Sunday, March 16, 2008

MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE

March 16, 2008

MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE


I thought i might try and sort things out about this a bit. Some folks seem to be a bit confused,(confusious included has been confused a time or two to be sure). but i think some clarification needs to be done. you can interpret it the way you want. i have my opinions on why i interpret the science one way, you may have yours. here goes ;

WE first heard of the atypical called BASE Bovine Amyloidotic Spongiform Encephalopathy (Italy), and it was said then that the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease. The Italian BASE Bovine Amyloidotic Spongiform Encephalopathy termed that due to the 'amyloid plaques'.

THIS is where i start to have problems with the term. if you will recall, the first ten nvCJD in young adolescents, 'amyloid plaques' were used then to differentiate between the sporadic CJDs and nvCJD, UNTIL the 'amyloid plaques' stared showing up in some sporadic CJDs. now (10%) amyloid deposits, called prion protein (PrP) amyloid plaques, may be observed in sporadic CJD.

ALSO, with the BASE, you will find that some want to hypothesize that the BASE is just BSE in older cattle.

well, if that was the case, then would not sporadic CJD be just nvCJD in old people?

ALSO, it was said that nvCJD was only in the young. this too was part of a diagnostic criteria to differentiate between the nvCJD and sporadic CJDs, until sCJD started showing up in young adolescents.

ALSO, it was said that only the nvCJD have long incubation period, this too was part of diagnostic criteria to differentiate between the nvCJD and sporadic CJDs, until the long incubation started showing up in some sporadic CJDs.

ALSO, it was said that on the nvCJD victims had psychological mental symptoms, not the sporadic CJDs,that too until the psychological and mental symptoms started showing up in some of the sporadic CJDs.

FOR these reasons, I cannot accept that the difference in bands and mass (heavier or lighter), are the meaning of another different strain differentiating between UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE.

I think i might be partly to blame for the confusion, because sometimes i will use BASE, and sometimes i will use atypical BSE, h or l. same with the nvCJD, i still catch myself using that term, as opposed to the newest terminology of vCJD.

kind regards,

New form of BSE resembles sporadic CJD

Robert Roos * News Editor

Feb 19, 2004 (CIDRAP News) – Italian researchers this week reported a new form of bovine spongiform encephalopathy (BSE), or mad cow disease, that resembles sporadic Creutzfeldt-Jakob disease (CJD), a human brain disease that has not previously been linked to BSE.

Eating meat products from cows infected with BSE is believed to be the cause of variant Creutzfeldt-Jakob disease (vCJD), which has killed about 150 people, nearly all of them in the United Kingdom, since 1990. Sporadic CJD, so called because its cause is unknown, afflicts about 1 in 1 million people in the United States annually.

The Italian researchers found the new form of BSE in two of eight BSE-infected cows they analyzed, according to the online report in the Proceedings of the National Academy of Sciences. The two cows had a different pattern of brain damage and a different form of misfolded prion protein than what is normally seen in BSE. The cow brains had the spongy holes typically seen in BSE but also featured amyloid plaques, or waxy clumps, not previously described in BSE-infected cows.

Both the pattern of brain damage and the strain of misfolded prion resembled what is seen in one subtype of sporadic CJD, according to the report. The findings suggest the possibility that some cases of sporadic CJD may actually come from eating beef. But the Italian researchers caution against jumping to conclusions and say further research is needed to better characterize the prion proteins associated with the new type of BSE and sporadic CJD.

The Italian report was edited by Stanley Prusiner, a pioneering prion-disease researcher. The eight BSE-infected cows were among 103 cases found since 2001 in Italy, where more than 1.6 million cattle have been tested for the disease in that time. In examining the cows' brains, the researchers found that two of the cattle, which were older than the others at 15 and 11 years, had "striking differences in the patterns and topography" of prion protein deposition, the report says.

The six younger cows had granular and thread-like deposits of prion protein, mainly in the brain stem and thalamus—typical findings in BSE. In contrast, the two older cows had amyloid plaques of prion protein concentrated in the thalamus, cerebral cortex, and olfactory bulb, with little deposition in the brain stem. BSE typically involves prion deposits in the dorsal nucleus of the vagus nerve, but these were absent in the two older cows.

The researchers also found differences in the "molecular signatures" of the prion protein from the two groups of cows. Brain tissue from the cows was compared with samples from sporadic CJD–infected brains featuring different subtypes of prion protein. "Strikingly, the molecular signature of this previously undescribed bovine PrPSc [pathogloic prion protein] was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease," called sporadic CJD methionine/valine 2 (sCJD M/V 2), the authors write.

Because of the distinct brain pathology and prion-protein properties in the two older cows, the researchers propose to name the disease "bovine amyloidotic spongiform encephalopathy," or BASE. They write that the absence of disease in the vagus nerve and slight involvement of the brainstem suggests that the cows contracted the disease by some route other than feeding. "It is possible that this disorder represents a sporadic form of cattle TSE, which would also explain the difference in ages between the two groups of infected animals," the report states.

The researchers note that while the brain pathology and the type of prion protein in the older cows resembled those seen in sporadic CJD M/V 2, there were some differences in the distribution of the prion protein in the brain. "Although BASE and sCJD share several characteristics, caution is dictated in assessing a link between conditions affecting two different mammalian species, based on convergent biochemical properties of disease-associated PrPSc types," the article states.

The authors add that they hope to gather more information about strains of transmissible spongiform encephalopathy (TSE) agents through research in genetically modified mice. "Until this is accomplished, our present findings suggest a strict epidemiological surveillance of cattle TSE and sCJD based on molecular criteria," they conclude.

Shaun Kennedy, associate director of the University of Minnesota Center for Animal Health and Food Safety, commented, "If this study is proven correct, it would suggest there is a sporadic form of cattle TSE, or less likely, that there's another way for propagation of BSE other than the alimentary tract, which would be unusual." If a sporadic form of cattle TSE exists, it could be what started the BSE outbreaks in Britain in the 1980s, he suggested.

Concerning the possibility that sporadic CJD could be related to eating beef, Kennedy said, "It's already been demonstrated that humans can get [vCJD] from eating infected meat, so that's not new." He said the existence of BASE wouldn't change the US Department of Agriculture's approach to testing cattle for BSE or other BSE safeguards. The disease was found in older cattle, and the USDA testing program focuses on older animals as well as those with signs of disease, he said. "You'd find this kind [of BSE] just like you'd find the others," he added.

Pam Skinner, a microbiologist in the University of Minnesota Department of Veterinary and Biomedical Sciences, said the report prompts her to wonder about the transmissibility of BASE. BSE doesn't spread directly from animal to animal, but chronic wasting disease, a TSE found in deer and elk, does spread that way, she noted. "We don't know about this new strain of BSE, what it takes to transmit from one animal to another,"she said. "If it's more easily transmitted, that would have serious implications." Another question, she added, is whether the disease can cross into different species.

Casalone C, Zanusso G, Acutis P, et al. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt-Jakob disease. Proc Nat Acad Sci 2004;101(9):3065-70 [ Abstract]

Proc Natl Acad Sci U S A. 2004 March 2; 101(9): 3065–3070.
Published online 2004 February 17. doi: 10.1073/pnas.0305777101.

