comprises of two-third of the cases globally with 83 cases of iCJD being reported till 2005s this may be due to long incubation period. On the other hand, a total of 206 cases were observed in Caucasian population due to transplantation of contaminated Dura graft [Citation84]. Asian countries reported four cases of iCJD cases due to neuronal instruments and corneal transplants whereas no cases were seen in Caucasian population corresponding to former route of exposure, but four deaths were recorded among the patients who have previously undergone corneal transplant [Citation85]. Overall, the frequency of iCJD cases was observed greater in Asian population as compared to Caucasian population.

8. Prevalence of other genetic prion diseases

Other Genetic Prion diseases include Gerstmann – Sträussler – Scheinker disease (GSS) and Fatal Familial Insomnia (FFI). GSS can initially present as ataxia or Parkinsonism, with dementia appearing later. The duration of the disease varies, with some patients succumbing within a year and others enduring for over 10 years. Amyloid plaques containing Aβ peptide can be found in the brain, especially the cerebellum [Citation86]. The initial signs of FFI typically involve difficulty sleeping and problems with the autonomic nervous system. As the disease progresses, there are additional challenges with movement and cognition. The duration of the illness is often short, with some patients dying within 2 years of onset. FFI can affect various parts of the nervous system, such as the thalamic nerves, leading to their loss or atrophy. Additionally, there may be PrPSc deposition in the midbrain or hypothalamus [Citation87]. Prevalence of GSS and FFI cases identified in China, Japan, Korea and India are discussed in this review article.

8.1. China

In a study carried out in 2017, five cases of GSS with the P102L mutation were identified. The patients developed the disease at different ages. All cases began with difficulty in walking and progressive ataxia. Affected family members displayed different symptoms. Cognitive decline was common among the patients, but only two had early symptoms. Two individuals had cognitive dysfunction later. The study suggests that unknown genetic or environmental factors may contribute to the phenotypic diversity [Citation88].

In 2017, another case of GSS was identified. The female patient exhibited unstable gait and dysarthria at 44 years old. The patient displayed dysarthria, nystagmus, wide base, and unsteady gait. Brain MRI showed mild diffuse atrophy. The patient’s spinal cord was damaged by herniation [Citation89]. In a study conducted in 2019, 12 GSS patients were identified. Most of these patients exhibited motor dysfunction as an initial symptom [Citation90]. The occurrence of the P105L mutation in Chinese patients is potentially rare, evidenced by the reporting of only a single instance of GSS mutation [Citation91]. FFI with the D178N mutation is also observed frequently in China, with 39% of the analysed cases exhibiting this mutation [Citation92].

8.2. Japan

The P102L mutation is prevalent among Japanese patients diagnosed with GSS. The CJD Surveillance Committee has documented the occurrence of this mutation in 39 patients [Citation93]. Familial GSS is the most commonly observed form of the disease, with the age of onset varying among individuals. Additionally, positive cases of the 14-3-3 protein were detected in patients with the P102L mutation. The primary symptoms observed in these patients included spastic paraparesis, gait disturbances, ataxia, and tremor. It is worth noting that not all patients with the P105L mutation exhibited spastic paraparesis. Finally, a recent case involving the P105L mutation was characterized by severe cognitive and gait disturbances, parkinsonism, and swallowing dysfunction [Citation94].

Three cases of the D178N mutation with the MM genotype with FFI were reported. The age of onset ranged from 46 to 57 years, and no PWSC or MRI hyperintensities were observed in these patients. However, at least one case tested positive for 14-3-3 on CSF, and another case involved a 79-year-old patient with D178N and 129 MV genotype who developed sporadic prion disease and tested positive for 14-3-3 on CSF. No abnormalities were seen on MRI or EEG [Citation81]. In another study, a patient with FFI exhibited symptoms such as dysphagia, loss of appetite, abnormal sleep movements, insomnia or hypersomnolence, and later sleep apnoea, as well as tremor, excessive sweating, constipation, impotence or ataxia. MRI showed mild atrophy, but EEG revealed no abnormalities. Histology revealed spongiform changes in the cingulate gyrus and subiculum, gliosis in the thalamus and inferior olivary nucleus, and Western blot analysis indicated a low amount of type 2 PrPSc with the FFI-type glycosylation pattern [Citation95].

8.3. Korea

The first cases of GSS in Korea was identified in 2010. The patient was a 46-year-old female that exhibited P102L mutation and displayed symptoms of ataxic gait, language impairment, and cognitive dysfunction. The patient tested positive for the 14-3-3 protein in the CSF and had atypical non-specific slow waves in EEG [Citation96]. P102L was also observed in a patient from another study with definite GSS, but no clinical symptom details were provided by the investigators [Citation97]. In 2019, P102L was reported in another patient, without any family history and the symptoms included gait disturbance, slurred speech, hand clumsiness, and memory dysfunction. MRI showed high signal intensities in the bilateral cortices and mild cerebellar atrophy, while EEG was normal and the CSF tested positive for 14-3-3 protein [Citation98]. A recent report described the first familial case of GSS in Korea. In this family, there was phenotypic heterogeneity. Imaging showed abnormalities in the hemispheric and caudate nuclei. EEG showed mild diffuse slowing and CSF 14-3-3 was positive [Citation99].

