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-------------------------------------------------------------------------------- SEAC response to the SEAC epidemiology subgroup position statement on the vCJD epidemic A substantial number of subclinical carriers of vCJD infection may exist in the UK population who cannot, at present, be identified. As a result a secondary, possibly self-sustaining, vCJD epidemic could arise due to human-to-human transmission via medical interventions such as blood transfusion and surgery. In order to implement the most appropriate precautionary measures, there is an urgent need to ascertain better the prevalence, age and genotype distribution of subclinical vCJD infection in the UK population. These data will inform assessment and subsequent management of the risks of secondary transmission. New information on the prevalence, age and genotype distribution of vCJD infection will be provided by the planned testing of samples under collection for the National Anonymous Tonsil Archive (NATA). This testing should be progressed with urgency. However a large proportion of tonsils will be collected from young individuals with relatively low dietary exposures to BSE, and there is uncertainty about the sensitivity of tonsil tests to detect subclinical vCJD infection. It is, therefore, very important that additional programmes to test a range of tissues collected from other age groups in the population are considered. Testing of tissues collected from autopsies could, potentially, provide substantial data on the prevalence, age and genotype distribution of infection which would complement data from NATA. However, there are practical, ethical and legal issues around post mortem testing. The committee recommends that an expert group is convened with some urgency by the Department of Health to consider and advise how such post mortem testing, or other testing designed to ascertain the prevalence, age and genotype distribution of vCJD in the UK population, might best be undertaken. SEAC 1SEAC Epidemiology Subgroup. Position statement on the vCJD epidemic. November 2005. Page updated: 26 January 2006 http://www.seac.gov.uk/statements/state260106.htm SEAC epidemiology subgroup position statement on the vCJD epidemic 1. SEAC asked the SEAC Epidemiology Subgroup to reassess the nature and future profile of the vCJD epidemic, taking into account new research and the possibility of human to human infection. SEAC identified a number of issues for the Subgroup to consider (see Annex 1). Background 2. Incidence of vCJD has declined over the past 4 years in the UK1,a. Projections based on the case data suggest the number of additional cases of vCJD arising from the consumption of BSE-infected material might be relatively small (less than 100)2. However, findings from a retrospective survey of appendix and tonsil tissue from operations carried out between 1995 and 2000 on individuals predominantly (83%) in the age range 10-30 years suggest that the number of infected individuals may be greater than projections based on backcalculation from vCJD cases suggest3. Furthermore, research in animal models suggests it is possible that a proportion of infections may not develop into clinical disease, or do so over a longer time scale, and remain at a subclinical level4-7. Although all vCJD cases tested to date (about 85% of cases) have been of the M/M genotype at the polymorphic codon 129 of the human prion protein gene, the effect of other genotypes on the susceptibility to, infectiousness of, and phenotype of, vCJD is uncertain. The finding of an asymptomatic case of probable blood transfusion associated transmission of vCJD of the M/V genotype8 suggests individuals of this genotype are also susceptible to secondary transmission by the intravenous route. It is possible that secondary infection via medical procedures may give rise to additional infections and potentially enable a self-sustaining secondary epidemic. 3. To address the SEAC request, the Subgroup met twice in 2005 to consider data on the epidemiology of the disease, predictions about the epidemic based on infectious disease models and relevant published and unpublished research. This initial position statement has been produced on the basis of these discussions. It is intended that the Subgroup will keep the statement under review in light of emerging scientific or medical information that improves understanding of the epidemiology of vCJD. General observations 4. It is currently not possible to answer in full the questions set by SEAC due to continued uncertainty about key characteristics of the vCJD epidemic, in particular: the prevalence and distribution of primary and secondary infection in the UK population and incubation periods of the primary and secondary disease. Although infectious disease models provide a very useful means to test hypotheses, firm conclusions about the epidemic can only be drawn by the acquisition of better estimates of the prevalence, age and genotype distribution of infection based on population studies. Continued surveillance to identify new cases of vCJD will also provide valuable information to understand better the epidemic, in particular: trends in the incidence of vCJD, the age and genotype distribution of those who develop vCJD and identification of possible routes of secondary transmission (e.g. maternal or related to invasive medical procedures). Influence of age on infection 5. Direct evidence to inform assessment of the influence of age on the prevalence of infection is presently limited to data from vCJD cases and the retrospective survey of appendix and tonsil tissue3. The age distribution of vCJD cases has remained relatively stable since the start of the epidemic. This is likely to be due to a combination of