PMCID: PMC365745
Copyright © 2004, The National Academy of Sciences
Medical Sciences

Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt-Jakob disease

Cristina Casalone,*† Gianluigi Zanusso,†‡ Pierluigi Acutis,* Sergio Ferrari,‡ Lorenzo Capucci,§ Fabrizio Tagliavini,¶ Salvatore Monaco,‡∥ and Maria Caramelli*
*Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna, 148, 10195 Turin, Italy; ‡Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134 Verona, Italy; §Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale Neurologico ”Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
∥ To whom correspondence should be addressed. E-mail:
†C.C. and G.Z. contributed equally to this work.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003
Received September 9, 2003.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called ”species barrier” between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease.

FC5.5.2 Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease

Zanusso, G1; Lombardi, G2; Casalone, C3; D’Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2 1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy

The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that

***BASE is caused by a distinct prion strain which is extremely virulent.

A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle *** and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease.

May 16, 2007)

TAFS1 Position Paper on Atypical scrapie and Atypical BSE

Is there more than one strain of atypical BSE?

At this stage it is too early to say, but there are early indications that this may be so. Caution is needed because there is a need to be certain that the variations in results are not artifacts, either generated by differences in test methods between countries, or due to degradation of samples before they are tested. This has been shown to generate variations in blotting patterns, but is unlikely to have produced the extensive variations seen in the Italian cases or the H form detected in France and elsewhere. So the key to confirming whether or not H and L isolates actually represent different strains will be further characterization following transmission to laboratory rodents and/or cattle. These are the methods normally used to characterize prion strains comprehensively.

This will also help to confirm the extent to which the atypical BSE cases differ from BSE. In the meantime, especially if it proves possible to transmit isolates to other animals, additional biochemical methods can be used to investigate other aspects of prion protein biology of the different isolates.

Two publications have already highlighted the difficulties of interpreting data on biological transmissibility. One demonstrates that BSE and “H-type” BSE are different, based upon their behaviour in genetically modified mice, examination of fixed and unfixed brain tissue, and comparison of incubation periods(6).

The other, studying “L-type” BSE (Italian BASE),

and using different mouse models, acknowledges apparent differences between it and BSE when first inoculated into mice, but claims that further transmission from mouse to mouse by inoculation produces a strain indistinguishable from BSE (by the limited criteria used in the study) (11).

These findings suggest that it may prove possible to understand the relationship between BSE and atypical BSE isolates, and between the criteria used to classify them at present, and the actual strain of prion that infects the animal.

============================================ *** The different “strains” are now called atypical BSE 2006*** ============================================

Atypical BSE: What is it and what is the significance

Linda A. Detwiler, Paul Brown, Lisa M. McShane, and Gianluigi Zanusso

For almost the entire two decades that BSE has been known in the world it was thought that there was only one “strain” that infected cattle and caused disease in some other species such as humans ( Bruce et al., 1997; Hill et al., 1997; Casalone et al., 2004). We now know that there are other manifestations of prion diseases in cattle which have been termed atypical BSE. Atypical BSE is a study in progress with more unknowns than knowns. One of the most important of the unknowns is the significance of atypical BSE in regard to human and animal health. Previous research in mice had suggested the existence of a number of scrapie strains. Historically, research involving the differentiation of Transmissible Spongiform Encephalopathy (TSE) strains was based on biological typing using panels of inbred mice inoculated with homogenates of infected tissues. If the mice developed a TSE it was characterized by length of incubation and lesion pattern in the brain. (Bruce et al. 1992; Bruce et al. 1994) More recently it has been determined that the human and animals variations may be biochemically differentiated on the basis of molecular mass of the protease resistant prion protein (PrPres) and the degree of glycosylation (Collinge et al., 1996) In 2004, cases of a bovine prion disease molecularly different than already documented as classical BSE were described by scientists in both Italy (Casalone et al., 2004) and France (Biacabe et al., 2004). In both countries the cattle were over 8 years of age. The Italian cases (11 and 15 years of age) originally named bovine amyloidotic spongiform encephalopathy (BASE) were characterized by an unglycosylated protein band with a lower molecular mass (thus named L cases) and the predominance of the monoglycosylated band. In addition, immunohistochemical detection of PrPres in these cases found greater deposits in the cerebral cortex and thalamus versus the brain stem. The French cases found a higher molecular mass associated with the unglycosylated protein band and were called H cases (see figure 1). *** The different “strains” are now called atypical BSE. ***

full text, skroll down to page 6 ;

Creutzfeldt-Jakob disease, Emerg. Inf. Dis., 2006, 12: 1816-21, in press, December 2006. (A

copy of the article is attached to this declaration as Attachment C.)

9. Although these cases of asymptomatic, atypical BSE have been found in older cattle, we do not currently know the concentration and distribution of infection and infectivity that might have been found in these cattle at an earlier age. Another issue concerns evidence that atypical BSE may be more virulent for humans than typical BSE. This evidence comes from experimental transmission studies in at least 4 different laboratories. All have shown more rapid onset of disease (shorter incubation periods) following inoculation with atypical BSE than with typical BSE, and in one study, BSE did not transmit at all. These studies involved the use of wild-type mice, bovinized and humanized transgenic mice, and (most worrisome) non-human primates as recipient animals. Prion2006


SEAC Position Statement


New forms of Bovine Spongiform Encephalopathy


1. SEAC considered the implications of scientific research on recently identified novel forms of bovine spongiform encephalopathy (BSE).


2. Very low numbers of cattle with abnormal prion proteins (PrPsc) with different biochemical properties from those normally associated with BSE have been detected in active surveillance programmes in a number of countries. SEAC considered (SEAC 97, May 2007) published and unpublished research relating to these putatively new forms of BSE.

Characterisation of cases

3. Different forms of BSE were initially identified and distinguished from classical BSE on the basis of their PrPsc profiles in biochemical tests. All BSE cases identified to date conform to one of three different PrPsc profiles on western blot tests. The European Union (EU) Community Reference Laboratory has suggested that cases be classified on the basis of these profiles as classical, L- or H-type BSE. The key distinguishing features in western blot tests are the lower concentration of the diglycosylated band and the slightly lower molecular mass of unglycosylated band of PrPsc in L-type BSE, and the higher molecular mass of the unglycosylated band in H-type BSE, compared with classical BSE. A western blot method to discriminate between the three types of BSE has been developed .

4. All the reported cases of L-4,5,6,7 and H-type7,9,8,9 BSE have been detected during active surveillance of healthy slaughtered animals or fallen stock. In the majority of cases, retrospective investigations indicated that these animals either showed no clinical signs of BSE or showed non-specific signs such as ataxia and recumbency. As these cases have been detected following active rather than passive surveillance, it has not been possible to observe the clinical signs associated with L- or H-type BSE in sufficient detail to assess whether there are differences in the clinical features between L-type, H-type and classical BSE. However, a significant distinction between classical BSE and L- and H-type BSEs is the age distribution of cases as L- and H-type BSE are found in older cattle with an age range of 5.5 to 19 years. One putative L-type BSE case was aged two years6, however the BSE typing of this case has not been verified. Around 85% of L- or H-type BSE cases have been found in animals more than 10 years old, which is much older than most cases of classical BSE.