Additionally, the first case of FFI was reported in Korea in 2014, the patient was a 34-year-old male that exhibited D178N mutation (homozygous at residue 129) [Citation100]. Another instance of the D178N mutation was described in a 57-year-old male, who was diagnosed with FFI. The patient presented with an irregular sleep-wake cycle, visual hallucinations, myoclonus, ataxic gait, and weight loss. The CSF analysis for 14-3-3 protein yielded negative results, while the EEG indicated widespread slowing without periodic discharge. MRI and PET scans revealed lesions in the white matter and reduced uptake in the bilateral thalamus, respectively [Citation101].

8.4. India

In accordance with a study conducted in the year 2020, the initial instance of GSS syndrome was discovered within India, specifically within an Indian household. This family exhibited a notable occurrence of the 305C > T, p.Pro102Leu mutation within the PRNP gene [Citation102].

9. Conclusion

The current review attempted to analyse the epidemiological characteristics, clinical examinations, and laboratory features of CJD patients in Asia. sCJD accounts for the highest number of CJD cases out of the three types and is mainly reported in China. gCJD cases have been observed in different ethnicities – T188K, E200 and E196A are most prevalent in China whereas, in Europe, the most dominant mutations are E200K, V210I, and D178N, and in America, the most common mutations are E200K, and D178N [Citation103,Citation104]. China and Japan have differences in PRNP variant profiles, and the most prevalent mutations in Japan (V180I and M232R) are not reported in China. iCJD incidence has declined with the innovation in medical procedures globally as well as in Asia. Epidemiological studies conducted in the Asian region showed the highest incidence of iCJD in Japan. On the other hand, some countries have not reported a single case which corresponds to the lack of surveillance units in those countries.

The current review establishes the presence of all variants of CJD across Asia (Figure 2). However, in most Asian countries in general and Southeast Asian countries in particular, CJD cases are misdiagnosed and often underreported. There is no proper regional surveillance system for CJD. Since Asia is the most populated continent in the world, the actual global prevalence of CJD cannot be estimated until and unless these countries are accounted for. Concrete and reliable surveillance networks are needed across Asia to evaluate the prevalence and incidence of CJD in the region. Ever since we started working on documenting CJD cases in Asia, some cases have been reported in Pakistan with patients exhibiting symptoms of CJD, however, due to a lack of awareness and proper diagnostic measures, the majority remain underdiagnosed and underreported.

Figure 2. Total cases of CJD reported in Asia from 1986 to 2023. this graph indicates the number of CJD cases reported from the year 1986 to 2023 in Asia. sCJD were the highest among all CJD cases. China (1957) and Japan (1705) reported more cases of sCJD than any Asian country and Hong Kong (1) reported the least. On the other hand, gCJD was highest in Japan (370) and least in India (2). Iatrogenic cases were found to be the least among all CJD types and showed 85 cases overall in Asia, 82 being in Japan and 3 in India.


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

snip...

Overall, the AAPCs of age-adjusted CJD-associated mortality rates rose significantly over the study period (3.2%; 95% confidence interval [CI] 1.4–5.1%). The AAPC of the age-adjusted incidence rates also increased (overall 6.4%; 95% CI 4.7–8.1%). The CJD-associated increases in the mortality and incidence rates were especially prominent among adults over the age of 70 years. Given this trend in aging of population, the disease burden of CJD will continue to increase in severity. Our findings thus recommend that policymakers be aware of the importance of CJD and focus on preparing to address the increasing prevalence of dementia.

snip...


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 


TUESDAY, MAY 19, 2020 

China Sporadic Creutzfeldt-Jakob disease: A retrospective analysis of 104 cases 


Professor John Collinge on tackling prion diseases

“The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide.”

it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.

We defined iatrogenic cerebral amyloid angiopathy as a new disease, with relevance to Alzheimer’s disease and public health.

it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.

We defined iatrogenic cerebral amyloid angiopathy as a new disease, with relevance to Alzheimer’s disease and public health.



MONDAY, JANUARY 29, 2024

Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone

''The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.''


Monday, January 29, 2024

iatrogenic Alzheimer’s disease, Alzheimer’s disease should now be recognized as a potentially transmissible disorder

Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone


WEDNESDAY, JANUARY 31, 2024

Creutzfeldt Jakob Disease, CJD Support Group for short statured children of the 1970's and 1980's And 2024 Alzheimer’s iatrogenic Transmission


26 MARCH 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

Terry S. Singeltary, retired (medically)

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?


Singeltary 2001

Subject: CJD or Alzheimer's or the same ???

Date: Sun, 29 Apr 2001 12:45:28 -0700

From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de

Bovine Spongiform Encephalopathy

Greetings List,

thought some might be interested in this. I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity scale. i also believe in the accumulation theory. by dose, you could be killed by one sitting, or one injection, or one whatever, depending on the titre of infectivity of that whatever. on the other hand, if the dose is not a lethal dose, over a period of time, the accumulation will become lethal (if consumption continued), and i believe the route/source/titre of infectivity, will be a key roll to the incubation period, and symptoms.

just my opinion...

snip...

kind regards,

Terry S. Singeltary Sr., Bacliff, Texas USA

http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html

SATURDAY, JULY 22, 2023

Alzheimer's Disease Update


TSE Prion and Endoscopy Equipment

Subject: Re: CJD * Olympus Endoscope

Date: Tue, 12 Oct 1999 15:57:03 –0500

From: "Terry S. Singeltary Sr."