age-related differentials in dietary exposure to BSE and in susceptibility to the disease. Modelling studies based on the assumption that the vCJD epidemic is best defined by age-related differentials in susceptibility to vCJD together with a constant incubation period and a time window of dietary BSE exposure related directly to the observed BSE epidemic, which appears to be the most likely scenario, have produced broadly similar results9-11. These studies suggest that age-related susceptibility / exposure was greatest in the 10-20 year old age range, lower in early childhood and much lower later in adult life. However, although this profile might be expected to be reflected in the prevalence of primary infections leading to disease, it is derived from data on vCJD cases. Thus, it is possible that it may not apply to infections in the non-M/M population or to infections that remain at a subclinical level (see later). 6. Given these uncertainties, it is not possible to predict with confidence the relative risk that age groups are infected for all age groups of the population. However, it is almost surely the case that, due to the BSE control measures introduced in the UK, dietary exposure of the post-1996 birth cohorts would be very much lower or even negligible compared with older birth cohorts. Children 9 years old and younger would, therefore, very clearly be at the lowest risk of primary infection. Furthermore, despite relatively large dietary exposure to BSE9, only a single case has been observed in the pre-1940 birth cohort. This strongly suggests that adults over 66 years of age are at relatively low risk of developing primary vCJD, assuming there is no major under ascertainment of the disease in the elderly. 7. If it is assumed that susceptibility to primary vCJD infection (in terms of infections that lead to disease and infections that remain at a subclinical level) was greatest within the 10-20 year age range, it would be predicted that individuals in the 1965-1985 birth cohorts, given the peak in dietary BSE exposure around 1990, are at the greatest risk of being infected. However, as discussed above this hypothetical profile of age-related susceptibility to primary vCJD infection may not apply to the non-M/M population or to infections that remain at a subclinical level. Given the decline in the BSE epidemic, the 1990-1995 birth cohorts are at a much smaller risk, and this risk lowers progressively with year of birth. A continuing lack of vCJD cases in the post-1990 birth cohort will provide reassurance about the validity of this hypothesis. Influence of genotype on infection 8. There is an indication that non-M/M genotypes are susceptible to vCJD infection from the case of probable blood transfusion associated transmission of vCJD of the M/V genotype8. In addition, atypical immunohistochemical results from two of the three positive appendix samples in the appendix and tonsil survey may also be an indicator of infection in non-M/M genotypes3. 9. Polymorphisms at codon 129 of the human prion protein gene influence susceptibility to, and the incubation of period of, human prion diseases12-14. Observations of kuru suggest that individuals of non-M/M genotypes are generally less susceptible to this disease and have longer incubation periods than individuals of the M/M genotype14. On the basis that these general characteristics are a valid model for vCJD infection, it seems reasonable to assume that primary and secondary vCJD cases in individuals of the M/V and V/V genotypes might arise, although they can be expected to be proportionately fewer in number and possibly appear over a long time scale. Recent projections from an infectious disease model suggest that, in the unlikely situation that other genotypes are equally susceptible to clinical disease, the number of future primary cases may increase up to five-fold compared with current estimates for future cases of the M/M genotype2. 10. It is not possible to predict the clinical phenotype of vCJD cases in non-M/M genotypes, should they arise. However, evidence from fatal familial insomnia and sporadic CJD indicates that codon 129 genotype affects clinical phenotype15,16. Experiments in transgenic mice expressing human forms of the prion protein gene suggest that the neuropathological phenotype of vCJD is influenced by genotype7. Subclinical carriers of infection 11. Experimental studies in mice suggest primary prion infections may remain at a subclinical level but on secondary transmission result in clinical disease4,5. Thus, asymptomatic animals can be subclinical carriers of infection. The reason that infection in some animals remains at a subclinical level while clinical disease develops in others is not fully understood. The potential existence of subclinical carriers of vCJD may explain the apparent discrepancy between prevalence estimates of primary vCJD infection based on the appendix and tonsil survey and the vCJD case data. Recent projections to explore this possibility suggest the number of subclinical carriers could be of the order of several thousand2. There are currently no data to allow the possible age and genotype distribution of subclinical carriers of infection to be determined. Additional data to understand the epidemic better 12. As discussed above, knowledge of the prevalence of infection cannot be determined accurately from quantitative models because of the uncertainties regarding the effect of genotype and age at infection and the possibility of secondary transmission from subclinical carriers of infection. Further data are required to understand better the prevalence, age and genotype distribution of both primary and secondary vCJD infection. 