5. Neuropathological investigations suggest that PrPsc may be more widely distributed, with a different brain distribution pattern for L- and H-type BSE, compared with classical BSE. However, these investigations are limited by the very low number of animals for which a complete brain has been available for analysis. There are no data on the peripheral distribution of PrPsc or infectivity of L- and H-type BSE or on the pathogenesis of these diseases. However, studies to assess the tissue distribution of infectivity and PrPsc in animals throughout the incubation period following intracerebral challenge are underway.


6. As there is no regulatory requirement to specify the type of BSE when notifying the EU or the World Organisation of Animal Health of BSE cases, it is not possible to accurately quantify the number of H- or L-type BSE cases that have occurred world-wide. Information presented to SEAC indicated that at least 37 cases of L- and H-type BSE have been identified world-wide to date. These cases are widely distributed geographically with L-type cases identified in a number of European countries and Japan, and H-type cases identified in a number of European countries and North America.

7. Due to the different approaches to surveillance between countries, proportions of animals tested and methods used, which do not necessarily include systematic molecular typing, these surveillance systems are not equally capable of detecting L- and H-type BSE. Furthermore, surveillance procedures, including the most appropriate brain region to sample, have not been optimised for the detection of L- and H-type BSE. Therefore, it is not possible to accurately assess and compare the prevalence of L- and H-type BSE in different countries. Origins and Causes

8. It is not known whether L- or H-type BSE are newly emerging forms of BSE or whether they have existed for some time and have only come to light following extensive active surveillance programmes in the EU and elsewhere, together with the introduction and development of new biochemical tests. Studies using historic frozen brain samples from cattle collected from passive surveillance during the early years of the UK BSE epidemic are underway to investigate whether L- and H-type BSE existed in the UK in the past. However, if the prevalence of these BSE types was low, these studies may not identify many, if any, cases.

9. Genetic analyses of a few L- and H-type BSE cases4,5,8,9 have not identified associations between the occurrence of such cases and known genetic polymorphisms in the prion protein gene. There are no mutations in the prion protein gene open reading frame in all, but one, sequenced case. However, the analyses conducted to date are limited by the small number of cases and controls analysed. Thus, a genetic cause of the disease cannot be ruled out.

10. No detailed epidemiological investigations have been conducted to investigate the possible causes for, or links between, L- and H-type BSE cases. No geographical clusters of L- and H-type BSE cases have been found to date. Therefore, it is not possible to rule out feed related, environmental or spontaneous causes for these types of cases.

Transmission studies

11. Transmission studies5,10,11 have demonstrated that both L- and H-type BSE are transmissible to other species by the intracerebral route. No studies have assessed the transmissibility by the oral route. Thus, the available information shows that it is possible for species other than cattle to develop these diseases upon infection. However, these data do not allow an assessment of the susceptibility to infection from the most likely natural route of exposure.

12. L-type BSE has been transmitted to wild-type, bovinised, ovinised and humanised mice as well as to cattle and a cynomolgus macaque by intracerebral inoculation. Incubation periods, clinical signs, neuropathology as well as the neurological distribution of PrPsc were distinct from classical BSE13,12. With the exception of transmissions to wild-type mice, primary transmissions resulted in clinical disease. Although primary transmission to wild-type mice did not result in clinical disease, secondary transmissions from some of these animals resulted in clinical disease. Sub-passage of L-type BSE in wild-type12 and ovinised mice13 suggests that L-type BSE may be converted to an infection of a similar phenotype to classical BSE. However, further experiments using serial sub-passages of infections in a range of species are required to more fully investigate whether L-type BSE may convert to a disease with a classical BSE phenotype.

13. H-type BSE has been transmitted to wild type, bovinised and ovinised mice by intracerebral inoculation with incubation periods, neuropathology and neurological distribution of PrPsc distinct from classical and L-type BSE.

14. Studies of intracerebral transmission of H-type BSE to cattle and cynomolgus macaques . To date, clinical disease has developed from one intracerebral inoculation of H-type BSE to cattle. Oral transmissions of L- and H-type to cynomolgus macaques are underway.

Human and animals health implications

15. There are too few data to enable an assessment of the natural transmissibility of L- and H-type BSE between cattle, or to sheep or goats. The present feed control measures which prevent feeding of mammalian meat and bone meal to ruminants would limit the spread of these forms of BSE to cattle, sheep and goats should they be transmissible to these species by the oral route.

16. Similarly, the lack of data on the oral transmissibility of L- or H-type BSE to humanised mice or non-human primates does not allow an assessment of the human health implications of ingestion of meat from animals infected with L- or H-type BSE. The differing clinical features of L-type and classical BSE in the cynomolgus macaque suggest that if L-type BSE were ever to be transmitted to humans, its clinical presentation may differ from that of vCJD. It is possible, therefore, that, if transmitted to humans, it could be identified by continuing surveillance of unusual neurological conditions in place in the UK.


17. L- and H-type BSE have not yet been fully characterised, however data from biochemical, neuropathological and transmission studies suggest that L- and H-type and classical BSE may be distinct strains of prion disease. In contrast to classical BSE, L- and H-type BSE infections are mostly detected in animals of older age with most of the infected animals identified to date over 10 years of age. Although L- and H-type BSE may be diseases that predominantly affect older cattle, it is possible that infections may occur at a young age and develop over a long period of time. The origins and possible routes of transmission, if transmissible under natural conditions, of L- and H-type BSE are not known. Due to the older age of the cases identified, wide geographical distribution and their apparent low number, it is possible they may have arisen spontaneously, however feed borne or environmental transmission cannot be ruled out.

18. As data on the oral transmissibility of L- and H-type BSE are lacking, it is not possible to fully assess the animal and human health implications. However, as the occurrence of L- and H-type BSE appears to be low, and due to the feed control measures in place, the risk of spread to other cattle, sheep and goats is likely to be very low assuming that, as with classical BSE, environmental transmission is negligible. For these reasons, and because of the BSE control measures in place to protect the food supply, assuming that the specific risk material controls are similarly effective for L- and H-type and classical BSE, the risk to human health is likely to be very low to negligible. However, given the paucity of data on L- and H-type BSE, a close watching brief should be maintained on the findings of research in this area.

SEAC July 2007

Lancet 1996; 347: 921- 25

A new variant of Creutzfeldt-Jakob disease in the UK

R G Will, J W Ironside, M Zeidler, S N Cousens, K Estibeiro, A Alperovitch, S Poser, M Pocchiari, A Hofman, P G Smith


Background Epidemiological surveillance of Creutzfeldt-Jakob disease (CJD) was reinstituted in the UK in 1990 to identify any changes in the occurrence of this disease after the epidemic of bovine spongiform encephalopathy (BSE) in cattle.