To: GOLDSS@...

References: 1

Dear Mr. Goldstine, Hello again, I hope the CDC has not changed your mind, since our phone call, about sending me the information, in which we spoke of. I am still waiting for the information, re-fax. Someone had told me, you would not send me the information, but I told them you would, due to the importance of it pertaining to public safety, and the fact, you are a Doctor. I hope you don't disappoint me, and the rest of the public, and hide the facts, as the CDC and NIH have for years. Olympus can be part of the Truth, or you can be part of the cover-up. We are going to find out, sooner or later.

I already know, as do many more.

Still waiting,

Kind Regards,

Terry S. Singeltary Sr.

Wednesday, March 02, 2016

Endoscope Maker Olympus Agrees To $646 Million Settlement Over Kickbacks, while still ignoring the elephant in the room, CJD TSE PRIONS Health Inc.

*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al ***

Evidence For CJD/TSE Transmission Via Endoscopes

From Terry S. Singletary


see full text;

Evidence For CJD/TSE Transmission Via Endoscopes

From Terry S. Singletary, Sr flounder@wt.net 1-24-3

I have researched human/animal TSEs now for over 5 years due to the death of my Mother from the Heidenhain Variant Creutzfeldt Jakob disease, one of six - known - variants of the infamous 'sporadic' CJD.

I did a little survey several years ago about CJD and ENDOSCOPY in 2001, and then went there again when another article was released recently. However, they seemed to only be concerned with the vCJD strain and risk from endoscopy equipment.

My concerns are if vCJD can be transmitted by blood, and there are now 6 variants of the infamous sporadic CJDs that they are documenting to date, how do they know that none of these 6 variants will not transmit the agent (prion) via blood?...especially since the sporadic CJDs are the only ones documented to date to transmit via the surgical arena and now that the CWD is spreading more and more, who knows about the cattle?

I would always read this study and it would bring me back to reality as to how serious/dangerous this agent is in the surgical/medical arena. You might want to read this short abstract from the late, great Dr. Gibbs twice, and let it really sink in. And please remember while reading some of these transmission studies, that most all, if not ALL these agents transmit freely to primates. Humans, of course, are primates.

Regarding claims that:

'Well, it has never been documented to transmit to humans."

There are two critical factors to think about:

A. CJD/TSEs in the USA are NOT reportable in most states and there is NO CJD/TSE questionnaire for most victims and their families, and the one they are now issuing asks absolutely nothing about route and source of the (prion) agent, only how the disease was diagnosed. Furthermore, the elderly are only very rarely autopsied, ie looking for Alzheimer's or 'FAST Alzheimer's' OR prion disease-related factors and phenomena, such as heart failure caused by disease.

B. It is unethical and against the law to do transmission studies of TSEs to humans, they are 100% FATAL.

I suggest you read these case studies about medical arena CJD transmission very carefully:

1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8

Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.

Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.


Evidence For CJD/TSE Transmission Via Endoscopes

From Terry S. Singletary, Sr flounder@wt.net 1-24-3


Thursday, January 25, 2024

TSE Prion Disease, Eyes, Ophthalmology Diagnostic Equipment, Iatrogenic, What If


Friday, January 10, 2014

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???


22 years ago;

2001 Singeltary on CJD

February 14, 2001

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Terry S. Singeltary, Sr

Author Affiliations

JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214

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.



26 MARCH 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

Terry S. Singeltary, retired (medically)

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc


Singeltary 1999 THE EYES HAVE IT, CJD, AND THEY COULD BE STEALING THEM FROM YOUR LOVED ONE!


France iatrogenic CJD TSE Prion

Friendly fire, pass it forward, they call it iatrogenic cjd, or what i call 'tse prion poker', are you all in $$$

all iatrogenic cjd is, is sporadic cjd, before the iatrogenic event is discovered, traced back, proven, documented, put into the academic domain, and then finally the public domain, this very seldom happens, thus problem solved, it's all sporadic cjd...

Direct neural transmission of vCJD/BSE in macaque after finger incision CORRESPONDENCE

Direct neural transmission of vCJD/BSE in macaque after finger incision

Jacqueline Mikol1 · Jérôme Delmotte1 · Dolorès Jouy1 · Elodie Vaysset1 · Charmaine Bastian1 · Jean‑Philippe Deslys1 ·

Emmanuel Comoy1 Received: 10 July 2020 / Revised: 8 September 2020 / Accepted: 25 September 2020 / Published online: 6 October 2020 © The Author(s) 2020

Non-human primates appeared as the closest model to study human iatrogenic prion diseases [14]: we report here the consequences of variant Creutzfeldt–Jakob disease/bovine spongiform encephalopathy (vCJD/BSE) inoculation in a cynomolgus macaque finger, with the demonstration of an original mode of propagation and the practical risk for professional exposure.

The distal right middle finger handpad of a 4-year-old macaque was incised on both lateral sides to induce local inflammation, and then injected with the equivalent of 10 mg of a BSE, orally challenged macaque brain [18]. After an 18 months period of finger clumsiness, the clinical disease (behaviour abnormalities, fear, hyperesthesia, gait disturbances, shaking) began 7.5 years after inoculation and euthanasia took place 2 months later for welfare reasons. Motor conduction velocity of the right median nerve was reduced to one-third of the left counterpart and sensory potential was not detected.