13. The PrPSc screening programme, due to begin in 2006, of the very large number of samples under collection for the National Anonymous Tonsil Archive (NATA) will allow more accurate assessments of the prevalence and age and genotype distribution of infection (see table). It is strongly recommended that testing of samples collected by NATA is progressed with all possible urgency. 14. However, although PrPSc tests have always proved positive in tonsils of clinical vCJD cases, there are uncertainties about the sensitivity of tonsil tests to detect asymptomatic and subclinical infection. In addition, although tonsils will be collected from a wide age range of individuals, tonsillectomy is more commonly conducted at relatively young ages. Thus, many of the samples will be collected from individuals with relatively low dietary exposures to BSE. Additional programmes to test other tissues collected from a different age distribution of individuals would provide further data as well as assurance about the findings from NATA (see table). 15. Principally as an infection control measure, a pilot study is underway to investigate the feasibility of testing the spleen, tonsil and / or appendix from cadaveric tissue / organ donors. Pilot studies to screen corneal and multi-organ donors are also under consideration. Although, testing of tissue from cadaveric, corneal and multi-organ donors might provide a limited amount of data, pilot studies to assess the feasibility of such testing are welcomed and encouraged. 16. PrPSc testing of a range of tissues collected from autopsies would, in principle, provide substantial data on the prevalence and age and genotype distribution of the section of the population presumed most likely to carry the majority of primary vCJD infections. However, such a programme relies heavily on consent for testing, which is a legal requirement, from the deceased (in life) or a close relative / carer. Practical and cost considerations around informed consent could have a substantial detrimental impact on the feasibility of such a programme. Nevertheless, it is recommended that serious consideration be given to testing samples collected from autopsies. By comparison, retrospective survey of residual appendectomy or splenectomy tissues, although informative, would be less useful (see table). 17. It is also recommended that enhanced clinical surveillance in the elderly be considered (see table). Although vCJD cases arising from primary transmission of BSE are observed mostly in young adults, there may be potential under-ascertainment of cases in the elderly, possibly due to misdiagnosis. Enhanced surveillance of this section of the population would allow this possibility to be tested. Furthermore, such enhanced surveillance would provide additional assurance that clinical cases of secondary transmission of vCJD may be detected since this section of the population is the group most likely to have undergone invasive medical procedures and / or to have received blood transfusions. Should cases be detected in older age groups, it would be important to undertake statistical analyses to estimate the proportion of cases that might have arisen from the dietary route versus medical interventions, i.e. the proportion of disease that could have arisen from primary or secondary transmission. 18. Clinical monitoring and, with patient consent, post mortem vCJD tests on individuals considered to be ‘at risk of vCJD for public health purposes’ would help to inform assessment of secondary transmission risks. Proposals are currently being developed for blood component recipients and should be considered for all at risk groups. Self-sustaining epidemic 19. Current risk assessments of secondary transmission through surgery, blood transfusion, dentistry and bone / tissue / organ transplantation17 suggest that, on the basis of what is presently known, transmission via the surgical and blood routes are the most important in terms of the possible contribution to a secondary epidemic. This is on the basis of the relatively high number of surgical procedures and blood transfusions and estimated transmission efficiencies via these routes. By comparison, the risk of transmission via dentistry per procedure is thought to be relatively low, although the number of procedures is relatively large. In contrast, the risk of transmission via transplantation, depending on what tissues / organs are transplanted, is thought to be relatively high but the number of procedures is relatively low. However, uncertainties in key parameters in the risk assessments remain, such as the profile of the primary epidemic, infectivity levels in tissues, transmission efficiencies via routes and the effectiveness of decontamination / infectivity reduction methods. 20. The information currently available from follow up of children born to vCJD cases cannot exclude the possibility of maternal transmission of vCJD. However, on the basis of the information available on prion diseases of humans and animals, maternal transmission of vCJD, if it occurs, is unlikely on its own to support a self-sustaining secondary epidemic. 21. On the basis of current understanding, the transmission risk from the surgical route on its own could create a self-sustaining epidemic under worst case conditions of long incubation period for iatrogenic vCJD and long patient survival times. The National Institute for Health and Clinical Excellence is currently conducting an assessment of precautionary measures to reduce potential transmission risks via surgery. Blood borne transmission on its own is thought unlikely to result in a self-sustaining epidemic, especially given the precautionary measures already enacted (e.g. (deferral of donations from blood recipients, import of plasma for fractionation and leucodepletion). The large number of dental procedures (coupled with good patient survival) implies that any significant risk via that route could have a major impact on the dynamics of secondary infection. In addition, interactions between routes of transmission will also make a self-sustaining epidemic more likely. 