Methods Case ascertainment of CJD was mostly by direct referral from neurologists and neuropathologists. Death certificates on which CJD was mentioned were also obtained. Clinical details were obtained for all referred cases, and information on potential risk factors for CJD was obtained by a standard questionnaire administered to patients' relatives. Neuropathological examination was carried out on approximately 70% of suspect cases. Epidemiological studies of CJD using similar methodology to the UK study have been carried out in France, Germany, Italy, and the Netherlands between 1993 and 1995.

Findings Ten cases of CJD have been identified in the UK in recent months with a new neuropathological profile. Other consistent features that are unusual include the young age of the cases, clinical findings, and the absence of the electroencephalogram features typical for CJD. Similar cases have not been identified in other countries in the European surveillance system.

Interpretatlon These cases appear to represent a new variant of CJD, which may be unique to the UK. This raises the possibility that they are causally linked to BSE. Although this may be the most plausible explanation for this cluster of cases, a link with BSE cannot be confirmed on the basis of this evidence alone. It is essential to obtain further information on the current and past clinical and neuropathological profiles of CJD in the UK and elsewhere.


Neuropathological features

Neuropathological examination in all ten cases showed spongiform change and PrP plaques confirming the diagnosis of CJD[6]. In two cases investigated by cerebral biopsy and in the eight necropsy cases, neuropathological features were uniform, with spongiform change in a relatively sparse distribution throughout the cerebral cortex (although all areas were involved to a variable extent in each case who came to necropsy). Spongiform change, neuronal loss, and astrocytosis were most evident in the basal ganglia and thalamus, and were present focally in the cerebrum and cerebellum, most evidently in areas with confluent spongiform change.

The most striking and consistent neuropathological abnormality in all cases was PrP plaques. In the eight necropsy cases, plaques were extensively distributed throughout the cerebrum and cerebellum, with smaller numbers in the basal ganglia, thalamus, and hypothalamus. Many of these plaques resembled kuru-type plaques with a dense eosinophilic centre and pale periphery and, unusually for this type of lesion, were surrounded by a zone of spongiform change (figures 1 and 2). This unusual feature was not seen in any of the other 175 sporadic CJD cases investigated. Similar lesions have, however, been described in scrapie, where they have been referred to as "florid" plaques[7]. Immunocytochemistry for PrP showed strong staining of these plaque-like lesions, but also showed many other smaller plaques, which appeared both as single and multicentric deposits. PrP deposition was also seen in a pericellular distribution in the cerebral cortex and in the molecular layer of the cerebellum, the pattern of which suggested deposition around small neurons (figure 3). Plaque and pericellular PrP deposits occurred throughout the cerebrum and cerebellum, and were clearly visible in the absence of confluent spongiform change in the surrounding neuropil. In the basal ganglia and thalamus, a perivacuolar pattern of PrP staining was also seen, with linear tract- like deposits within the grey matter. PrP plaques were also noted in these regions although there were fewer than in the cerebrum and cerebellum (figure 4).


Sporadic Creutzfeldt–Jakob disease in two adolescents

K Murray1, D L Ritchie1, M Bruce2, C A Young3, M Doran3, J W Ironside1, R G Will3

1 National Creutzfeldt–Jakob Disease Surveillance Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK 2 Institute for Animal Health Neuropathogenesis Unit, Ogston Building, Edinburgh, UK 3 The Walton Centre for Neurology and Neurosurgery, Fazakerley, Liverpool, UK

Correspondence to:

Professor R G Will, National Creutzfeldt–Jakob Disease Surveillance Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2 XU, UK;

Background: Sporadic Creutzfeldt–Jakob disease (CJD) is a condition predominantly affecting older age groups, with cases aged less than 45 years rare and an age at onset or death of less than 20 years exceptional. Methods: Data from the systematic study of sporadic CJD in the UK are available from 1970 onwards. Clinical and pathological data are reviewed in order to identify atypical cases, including those at the extremes of the age range of sporadic CJD. Detailed analysis of atypical cases is undertaken, and in selected cases laboratory transmission studies are carried out in order to provide information on the characteristics of the infectious agent.

Results: In the UK, two cases of sporadic CJD in adolescents have been identified, dying at ages 16 and 20 years. The first case predated the epidemic of bovine spongiform encephalopathy and the characteristics of the second case, including laboratory transmission studies, are consistent with a diagnosis of sporadic rather than variant CJD.

Conclusion: The cases in this report indicate that sporadic CJD can develop at a very young age, that variant CJD is not the only form of CJD occurring in this age group and that neuropathological examination is essential for accurate diagnosis of human prion disease.

Arq. Neuro-Psiquiatr. vol.56 n.3A São Paulo Sept. 1998 doi: 10.1590/S0004-282X1998000300003




In some cases (10%) amyloid diposits, called prion protein (PrP amyloid plaques, may be observed in sporadic CJD. ...

Gerstmann-Sträussler syndrome — A variant type: amyloid plaques and Alzheimer's neurofibrillary tangles in cerebral cortex

Journal Acta Neuropathologica Publisher Springer Berlin / Heidelberg ISSN 0001-6322 (Print) 1432-0533 (Online) Issue Volume 84, Number 1 / January, 1992 Category Regular Papers DOI 10.1007/BF00427210 Pages 15-23 Subject Collection Medicine SpringerLink Date Saturday, December 11, 2004

Naoji Amano1, 2 Contact Information, Saburo Yagishita1, 2, Susumu Yokoi1, 2, Yoji Itoh1, 2, Jun Kinoshita3, Toshio Mizutani4 and Takeshi Matsuishi5 (1) Division of Neuro-psychiatry, The Kanagawa Rehabilitation Center, 516 Nanasawa, 243-01 Atsugi, Kanagawa, Japan (2) Division of Pathology, The Kanagawa Rehabilitation Center, 516 Nanasawa, 243-01 Atsugi, Kanagawa, Japan (3) Takanedai Hospital, Hiratsuka, Kanagawa, Japan (4) Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan (5) Faculty of Education, Yokohama National University, Yokohama, Kanagawa, Japan

Received: 13 September 1991 Revised: 23 December 1991 Accepted: 10 January 1992

Summary This report presents a variant of Gerstmann-Sträussler syndrome (GSS). A 53-year-old female had developed slowly progressive dementia and atactic gait since the age of 45. No myoclonic jerks and periodic synchronous discharges were observed throughout the illness. The neuropathological study revealed that many amyloid plaques and widespread Alzheimer's neurofibrillary tangles (NFTs) appeared in the cerebral cortex. Characteristically, the plaques reacted with anti-prion protein and none of them reacted with anti-beta protein, and they were made of many components, including amyloid cores, macrophages laden with lipid granules and/or degenerated neurites. Neuropil threads were seen mainly in amyloid plaques. Moreover, plaques appeared which were confluent and laminar in arrangement in the fifth and sixth cortical layers and had a close relationship to the neuronal loss. There was no spongiform change in the cerebral cortex or cerebellum. The cerebellum was almost intact except for a few amyloid plaques. Ultrastructurally, some of the plaques simulated kuru plaques and others had many degenerated neurites possessing paired helical filaments and other accumulated organelles. GSS has been proposed to include cases with progressive ataxia, dementia and massive multifocal plaques in the brain with or without cerebral spongiform changes. The case presented here is a very peculiar case of GSS. Recently, similar cases have been reported in some large families, diagnosed as familial Alzheimer's disease. These cases may be a telencephalic form with numerous NFTs of GSS.