Histological and biochemical studies were performed as previously described. All the elements of the triad were present [7–9]: spongiform change was moderate in neocortex, striatum, brain stem, mild in spinal cord but severe in thalamus and cerebellum; neuronal loss was globally moderate, but severe in cerebellum and sacral spinal cord (vacuolated neurons); gliosis was severe in thalamus, cerebellum and brain stem and moderate elsewhere (Supplementary Fig. 1). ELISA and western blot (WB) showed the expected accumulation of PrPres with BSE glycophoretic pattern at all levels of brain and spinal cord (Supplementary Fig. 2).

In the brain, PrPd deposits were laminar into the cortical deep layers, massive into thalamus, basal ganglia, cerebellum, and brain stem. In spinal cord, PrPd was symmetrically distributed, intense in the Substantia gelatinosa and nucleus dorsal of Clarke while decreased at sacral level. Deposits were diverse into the whole CNS: synaptic, perineuronal, reticular aggregates, mini-plaques, plaques, and incomplete florid plaques. The retinal plexiform layers were labelled (Supplementary Fig. 1i). There were no amyloid or tau deposits.

Unusual PrPd deposits were observed along dendrites, short and long axons, neuritic threads tracing fne networks of straight lines or like strings of pearls (Supplementary Fig. 3). They were present into deep neocortex, basal ganglia, and motoneurons. Such long processes are not frequent but have been reported in human [13] and experimental studies [10, 22]. PrPd deposits were also noted as very mild into striato-pallidal projections, both limbs of internal capsule and fornix (Supplementary Fig. 3). The presence of PrPd in white matter has been reported (Supplementary text 4).

Peripherally, the expected PrPd was undetectable in lymphoid organs, including spleen, through biochemical or immunohistochemical analyses, while prion replication was detected in the peripheral nervous system (PNS): PrPd staining was visualized in many dorsal root ganglia (DRG) but only in nerves innervating the forelimb site of injection (median and ulnar nerves). At the cellular level, PrPd was limited to ganglia and satellite cells in DRG and Schwann cells (Scs) all along nerves whereas axons were never labelled (Fig. 1). Previously, using postmortem immunohistochemical studies (listed in Supplementary text 5), PrPd has been shown in peripheral nervous system in all forms of human neuropathies, albeit more frequently in vCJD, mostly in posterior root nerve fbres at adaxonal location and/or in ganglion and satellite cells. The restricted amount of PrPd was repeatedly underlined but, recently, prion RTQuiC was positive in all nerves examined [2]. PrPd has also been described, frst in scrapie [17] then in BSE, as limited “adaxonal deposits” or/and Sc deposits, with or without DRG cell involvement (review in [4] and Supplementary text 6). Previous studies of the mode of propagation of PrPd have reported variable observations and analyses depending on strains, host species and genotype (Supplementary text 6); the authors discussed the role of the sensory route of trafficking of prions, the modifications of axonal transport, the centrifugal versus centripetal spread of PrPd .

After peripheral infection, accumulation of infectious agent is reputed to occur in lymphoid tissues before direct neuroinvasion [18, 19], even with very little apparent peripheral lymphoreticular deposition [6, 20]. Here, there is no apparent replication/amplification of vCJD/BSE agent in the lymphoid tissues of the exposed macaque. In this model, the neural contamination occurred directly in the highly innervated finger while neuroinvasion appears to occur in Scs along the median nerve to the DRG, with the appearance of the classical labelling of ganglion cells which indicates the onset of the first level of neuronal infection. This model provides direct evidence of the hypothesis of a sequential infection of Scs from the periphery to the CNS, followed by a secondary diffusion into the spinal cord, as already considered by our group [15] and others [1, 3, 11, 12, 21]. It is to note that studies based on intra-sciatic nerve injections in hamsters [16] and transgenic mice [12] had established a rate of transport of infectivity of, respectively, 0.5–2 mm and 0.7 mm per day. This key role of Scs could explain both the low speed of propagation and the discrepancy between the paucity of PrPd into the distal part of the sensory nerves followed by the positivity of DRG, satellite cells and proximal roots.

In conclusion, we have observed that the exposure of a primate to vCJD/BSE through a distal finger lesion induces, after more than 7.5 years of silent incubation, a massive deposit of PrPd , strictly restricted to the nervous system and the eye.

Our data suggest a new type of pure unique peripheral nervous contamination in which the Scs would have a major role in the mode of centripetal progression of PrPd in the peripheral nervous system. Moreover, considering the fact that, recently, “a variant CJD diagnosed 7.5 years after occupational exposure” (cryomicrotomy) in a technician was observed [5], this experimental case report supports the risk linked to professional exposure and reinforces the necessity of adequate measures of prevention.


Second death in France in a laboratory working on prions

Creutzfeldt-Jakob disease has killed a person who handled this infectious agent at Inrae in Toulouse. After a first death in 2019, a moratorium on work on this pathogen has been extended.

By Hervé Morin

Creutzfeldt-Jakob disease killed a few days ago a retired research technician from the National Research Institute for Agriculture, Food and the Environment (Inrae), who had worked in Toulouse in contact of biological tissue infected with prions. This death sows consternation and concern in the scientific community working with these infectious agents. It follows the death, on June 17, 2019, of Emilie Jaumain, a 33-year-old laboratory technician, suffering from the same incurable neurodegenerative disease. The young woman is said to have contracted it in 2010, cutting herself while handling fragments of the brains of mice infected with prions, in another unit of INRAE, in Jouy-en-Josas.