22. The likelihood of a self-sustaining epidemic cannot be quantified at present. The complexity and number of interactions between potential routes of transmission make development of a workable model to quantify interactions within and between routes and the effect interactions might have on transmission risks very difficult. Work is underway to develop population level models for the surgical and blood routes with a view to developing a combined model to explore the effect of interactions between these routes. This work should continue to be supported. 23. On the basis of current risk assessments of transmission routes considered in isolation, factors such as the number of potential transmissions, infectivity of tissues, the efficiencies of transmission and the effectiveness of decontamination / infectivity reduction methods are all, to varying extents, key influences on the likelihood of a self-sustaining epidemic arising and the rate that it might develop. 24. On the basis of current understanding, a secondary epidemic is more likely if many individuals are exposed to potentially infectious material from a single individual (e.g. through dispersion of surgical instruments between sets) or vice versa (e.g. if blood products are pooled, exposing each recipient to multiple donors). A secondary epidemic is also generally more likely if patients who have undergone one potentially infectious procedure are at increased risk of undergoing further procedures. SEAC Epidemiology Subgroup November 2005 a Number of deaths from vCJD in the UK in the years 1999 to 2005: 15 (1999), 28 (2000), 20 (2001), 17 (2002), 18 (2003), 9 (2004) and 3 (end September 2005). Table of potential investigative programmes to improve understanding of the vCJD epidemic (27 KB) References 2. Clarke & Ghani (2005) Projections of future course of the primary vCJD epidemic in the UK: inclusion of subclinical infection and the possibility of wider genetic susceptibility R. J. Soc. Interface. 2, 19-31. 3. Hilton et al. (2004) Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol. 203, 733-739. 4. Hill et al. (2000) Species-barrier-independent prion replication in apparently resistant species. Proc. Natl. Acad. Sci. USA. 97, 10248-10253. 5. Race et al. (2001) Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. J Virol. 75, 10106-10112. 6. Asante et al. (2002) BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 21, 6358-6366. 7. Wadsworth et al. (2004) Human prion protein V129 prevents expression of variant CJD phenotype. Science. 306, 1793-1796. 8. Peden et al. (2004) Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 364, 477-479. 9. Cooper & Bird (2003) Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the 1940 to 1969 and post-1969 birth cohorts. Int. J. Epidemiol. 32, 784-791. 10. Ghani et al. (2003) Updated projections of future vCJD deaths in the UK. BMC Infect. Dis. 3, 4-11. 11. Boelle et al. (2004) Epidemiological evidence of higher susceptibility to vCJD in the young. BMC Infect Dis. 4, 26-32. 12. Alperovitch et al. (1999) Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease. Lancet 353, 1673-1674. 13. Huillard d’Aignaux et al. (1999) Incubation period of Creutzfeldt-Jakob disease in human growth hormone recipients in France. Neurology 53, 1197-1201. 14. Lee et al. (2001) Increased susceptibility to kuru of carriers of the PRNP 129 methionine/methionine genotype. J. Infect. Disease. 183, 192-196. 15. Gambetti et al. (1995) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol. 5, 43-51. 16. Parchi et al. (1999) Classification of sporadic Creutzfeld-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46, 224-233. 17. Economics and Operational Research Division risk assessments, Department of Health. Annex 1 1. What are the implications of recent research for current models of the vCJD epidemic? (a) Do recent data on age- and genotype-related effects alter the predicted profile of the vCJD epidemic and the potential number of infective carriers? (b) Are there likely to be 'carriers' of infectivity who do not develop clinical vCJD within their lifetime, or who present with clinical features not currently recognised as vCJD, and if so, what are the limits on the possible prevalence / age distribution / genotype of such individuals? 2. What new evidence would lead SEAC to believe that the size of the vCJD epidemic is likely to be larger or smaller than current estimates (i.e. what new data would lead SEAC to believe that current estimates may be incorrect)? (a) Are the current and expected data from population level studies (i.e. tonsil and appendix and other tissue surveys) sufficient to enable estimation of the age / genotype distribution of infection, and what further information would help inform predictions of the profile of the vCJD epidemic? (b) What are the information barriers to determining the potential risks to public health from carriers of vCJD infectivity? 3. Is there a significant risk of a self-sustaining human vCJD epidemic through secondary transmission of BSE between humans? (a) What are the relative risks of secondary transmission through medical procedures (transfusion, transplantation, surgery)? (b) Taking all these potential routes of transmission and their interactions into account, how likely is a self-sustaining epidemic? (c) If a self-sustaining epidemic is possible, what factors determine its scale? 