Key words Gerstmann-Sträussler syndrome - Variant - Amyloid plaques - Alzheimer's neurofibrillary tangles - Prion protein


Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt- Jakob disease subtypes

Zanusso G,* Farinazzo A,* Prelli F, † Fiorini M,* Gelati M, * Ferrari S, * Righetti PG, ‡Rizzuto N,* Frangione B † and Monaco S* ¶

*From the Departments of Neurological and Visual Sciences, Section of Neurology, and of ‡Agricultural and Industrial Biotechnologies, University of Verona, Verona, Italy; † Department of Pathology, New York University Medical Center, New York City, USA.

¶ Corresponding author:

Salvatore Monaco, Department of Neurological and Visual Sciences, Section of Neurology, Policlinico G.B. Rossi, P.le L.A. Scuro, 10, 37134 Verona; Phone: +39-045-8074286, Fax: +39- 045-585933; E mail:

Running title: Novel truncated forms of PrP in Creutzfeldt-Jakob disease 1 JBC Papers in Press. Published on July 9, 2004 as Manuscript M405468200 Copyright 2004 by The American Society for Biochemistry and Molecular Biology, Inc. by on March 16, 2008 Downloaded from


In prion diseases, the cellular prion protein (PrPC) is converted to an insoluble and proteaseresistant abnormal isoform, termed PrPSc. In different prion strains, PrPSc shows distinct sites of endogenous or exogenous proteolysis generating a core fragment named PrP27-30. Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, clinically presents with a variety of neurological signs. As yet, the clinical variability observed in sCJD has not been fully explained by molecular studies relating two major types of PrP27-30, with unglycosylated peptides of 21 (type 1) and 19 kDa (type 2), and the amino acid methionine (M) or valine (V) at position 129. Recently, smaller C-terminal fragments migrating at 12 and 13 kDa have been detected in different sCJD phenotypes, but their significance remains unclear. By using two-dimensional immunoblot with anti-PrP antibodies, we identified two novel groups of protease-resistant PrP fragments in sCJD brain tissues. All sCJD cases with type 1 PrP27-30, in addition to MM subjects with type 2 PrP27-30, were characterized by the presence of unglycosylated PrP fragments of 16-17 kDa. Conversely, brain homogenates from patients VV and MV with type 2 PrP27-30 contained fully glycosylated PrP fragments, which after deglycosylation migrated at 17.5-18 kDa. Interestingly, PrP species of 17.5-18 kDa matched deglycosylated forms of the C1 PrPC fragment, and were associated with tissue PrP deposition as plaque-like aggregates or amyloid plaques. These data show the presence of multiple PrPSc conformations in sCJD and, in addition, shed new light on the correlation between sCJD phenotypes and disease-associated PrP molecules.


J Neuropsychiatry Clin Neurosci 17:489-495, November 2005 doi: 10.1176/appi.neuropsych.17.4.489 © 2005 American Psychiatric Publishing, Inc.

Psychiatric Manifestations of Creutzfeldt-Jakob Disease: A 25-Year Analysis

Christopher A. Wall, M.D., Teresa A. Rummans, M.D., Allen J. Aksamit, M.D., Lois E. Krahn, M.D. and V. Shane Pankratz, Ph.D.

Received April 20, 2004; revised September 9, 2004; accepted September 13,

2004. From the Mayo Clinic, Department of Psychiatry and Psychology, Rochester, Minnesota; Mayo Clinic, Department of Neurology, Rochester, Minnesota. Address correspondence to Dr. Wall, Mayo Clinic, Department of Psychiatry and Psychology, Mayo Building-W11A, 200 First St., SW, Rochester, MN 55905; (E-mail).

This study characterizes the type and timing of psychiatric manifestations in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been characterized by prominent neurological symptoms, while the variant form (vCJD) is described as primarily psychiatric in presentation and course: A retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from 1976-2001 was conducted. Cases were reviewed for symptoms of depression, anxiety, psychosis, behavior dyscontrol, sleep disturbances, and neurological signs during the disease course. Eighty percent of the cases demonstrated psychiatric symptoms within the first 100 days of illness, with 26% occurring at presentation. The most commonly reported symptoms in this population included sleep disturbances, psychotic symptoms, and depression. Psychiatric manifestations are an early and prominent feature of sporadic CJD, often occurring prior to formal diagnosis.



Historically, psychiatric manifestations have been described as a relatively infrequent occurrence in the sporadic form of creutzfeldt-Jakob disease. However, our findings suggest otherwise. In this study, a vast majority of the cases were noted to have at least one psychiatric symptom during the course of illness, with nearly one-quarter occurring in the prodromal or presenting phase of the illness. After comparing the frequency of neuropsychiatric symptoms in sporadic CJD to studies describing the variant form of CJD, we found that there are fewer clinical differences than previously reported.5-7 While the age of patients with vCJD presentation is significantly younger and the course of illness is longer, the type and timing of psychiatric manifestations appear similar between these two diseases. ...


Polish Journal of Neurology and Neurosurgery 6/2005



Mental disorders in a female patient with probable Creutzfeldt-Jakob disease

Neurol Neurochirur Pol 2005; 39, 6: 520–523

authors: Marek Gronkowski, Bozena Spila, Alina Nowicka, Piotr Machala, Grzegorz Przywara,

The paper presents an overview of the current knowledge about the etiology, classification of Creutzfeldt-Jakob disease, abnormalities in the results of the EEG, MR and laboratory examinations in patients with this disease. The diagnostic value of the CSF examination for presence of protein 14-3-3 is underlined. The article is based on both Polish and foreign literature, describing mainly the diagnostics of CJD. The case of a female patient with dementia, mental disorders and neurological symptoms in the course of probable CJD, who was hospitalized at the Psychogeriatric Department of the Neuropsychiatric Hospital in Lublin is described.