Computer representation of part of a prion protein on a light micrograph of pyramidal nerve cells (neurons, in black) in the cerebellum of the brain. ALFRED PASIEKA / SCIENCE PHOTO LIBRARY

Regarding the retiree from Toulouse, it will be necessary to determine whether she was the victim of a genetic or sporadic form of Creutzfeldt-Jakob disease, if the disease may have been caused by the ingestion of meat contaminated by the agent of encephalopathy. bovine spongiform (BSE, also called mad cow disease) or, as in the case of Emilie Jaumain, if accidental occupational exposure can be claimed. Prion diseases are caused by proteins taking an aberrant conformation, which gives them the property of replicating to form aggregates that are deleterious for neurons. There are around 150 cases per year in France, resulting in fatal degeneration of the central nervous system.


Temporary suspension of work on prions in French public research laboratories

PRESS RELEASE - The general directorates of ANSES, CEA, CNRS, INRAE and Inserm, have decided jointly and in agreement with the Ministry of Higher Education, Research and Innovation to suspend as a precaution all their research and experimentation work relating to prion diseases, for a period of three months.

This precautionary measure is motivated by the knowledge of a possible new case of a person suffering from Creutzfeldt-Jakob disease and who worked in a laboratory for research on prions.

Posted on July 27, 2021

The suspension period put in place as of this day will make it possible to study the possibility of a link between the observed case and the person's former professional activity and to adapt, if necessary, the preventive measures in force in the research laboratories.

The person with Creutzfeldt-Jakob disease (CJD)1, whose form is not yet known, is a retired INRAE agent. This could be the second case of infectious CJD affecting a scientist who worked on prions, after that of an assistant engineer who died of the disease in 2019, and who was injured in 2010 during of an experiment.

Following this death, a general inspection mission was launched in July 2019 by the ministries of research and agriculture with French laboratories handling prions. Submitted in October 2020, the report concluded on the regulatory compliance of the laboratories visited as well as the presence of a risk control culture within the research teams.

Research around prion proteins, with high public health issues, allows major advances in the understanding of the functioning of these infectious pathogens, and contributes to results that are transferable to other related degenerative diseases such as Alzheimer's and Alzheimer's diseases. Parkinson's.

At the level of each establishment, regular and transparent information will be provided to all the working communities concerned by this measure.

1 The disease Creutzfeldt-Jakob disease (CJD) is one of prion diseases - still called encephalopathies subacute spongiform transmitted(TSE) - of diseases rare, characterized by a degeneration rapid and fatal the system nervous central. They are caused by the accumulation in the brain of a normally expressed protein but poorly conformed - the prion protein - which leads to the formation of deleterious aggregates for neurons. For now , no treatment will allow to change the course of these diseases. It can be of origin sporadic , form the most frequent , original genetic or finally to form infectious following a contamination.



Eye procedure raises CJD concerns

BySTEVE MITCHELL, Medical Correspondent

WASHINGTON, Nov. 18 (UPI) 2004

Snip…

Terry Singletary, whose mother died from a type of CJD called Heidenhain Variant, told UPI health officials were not doing enough to prevent people from being infected by contaminated medical equipment.

"They've got to start taking this disease seriously and they simply aren't doing it," said Singletary, who is a member of CJD Watch and CJD Voice -- advocacy groups for CJD patients and their families.

Snip…

Ironside and colleagues noted in their study, however, many disinfection procedures used on optical instruments, such as tonometers, fail. They wrote their finding of cornea tissue on tonometers indicates that "no current cleaning and disinfection strategy is fully effective."

Singletary said CDC's assertion that no CJD cases from infected equipment or tissues have been detected since 1976 is misleading.

"They have absolutely no idea" whether any cases have occurred in this manner, he said, because CJD cases often aren't investigated and the agency has not required physicians nationwide report all cases of CJD.

"There's no national surveillance unit for CJD in the United States; people are dying who aren't autopsied, the CDC has no way of knowing" whether people have been infected via infected equipment or tissues, he said.


CORRESPONDENCE| VOLUME 20, ISSUE 12, P981, DECEMBER 01, 2021

Safe laboratory management of prions and proteopathic seeds

Simon Mead Thomas Evans

on behalf of the Advisory Committee for Dangerous Pathogens Transmissible Spongiform Encephalopathy Subgroup

Published: December, 2021DOI: https://doi.org/10.1016/S1474-4422(21)00379-3

Prions, the infectious agents of fatal and transmissible neurodegenerative disorders in humans and animals, are comprised of assemblies of misfolded forms of prion protein (PrP). The death of a 33-year-old researcher of prion diseases from variant Creutzfeldt-Jakob disease (ie, the strain of disease that is derived from bovine spongiform encephalopathy) 9 years after a percutaneous exposure to prion-contaminated material, and the death from or diagnosis of prion disease in two other people in Europe after working in prion research, emphasises the importance of statutory guidance for laboratory safety when working with dangerous pathogens.1 People in numerous laboratories handling diagnostic blood, CSF, and other low-risk biofluid samples from patients with or suspected to have Creutzfeldt-Jakob disease have contacted us to suggest that the existing guidance was not sufficiently clear or proportionate. Evidence has accrued for the potential for proteins that are linked to neurodegenerative diseases, other than PrP, to adopt abnormal conformations, self-propagate, and cause transmissible pathologies and diseases in humans and laboratory animals.2, 3 These proteins share a range of pathological properties but are also distinct from prions in important ways, including that there are no known animal or human epidemics or established occupational risks. Experiments that involve inoculating, concentrating, or synthesising these so-called proteopathic seeds have become routine in the past decade, but no statutory guidance is available for safety. Human–human transmission of amyloid β proteopathic seeds has been observed in some specific circumstances that were also shown to transmit prion infection (eg, use of cadaver-derived human pituitary hormones or dura mater in neurosurgery) and can cause iatrogenic cerebral amyloid angiopathy and fatal brain haemorrhage after long latencies.4 The popularity of this field of research, and the long latencies that are to be expected for diseases that are caused by these proteopathic seeds, mean that occupational exposures might not yet have resulted in any clinical consequences. It is prudent, therefore, to consider potential risks from laboratory work involving these agents.

The UK's Advisory Committee for Dangerous Pathogens convened a subgroup to revise guidance for safe working with prions and to consider whether any measures were needed for work with proteopathic seeds, involving experts from research laboratories for prion and other neurodegenerative diseases, infectious disease specialists, pathologists, veterinarians, and health and safety experts. In the new guidance, we emphasise a distinction between high-risk CNS tissues and research samples that contain high concentrations of prions, which need to be managed in specialised laboratories with strict policies, and low-risk biofluids, such as blood and CSF, from patients who are suspected to have Creutzfeldt-Jakob disease with no or low concentrations of prions, which can be managed in a high-throughput diagnostic laboratory setting through adherence to appropriate general laboratory practices.

We also concluded that the poorly defined pathogenicity in humans of proteopathic seeds when prepared in concentrated forms for biochemical, structural, or transmission studies means that they should now be considered as hazard group 2 pathogens, necessitating work in a containment level 2 facility. We recommend a range of safety measures,5 including special attention to risk assessment and staff training; recording of accidental exposures; special caution with the use of any sharp tools to avoid percutaneous injury; work inside a microbiological safety cabinet; and the use of spill trays, absorbent material, and defined procedures to decontaminate equipment and spills to avoid contamination of the laboratory environment.

Importantly, we do not recommend any changes to existing procedures for the routine handling of tissues and biofluids from patients with non-prion neurodegenerative conditions for diagnostic or research purposes. We hope that this new guidance will be seen as proportionate and precautionary and help organisations to have increased confidence about the safety of their employees.5

We declare no competing interests. Members of the Advisory Committee for Dangerous Pathogens Transmissible Spongiform Encephalopathy Subgroup are listed in the appendix.

Supplementary Material

Download .pdf (.45 MB)

Supplementary appendix


References 1.Brandel JP Vlaicu MB Culeux A et al. Variant Creutzfeldt-Jakob disease diagnosed 7·5 years after occupational exposure. N Engl J Med. 2020; 383: 83-85 View in Article Google Scholar

2.Lauwers E Lalli G Brandner S et al.

Potential human transmission of amyloid β pathology: surveillance and risks.

Lancet Neurol. 2020; 19: 872-878

View in Article Google Scholar

3.Jaunmuktane Z Brandner S

Invited review: the role of prion-like mechanisms in neurodegenerative diseases.

Neuropathol Appl Neurobiol. 2020; 46: 522-545

View in Article Google Scholar

4.Jaunmuktane Z Mead S Ellis M et al.

Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy.

Nature. 2015; 525: 247-250

View in Article Google Scholar

5.Department of Health and Social Care

Guidance: minimise transmission risk of CJD and vCJD in healthcare settings.


Date: Nov 27, 2012 Date accessed: November 2, 2021 

Article Info Publication History Published: December 2021 Identification DOI: https://doi.org/10.1016/S1474-4422(21)00379-3

Copyright © 2021 Elsevier Ltd. All rights reserved.




FRIDAY, DECEMBER 02, 2022

Creutzfeldt Jacob Disease CJD TSE Prion December 2022 Annual Update


The importance of ongoing international surveillance for Creutzfeldt–Jakob disease

Neil Watson1, Jean-Philippe Brandel2, Alison Green1, Peter Hermann3, Anna Ladogana 4, Terri Lindsay1, Janet Mackenzie1, Maurizio Pocchiari 4, Colin Smith1, Inga Zerr3 and Suvankar Pal 1 

Abstract | Creutzfeldt–Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.


see also;




ACDP TSE subgroup minutes, agendas and papers, history


TUESDAY, NOVEMBER 1, 2022

SEAC Scientific Steering Committee on TSE Prion


iatrogenic TSE PrP


MONDAY, DECEMBER 31, 2007

Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation


Thursday, November 14, 2013 

Prion diseases in humans: Oral and dental implications http://transmissiblespongiformencephalopathy.blogspot.com/2013/11/prion-diseases-in-humans-oral-and.html


O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?

Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

snip...see full Singeltary Nature comment here;

Alzheimer's disease

let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...

Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Posted by flounder on 05 Nov 2014 at 21:27 GMT

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Background

Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.

Methods

Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

Results

I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.

Conclusions

There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.

end...tss

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Posted by flounder on 05 Nov 2014 at 21:27 GMT


2023

Eur J Epidemiol. 2023; 38(7): 757–764.