Polish Journal of Neurology and Neurosurgery 6/2005

full text of the article:

Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

Emmanuelle Uro-Coste1#, Hervé Cassard2#, Stéphanie Simon3, Séverine Lugan2,Jean-Marc Bilheude4, Armand Perret-Liaudet5, James W. Ironside6, StéphaneHaik7,8, Christelle Basset-Leobon1, Caroline Lacroux2, Katell Peoch'9,Nathalie Streichenberger5, Jan Langeveld10, Mark W. Head6, Jacques Grassi3,Jean-Jacques Hauw8, Francois Schelcher2, Marie Bernadette Delisle1, OlivierAndréoletti2*

1 INSERM U858, Institut de Médecine Moléculaire de Rangueil and Serviced'Anatomie Pathologique et Histologie-Cytologie, C.H.U. Rangueil, Toulouse,France2 UMR Institut National de la Recherche Agronomique (INRA)/EcoleNationale Vétérinaire de Toulouse (ENVT) 1225, Interactions Hôtes AgentsPathogènes, ENVT, Toulouse, France3 Commissariat à l'Energie Atomique (CEA),Service de Pharmacologie et d'Immunologie, DRM, CEA/Saclay, Gif sur Yvette,France4 Bio-Rad, Research and Development Department, Marnes-la-Coquette,France5 Hôpital Neurologique, Services de Neurochimie et de Pathologie,Bron, France6 National Creutzfeldt-Jakob Disease Surveillance Unit, Divisionof Pathology, University of Edinburgh, Western General Hospital, Edinburgh,United Kingdom7 INSERM, Equipe Avenir, Maladies à Prions chez l'Homme,Paris, France8 Neuropathology Laboratory, Salpêtrière Hospital, AP-HP,Paris, France9 Service de Biochimie et Biologie Moléculaire, HôpitalLariboisière, Paris (Laboratoire associé au CNR ?ATNC?) et EA 3621 Facultéde Pharmacie, Paris, France10 Central Institute for Animal Disease ControlCIDC-Lelystad, Lelystad, The Netherlands


Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) undervariable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism orwestern blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability.


Prion Strains and PrPSc Phenotype

Although prion strains can only be identified definitively by bioassay, molecular in vitro tools to characterize PrPSc are more and more widely used for the rapid identification of particular agents, such as BSE in cattle, sheep, rodent and humans (vCJD) [20],[21]. This has come to be termed 'molecular strain typing' and although widely employed, the exact relationship between PrPSc biochemistry and the biological properties of the agents responsible remain to be determined. In sCJD, the presence of four distinct PrPSc biochemical forms apparently correlated to clinico-pathological phenotypes as defined by Parchi et al. [2] could be an indication of the involvement of different TSE agents.

iCJD cases are a consequence of accidental human to human TSE transmission, most likely representing transmission of sCJD. The identification in iCJD cases of the four PrPSc signatures identified in sCJD is consistent with the existence of distinct prions associated with these biochemical forms.

Three examples of human-to-human transmission of variant CJD through blood transfusion have now been identified. While all blood donors were MM at codon 129 PRNP, the recipients had either a MM (n = 2) or a MV genotype (n =1). Despite this genotype difference there appears to have been conservationof the disease phenotype and PrPres type in all 'secondary' vCJD cases[22]?[25]. These observations could suggest that in case of inter-human transmission, difference in donor/recipient genotype could result in un-altered abnormal PrP signature.

Our identification of MM GH iCJD cases harbouring similar PrPSc signature as a VV1 sCJD case or of a VV dura mater iCJD case similar to MM2 sCJD might indicate preservation of a specific PrPSc biochemical signature after human to human transmission between individuals of different codon 129 genotypes. Treatment with extracts of GH contaminated by CJD has lead to a high number of iCJD cases in France and the UK. The codon 129 genotypes of the affected individuals in the two countries differ, with the French cohort predominantly MM and MV and the British cohort MV and VV [26]. In the absence of any clear explanation for this finding, it was suggested that it might be due to contamination of different batches of GH with different prion strains from individuals of differing PRNP codon 129 genotypes. Our identification of different biochemical forms of PrPSc in GH French patients and in UK patients is consistent with this hypothesis. The variability observed within the French GH cases could signify involvement of different prion strains, consistent with multiple contaminated GH batches in the French epidemic.


The identification in this study of different PrPSc species in CJD patients with the same PRNP polymorphism at codon 129 and WB PrPres profile offers a new perspective on our understanding of the relationship between PrP biochemistry, prion disease phenotype and agent strain. We highlight two novel approaches to analysing PrPSc in sCJD and iCJD and offer evidence that these analyses provide potentially-strain associated information, which appears to be lacking from the conventional WB assay.



AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.


First case of vCJD reported in a Japanese patient: update

Editorial team (, Eurosurveillance editorial office

A detailed description of the first case of variant Creutzfeldt-Jakob disease (vCJD) in Japan, originally reported in February 2005, has just been published [1,2]. The patient was a 51 year old man, who had spent around 24 days in the United Kingdom in 1990, during the bovine spongiform encephalopathy (BSE) outbreak. He is known to have eaten mechanically recovered meat during his visit, and although exposure in other European countries he visited, including France and Japan, cannot be excluded, it is thought that he may have been exposed to the BSE agent during his UK visit. If exposure in the UK was the source of his infection, then the incubation period to illness onset was 11.5 years.

It is also noted that the patient’s illness duration was unusually long, at 42 months, and that periodic synchronous discharges (PSD), which have not been reported in other vCJD cases, appeared on the patient’s electroencephalogram, 12 months before death. The working group reporting on the case suggest that the World Health Organization vCJD case definition [3] be revised to state that PSD does not exclude the possibility of vCJD.

This article is adapted from reference 1


Yamada M, Variant CJD Working Group. The first Japanese case of variant Creutzfeldt-Jakob disease showing periodic electroencephalogram. Lancet 2006; 367: 874. Eurosurveillance. First case of vCJD reported in a Japanese patient. Eurosurveillance 2005; 10(2): 050210. (

The Revision of the Surveillance Case Definition for Variant Creutzfeldt-Jakob Disease (vCJD). Report of a WHO consultation, Edinburgh, United Kingdom 17 May 2001. WHO/CDS/CSR/EPH/2001.5. Geneva: World Health Organization; 2001 (


Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease

Magdalini Polymenidou, Katharina Stoeck, Markus Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi



The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.


We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.


We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.


The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and *** questions the rational basis of current CJD classifications.


The above results set the existing CJD classifications

into debate and introduce interesting questions about

human CJD types. For example, do human prion types

exist in a dynamic equilibrium in the brains of affected

individuals? Do they coexist in most or even all CJD

cases? Is the biochemically identified PrPSc type simply

the dominant type, and not the only PrPSc species?

Published online October 31, 2005

Neuropathology and Applied Neurobiology

© 2005 Blackwell Publishing Ltd


Blackwell Science, LtdOxford, UKNANNeuropathology and Applied Neurobiology0305-1846Blackwell Publishing Ltd, 2005


Review article

Phenotypic variability in human prion diseases

J. W. Ironside, D. L. Ritchie and M. W. Head

National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, University of Edinburgh, Edinburgh, UK

J. W. Ironside, D. L. Ritchie and M. W. Head (2005)

Neuropathology and Applied Neurobiology



Phenotypic variability in human prion diseases

Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller understanding of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the disease phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the concept of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic Creutzfeldt-Jakob disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases. ...

© 2005 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 31, 565-579


BSE prions propagate as either variant CJD-like or

sporadic CJD-like prion strains in transgenic mice

expressing human prion protein

The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002

Emmanuel A.Asante, Jacqueline M.Linehan,

Melanie Desbruslais, Susan Joiner,

Ian Gowland, Andrew L.Wood, Julie Welch,

Andrew F.Hill, Sarah E.Lloyd,

Jonathan D.F.Wadsworth and

John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease,

Institute of Neurology, University College, Queen Square,

London WC1N 3BG, UK

1Corresponding author


Variant Creutzfeldt±Jakob disease (vCJD) has been

recognized to date only in individuals homozygous for

methionine at PRNP codon 129. Here we show that

transgenic mice expressing human PrP methionine

129, inoculated with either bovine spongiform

encephalopathy (BSE) or variant CJD prions, may

develop the neuropathological and molecular phenotype

of vCJD, consistent with these diseases being

caused by the same prion strain. Surprisingly, however,

BSE transmission to these transgenic mice, in

addition to producing a vCJD-like phenotype, can also

result in a distinct molecular phenotype that is indistinguishable

from that of sporadic CJD with PrPSc

type 2. These data suggest that more than one BSEderived

prion strain might infect humans; it is therefore

possible that some patients with a phenotype consistent

with sporadic CJD may have a disease arising

from BSE exposure.

The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002

6358 ãEuropean Molecular Biology Organization

Archive Number 20071105.3602 Published Date 05-NOV-2007 Subject PRO/AH/EDR> Prion disease update 2007 (07)

PRION DISEASE UPDATE 2007 (07) ****************************** A ProMED-mail post


[2] USA: National Prion Disease Pathology Surveillance Center Date: June 2007 Source: National Prion Disease Pathology Surveillance Center (USA) [edited]

CJD Cases examined ---------------------- Year / Referrals / Prion disease / Sporadic / Familial / Iatrogenic / vCJD

1996 / 42 / 32 / 26 / 4 / 0 / 0 1997 / 115 / 68 / 57 / 9 / 0 / 0 1998 / 93 / 53 / 45 / 7 / 1 / 0 1999 / 114 / 69 / 61 / 8 / 0 / 0 2000 / 151 / 103 / 89 / 14 / 0 / 0 2001 / 208 / 116 / 106 / 9 / 0 / 0 2002 / 255 / 143 / 118 / 23 / 2 / 0 2003 / 272 / 174 / 132 / 41 / 0 / 0 2004 / 334 / 183 / 157 / 21 / 0 / 1* 2005 / 352 / 195 / 152 / 37 / 1 / 0 2006 / 372 / 186 / 143 / 30 / 0 / 1** 2007 / 120 / 68 / 35 / 7 / 0 / 0 TOTAL / 2428*** / 1390**** / 1121 / 210 / 4 / 2

*Acquired in UK ** Acquired in Saudi Arabia *** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007. **** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007).


-- Cases are listed based on the year of death when available. If the year of death is not available, the year of sample receipt is used.

-- Referrals: Cases with possible or probable prion disease from which brain tissue or blood in the case of familial disease were submitted.

-- Inconclusive: Cases in which the samples were not sufficient to make a diagnosis.

-- Non-vCJD type unknown are cases in which the tissue submitted was adequate to establish the presence but not the type; in all cases, vCJD could be excluded.

-- Communicated by: Terry S. Singeltary Sr.

[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP],F2400_P1001_PUB_MAIL_ID:1010,39963

There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

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?


Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk

Tracking spongiform encephalopathies in North America

Xavier Bosch

Available online 29 July 2003. Volume 3, Issue 8, August 2003, Page 463

"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." ...

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.

To the Editor:

In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

Like lambs to the slaughter

31 March 2001 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. ...


prepared February 20, 2008

Infected and Source Flocks

There were 27 scrapie infected and source flocks with open statuses (Figure 3) as of January 31, 2008. Two new source flocks and one new infected flock were reported in January (Figure 4) with a total of 22 reported for FY 2008 (Figure 5). ....


Positive Scrapie Cases

As of January 31, 2008, 58 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 7). Of these, 52 were field cases and 6* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by February 20, 2008). There were 8 positive cases for January which are depicted in Figure 8. Seventeen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 9). The most recent positive goat cases were from the SAME HERD and WERE BOTH CONFIRMED IN JANAURY 2008.


Caprine Scrapie Prevalence Study (CSPS)

CSPS was initiated in May 2007 to estimate the national prevalance of scrapie in adult goats at slaughter. If no scrapie is found we will be able to conclude that the prevalence in goats is greater than zero and less than 0.1 percent. AS of January 31, 2008, 2,942 goats have been sampled for scrapie testing (1,515 in FY 2007 and 1,427 in FY 2008). Collection numbers by quarter in FY 2008 is shown in Chart 8. To date, no goats have tested positive for scrapie as part of this surveillance program. HOWEVER, THREE POSITIVE GOATS have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and THE OTHER TWO WERE MEMBERS OF THE OF THE BIRTH HERD OF THE CLINICAL CASE.


please see full text ;


The flocks of origin are WY, CO, CA, IN, and MN.

personal communication USDA et al. ...TSS


INFECTED AND SOURCE FLOCKS AS of August 31, 2007, there were 33 scrapie infected and source flocks with open statuses (Figure 3). Five new source flocks and one new infected flock were reported n August (Figure 4) with a total of 64 reported for FY 2007(Figure 5).






a non-profit Swiss Foundation

(May 16, 2007)

TAFS1 Position Paper on Atypical scrapie and Atypical BSE

Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22).


Atypical BSE may arise spontaneously in a small proportion of cattle. The existence of sporadic CJD in humans has led to postulation that disease could arise spontaneously in any animal, but this is still not proven to happen. Despite the small numbers of atypical BSE detected so far, in some countries the numbers are too great to suggest that they all arise spontaneously, if it were assumed that such a phenomenon occurred at the same frequency as sporadic CJD in humans.

Tissue distribution. For atypical scrapie, what is PrPres and infectivity distribution within sheep of different genotypes, particularly with respect to SRM removal? For classical scrapie and experimental BSE in sheep, tissue distribution of infectivity is widespread. Thus, even with SRM controls in place, an infected sheep poses around 1000 times the risk to human health than does an infected cow22. Does the distribution depend on whether infection is by the oral or intracerebral route? Are some VRQ sheep carriers with no neurological symptoms?


21 Gubbins S. Prevalence of BSE in sheep: interpreting the results of retrospective and prospective testing of sheep TSE cases. SEAC 84 open meeting 22 paper presented to Food Standards Agency board on 9 December 2004. Also see paper SEAC/84/2 Annex 2: McLean, A. Page 13 © SEAC 27 February 2006


Aspects of the Cerebellar Neuropathology in Nor98

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway

Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. ***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;



full text ;

DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen) USA: Loch in der Mauer Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehörden sind lax. Link auf diesen Artikel im Archiv:

"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...

Thu Dec 6, 2007 11:38



2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.

Preliminary Investigation Suggests BSE-Infected Cow in Washington State Was Likely Imported from Canada

On December 23, 2003, the U.S. Department of Agriculture (USDA) announced a presumptive diagnosis of bovine spongiform encephalopathy (BSE, or "mad cow" disease) in an adult Holstein cow from Washington State. Samples were taken from the cow on December 9 as part of USDA's BSE surveillance program. The BSE diagnosis was made on December 22 and 23 by histopathology and immunohistochemical testing at the National Veterinary Services Laboratory, Ames, Iowa. The diagnosis was confirmed by an international reference laboratory in Weybridge, England, on December 25. Preliminary trace-back based on an ear-tag identification number suggests that the BSE-infected cow was imported into the United States from Canada in August 2001.