Published online 2023 May 16. doi: 10.1007/s10654-023-01004-5

PMCID: PMC10276107

PMID: 37191829

The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis

Angéline Denouel, corresponding author1 Jean-Philippe Brandel,1,2 Danielle Seilhean,1 Jean-Louis Laplanche,3,4 Alexis Elbaz,5 and Stéphane Haik1,2

snip...

Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology.

snip...

Besides risk factors explored in case-control studies, the possibility of zoonotic risk factors remains a possibility that could account for an exogenous origin in some sCJD cases. Research on atypical forms of BSE (L-BSE, H-BSE) has revealed molecular similarities between the L-BSE strain and molecular subtypes of human sCJD, in particular the MV2 subtype [39]. Furthermore, L-BSE has been experimentally transmitted to non-human primates as efficiently as classical BSE responsible for vCJD in humans, and could be even more virulent [40–42]. The zoonotic risk associated with natural sheep scrapie has also been recently updated with the demonstration of an intracerebral transmission of scrapie to mice expressing the human prion protein during serial passages, as well as transmission of scrapie to primates. These observations highlight the possibility of a causal link between exposure to sheep scrapie and sCJD in some cases [43, 44]. A large increase in animal product consumption and the generalization of mechanically separated meat in developed countries over the last century may have contribute to increase the zoonotic prion pressure [45]. It would be of interest to observe the effect of safety measures implemented since the “mad cow crisis” to avoid population prion exposure on sCJD mortality in the next decades.

Eur J Epidemiol. 2023; 38(7): 757–764.


''These observations highlight the possibility of a causal link between exposure to sheep scrapie and sCJD in some cases [43, 44]. A large increase in animal product consumption and the generalization of mechanically separated meat in developed countries over the last century may have contribute to increase the zoonotic prion pressure [45]. It would be of interest to observe the effect of safety measures implemented since the “mad cow crisis” to avoid population prion exposure on sCJD mortality in the next decades.''

MONDAY, DECEMBER 18, 2023

Change in Epidemiology of Creutzfeldt-Jakob Disease in the US, 2007-2020


TUESDAY, DECEMBER 12, 2023

CREUTZFELDT JAKOB DISEASE TSE PRION DISEASE UPDATE USA DECEMBER 2023


SUNDAY, NOVEMBER 26, 2023

The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis


MONDAY, APRIL 24, 2023

2023 CDC REPORTS CJD TSE Prion 5 cases per million in persons 55 years of age or older


USA 50 State Emergency BSE Conference Call 2001cjd


FRIDAY, DECEMBER 22, 2023

The Mad Cow That Stole Christmas, 20 Years Later


Wednesday, May 24, 2023

***> WAHIS, WOAH, OIE, United States of America Bovine spongiform encephalopathy Immediate notification




MAY 19, 2023


2 weeks before the announcement of this recent mad cow case in the USA, i submitted this to the APHIS et al;

***> APPRX. 2 weeks before the recent mad cow case was confirmed in the USA, in Tennessee, atypical L-Type BSE, I submitted this to the APHIS et al;

Document APHIS-2023-0027-0001 BSE Singeltary Comment Submission May 2, 2023

''said 'burden' cost, will be a heavy burden to bear, if we fail with Bovine Spongiform Encephalopathy BSE TSE Prion disease, that is why this information collection is so critical''...



spontaneous my ass, big outbreak of spontaneous mad cow disease evidently, around the same time, strange;

WEDNESDAY, NOVEMBER 08, 2023

Ireland Atypical BSE confirmed November 3 2023


TUESDAY, NOVEMBER 14, 2023

Ireland Atypical BSE case, 3 progeny of case cow to be culled


SUNDAY, JULY 16, 2023

Switzerland Atypical BSE detected in a cow in the canton of St. Gallen


WAHIS, WOAH, OIE, REPORT Switzerland Bovine Spongiform Encephalopathy Atypical L-Type

Switzerland Bovine Spongiform Encephalopathy Atypical L-Type

Switzerland - Bovine spongiform encephalopathy - Immediate notification



Monday, March 20, 2023

WAHIS, WOAH, OIE, REPORT United Kingdom Bovine Spongiform Encephalopathy Atypical H-Type




BRAZIL BSE START DATE 2023/01/18

BRAZIL BSE CONFIRMATION DATE 2023/02/22

BRAZIL BSE END DATE 2023/03/03



SPAIN BSE START DATE 2023/01/21

SPAIN BSE CONFIRMATION DATE 2023/02/03

SPAIN BSE END DATE 2023/02/06



NETHERLANDS BSE START DATE 2023/02/01

NETHERLANDS BSE CONFIRMATION DATE 2023/02/01

NETHERLANDS BSE END DATE 2023/03/13


BSE ATYPICAL USA: Netherlands Bovine Spongiform Encephalopathy BSE, atypical strain, L-type

PLEASE NOTE, USDA ET AL ONLY TESTING <25k CATTLE FOR MAD COW DISEASE, woefully inadequate, yet USDA just documented a case Atypical L-Type BSE, the most virulent strain to date...

Monday, May 22, 2023

***> BSE TSE Prion MAD COW TESTING IN THE USA COMPARED TO OTHER COUNTRIES?

BSE TSE Prion MAD COW TESTING IN THE USA COMPARED TO OTHER COUNTRIES?

NOW, BE AWARE, OIE AND USDA HAVE NOW MADE ATYPICAL SCRAPIE AND ATYPICAL BSE A LEGAL TRADING COMMODITY, WITH NO REPORTING OF SAID ATYPICAL CASES, EXCEPT FOR A VOLUNTARY NOTE ON ANNUAL REPORT...i don't make this stuff up...terry

cwd scrapie pigs oral routes

***> However, at 51 months of incubation or greater, 5 animals were positive by one or more diagnostic methods. Furthermore, positive bioassay results were obtained from all inoculated groups (oral and intracranial; market weight and end of study) suggesting that swine are potential hosts for the agent of scrapie. <***

*** Although the current U.S. feed ban is based on keeping tissues from TSE infected cattle from contaminating animal feed, swine rations in the U.S. could contain animal derived components including materials from scrapie infected sheep and goats. These results indicating the susceptibility of pigs to sheep scrapie, coupled with the limitations of the current feed ban, indicates that a revision of the feed ban may be necessary to protect swine production and potentially human health. <***

***> Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 month group was positive by EIA. PrPSc was detected by QuIC in at least one of the lymphoid tissues examined in 5/6 pigs in the intracranial <6 months group, 6/7 intracranial >6 months group, 5/6 pigs in the oral <6 months group, and 4/6 oral >6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%).

***> Conclusions: This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge. CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.




Conclusions: This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge. CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.


CONFIDENTIAL

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

LINE TO TAKE

3. If questions on pharmaceuticals are raised at the Press conference, the suggested line to take is as follows:-

"There are no medicinal products licensed for use on the market which make use of UK-derived porcine tissues with which any hypothetical “high risk" ‘might be associated. The results of the recent experimental work at the CSM will be carefully examined by the CSM‘s Working Group on spongiform encephalopathy at its next meeting.

DO Hagger RM 1533 MT Ext 3201


While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...


we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.


May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ...


3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ...


But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ...



Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....


BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001

Date: Tue, 9 Jan 2001 16:49:00 -0800

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de


Transmission of Idiopathic human prion disease CJD MM1 to small ruminant mouse models (Tg338 and Tg501).

Results: No evidence of transmission was found on a first passage in Tg338 nor Tg501ovinized mice, but on second passage, 4/10 Tg338 mice succumbed to CJDMM1 (40% attack rate after 645 dpi) and 1/12 Tg501 mice (519dpi, 10 still alive). The remaining 2nd passages are still ongoing.

Conclusions: In this poster, the neuropathological features of the resulting strain are discussed.


O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations

*** 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.

==============

PRION 2015 CONFERENCE


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 1933-690X

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.


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

***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.


***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.



Tuesday, December 16, 2014

Evidence for zoonotic potential of ovine scrapie prions

Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier Andréoletti1, Affiliations Contributions Corresponding author Journal name: Nature Communications

Volume: 5, Article number: 5821 DOI: doi:10.1038/ncomms6821 Received 07 August 2014 Accepted 10 November 2014 Published 16 December 2014

Abstract

Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE.

***The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans.

***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.

Subject terms: Biological sciences• Medical research At a glance


2001

Suspect symptoms

What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?

28 Mar 01

Like lambs to the slaughter

31 March 2001

by Debora MacKenzie Magazine issue 2284.

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.

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.


Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt– Jakob disease: Implications for human health

Corinne Ida Lasmézas, Jean-Guy Fournier, Virginie Nouvel, +8, and Jean-Philippe DeslysAuthors Info & Affiliations

March 20, 2001

The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.

snip...

Herein, we made the striking observation that the French natural scrapie strain (but not the U.S. scrapie strain) has the same lesion profile and transmission times in C57BL/6 mice as do the two human TSE strains studied. This strain “affiliation” was confirmed biochemically. There is no epidemiological evidence for a link between sheep scrapie and the occurrence of CJD in humans (25). However, such a link, if it is not a general rule, would be extremely difficult to establish because of the very low incidence of CJD as well as the existence of different isolates in humans and multiple strains in scrapie. Moreover, scrapie is transmissible to nonhuman primates (26). Thus, there is still a possibility that in some instances TSE strains infecting humans do share a common origin with scrapie, as pointed out by our findings.


why do we not want to do TSE transmission studies on chimpanzees $ 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.

snip... R. BRADLEY


TUESDAY, JANUARY 16, 2024 

CIDRAP launches international effort to prepare for possible chronic wasting disease spillover 

Chronic Wasting Disease CWD TSE Prion Spillover to other Species, What If? 


new prion disease in a new livestock species...

Friday, May 12, 2023

Camel prion disease, a new emerging disease in North Africa, Lymphoid Tropism, Neuropathological Characterization Update 2023

11th Iberian Congress on Prions Barcelona 2023



A Camelid Anti-PrP Antibody Abrogates PrPSc Replication in Prion-Permissive Neuroblastoma Cell Lines

Daryl Rhys Jones,William Alexander Taylor,Clive Bate,Monique David,Mourad Tayebi 

Published: March 22, 2010



15 Apr 2018 23:13 GMT MOST RECENT 

Prion Disease in Dromedary Camels, Algeria 

Posted by flounder on 15 Apr 2018 at 23:13 GMT





Terry S. Singeltary Sr., Bacliff, Texas, 77518, Galveston Bay, flounder9@verizon.net