Both of the U.S.-born BSE cases and two of the twelve Canadian-born BSE cases were 10 years of age or older and all three of these older North American cases for whom the BSE strain is presently known were linked to an atypical BSE strain known as the H-strain. Strain testing on the 13 year-old BSE-infected Canadian cow identified in December 2007 is pending.

In this context, a word is in order about the US testing program. After the discovery of the first (imported) cow in 2003, the magnitude of testing was much increased, reaching a level of >400,000 tests in 2005 (Figure 4). Neither of the 2 more recently indigenously infected older animals with nonspecific clinical features would have been detected without such testing, and neither would have been identified as atypical without confirmatory Western blots. Despite these facts, surveillance has now been decimated to 40,000 annual tests (USDA news release no. 0255.06, July 20, 2006) *** and invites the accusation that the United States will never know the true status of its involvement with BSE.

It will be critical to see whether the atypical BSE isolates behave similarly to typical BSE isolates in terms of transmissibility and disease pathogenesis. If transmission occurs, tissue distribution comparisons will be made between cattle infected with the atypical BSE isolate and the U.S. BSE isolate. Differences in tissue distribution could require new regulations regarding specific risk material (SRM) removal.

Volume 14, Number 2–February 2008 Dispatch Atypical Bovine Spongiform Encephalopathies, France, 2001–2007 Anne-Gaëlle Biacabe,* Eric Morignat,* Johann Vulin,* Didier Calavas,* and Thierry G.M. Baron* *Agence Française de Sécurité Sanitaire des Aliments, Lyon, France

TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties

page 19 of 62. ...tss

Dr. Detwiler: How would you explain that biochemically?

Dr. Bartz:


One really important thing I want to point out here is that strain properties can change upon inter-species transmission. Chronic wasting disease doesn't cause disease when you passage it in a hamster, but if you passage CWD into ferrets, and then take that ferret passage tissue, it can cause disease in hamsters. So inter-species transmission can expand the host range. Also, with the hyper and drowsy, the more hamster passages you do, if you back-passage the inoculum into mink, hyper loses pathogenicity for mink quite quickly, where drowsy retains pathogenicity for mink.The important point I want to make is that, when you're assessinginter-species transmission and you do a transmission study and it's negative, you have to be careful in saying it's negative for the strains you looked at. With this example, it's clear you could take hyper TME, inoculate mink, and they don't come down with the disease, so you might assume hamster prions don't cause disease in mink. That strain doesn't. You have to be careful assessing negative transmission results based on what's known about the strain properties. ...end...tss

Accomplished this day, Wednesday, December 11, 2003, Denver, Colorado

The roundtable presentations and discussions were recorded. A transcript will be made availableto the Academy of Veterinary Consultants, the American Association of Bovine Practitioners, and the Colleges of Veterinary Medicine through out theUnited States and Canada. A condensed version translated for the livestock industry will be made available to educate livestock producers about prion related diseases.

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

APHIS-2006-0041-0006 TSE advisory committee for the meeting December 15, 2006


[Federal Register: January 9, 2007 (Volume 72, Number 5)] [Proposed Rules] [Page 1101-1129] From the Federal Register Online via GPO Access [] [DOCID:fr09ja07-21]


Geographical BSE Risk (GBR) assessments covering 2000-2006

Date : 01.08.2006

WE WILL never know what strain TSE these cattle might have been ;

Witness testifies some ill cattle sent to rendering plant

By CHIP CHANDLER Globe-News Staff Writer


Mike Engler -- son of Paul Engler, the original plaintiff and owner of Cactus Feeders Inc. -- agreed that more than 10 cows with some sort of central nervous system disorder were sent to Hereford By-Products.

The younger Engler, who has a doctorate in biochemistry from Johns Hopkins University, was the only witness jurors heard Thursday in the Oprah Winfrey defamation trial. His testimony will resume this morning.

According to a U.S. Department of Agriculture report from which Winfrey attorney Charles Babcock quoted, encephalitis caused by unknown reasons could be a warning sign for bovine spongiform encephalopathy, or mad cow disease.

Encephalitis was indicated on the death certificates -- or ``dead slips'' -- of three Cactus Feeders cows discussed in court. The slips then were stamped, ``Picked up by your local used cattle dealer'' before the carcasses were taken to the rendering plant.


FOR IMMEDIATE RELEASE Statement May 4, 2004 Media Inquiries: 301-827-6242 Consumer Inquiries: 888-INFO-FDA

Statement on Texas Cow With Central Nervous System Symptoms On Friday, April 30 th , the Food and Drug Administration learned that a cow with central nervous system symptoms had been killed and shipped to a processor for rendering into animal protein for use in animal feed.

FDA, which is responsible for the safety of animal feed, immediately began an investigation. On Friday and throughout the weekend, FDA investigators inspected the slaughterhouse, the rendering facility, the farm where the animal came from, and the processor that initially received the cow from the slaughterhouse.

FDA's investigation showed that the animal in question had already been rendered into "meat and bone meal" (a type of protein animal feed). Over the weekend FDA was able to track down all the implicated material. That material is being held by the firm, which is cooperating fully with FDA.

Cattle with central nervous system symptoms are of particular interest because cattle with bovine spongiform encephalopathy or BSE, also known as "mad cow disease," can exhibit such symptoms. In this case, there is no way now to test for BSE. But even if the cow had BSE, FDA's animal feed rule would prohibit the feeding of its rendered protein to other ruminant animals (e.g., cows, goats, sheep, bison).

FDA is sending a letter to the firm summarizing its findings and informing the firm that FDA will not object to use of this material in swine feed only. If it is not used in swine feed, this material will be destroyed. Pigs have been shown not to be susceptible to BSE. If the firm agrees to use the material for swine feed only, FDA will track the material all the way through the supply chain from the processor to the farm to ensure that the feed is properly monitored and used only as feed for pigs.

To protect the U.S. against BSE, FDA works to keep certain mammalian protein out of animal feed for cattle and other ruminant animals. FDA established its animal feed rule in 1997 after the BSE epidemic in the U.K. showed that the disease spreads by feeding infected ruminant protein to cattle.

Under the current regulation, the material from this Texas cow is not allowed in feed for cattle or other ruminant animals. FDA's action specifying that the material go only into swine feed means also that it will not be fed to poultry.

FDA is committed to protecting the U.S. from BSE and collaborates closely with the U.S. Department of Agriculture on all BSE issues. The animal feed rule provides crucial protection against the spread of BSE, but it is only one of several such firewalls. FDA will soon be improving the animal feed rule, to make this strong system even stronger.


Specified Risk Material SRM

Thursday, February 21, 2008

TRANSCRIPT: Technical Briefing - Hallmark/Westland Meat Packing Company - (02/21/08)

Release No. 0054.08

Wednesday, March 12, 2008 CWD Update 90 March 7, 2008


Transmissible Mink Encephalopathy TME

now, ponder friendly fire from all the above ?

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518



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