4. What are the key points at which modification of practice could significantly reduce the risk of a self-sustaining epidemic? Page updated: 26 January 2006 http://www.seac.gov.uk/statements/state260106subgroup.htm#annex1 SEAC seems on insisting on forgetting about the OTHER victims, the sporadic CJDs. i personally don't think they want to know. i guess they figure if they don't speak the new science and findings, we will forget. not gonna happen. my question to SEAC, why is there no concern with the other victims of this nightmare? http://www.eurocjd.ed.ac.uk/sporadic.htm Diagnosis and Reporting of Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease Summary ratio of protease-resistant prion protein (PrPSc), and type 2 PrPSc display unglycosylated core fragments of acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to K cleavage sites. These antibodies, which were Findings We studied 114 brain samples from 70 patients Every patient classified as CJD type 2, and all variant cerebellum and other PrPSc-rich brain areas, with a Interpretation The regular coexistence of multiple electrophoretic PrPSc mobilities as surrogates for 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? http://neurology.thelancet.com Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,? Fred G. van Zijderveld,? Moira E. Bruce,? James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease (CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151-157; DOI: 10.2353/ajpath.2006.050766) snip... Discussion In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component brain. Western blot analysis of PrP in a sample of of vCJD during digestion with proteinase K is shown. are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). probed with 3F4, which detects both type 1 and type 2 which detects type 1. The insert shows a shorter course study from a separate experiment also probed included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Figure 7. A minority type 1-like PrPSc is found in vCJD to mice and in BSE. Western blot analysis of PrPSc in a sample of tonsil from a case of vCJD (Tonsil), in a of a wild-type mouse (C57BL) infected with vCJD and in BSE brain (BSE) is shown. Tissue extracts were digested Duplicate blots were probed with either 3F4 or 6H4, type 1 and type 2 PrPSc, and with 12B2, which detects included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this on vCJD, where type 1 is present in all samples but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the signature" of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative and that any mechanistic explanation of prion replication and the molecular basis of agent strain must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments snip... Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157 AJP January 2006, Vol. 168, No. 1 ...TSS (2005), 31 , 565-579 doi: 10.1111/j.1365-2990.2005.00697.x © 2005 Blackwell Publishing Ltd 565 Blackwell Science, LtdOxford, UKNANNeuropathology and 316565579 Review article Phenotypic variability in human prion diseases J. W. Ironside, D. L. Ritchie and M. W. Head National Creutzfeldt-Jakob Disease Surveillance Unit, J. W. Ironside, D. L. Ritchie and M. W. Head (2005) Neuropathology and Applied Neurobiology 31, 565-579 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 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 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 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 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 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 e-mail: j.collinge@prion.ucl.ac.uk 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 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. snip... These studies further strengthen the evidence that vCJD is caused by a BSE-like prion strain. Also, remarkably, the key neuropathological hallmark of vCJD, the presence of abundant ¯orid PrP plaques, can be recapitulated on BSE or vCJD transmission to these mice. However, the most surprising aspect of the studies was the ®nding that an alternate pattern of disease can be induced in 129MM Tg35 mice from primary transmission of BSE, with a molecular phenotype indistinguishable from that of a of sporadic CJD. This ®nding has important potential implications as it raises the possibility that some humans infected with BSE prions may develop a clinical disease indistinguishable from classical CJD associated with type 2 PrPSc. This is, in our experience, the commonest molecular sub-type of sporadic CJD. In this regard, it is of interest that the reported incidence of sporadic CJD has risen UK since the 1970s (Cousens et al., 1997). This has been attributed to improved case ascertainment, particularly as much of the rise is reported from elderly patients and similar rises in incidence were noted in other European countries without reported BSE (Will et al., 1998). However, it is now clear that BSE is present in many European countries, albeit at a much lower incidence than was seen in the UK. While improved ascertainment is likely to be a major factor in this rise, that some of additional cases may be related to BSE exposure cannot be ruled out. It is of interest in this regard that a 2-fold increase in the reported incidence of sporadic CJD in 2001 has recently been reported for Switzerland, a country that had the highest incidence of cattle BSE in continental Europe between 1990 and 2002 (Glatzel et al., 2002). No epidemiological case±control studies with strati®cation of CJD cases by molecular sub-type have yet been reported. It will be important to review the incidence of sporadic CJD associated with PrPSc type 2 and other molecular in both BSE-affected and unaffected countries in the light of these ®ndings. If human BSE prion infection can result in propagation of type 2 PrPSc, it would be expected that such cases would be indistinguishable on clinical, pathological and molecular criteria from classical CJD. It may also be expected that such prions would behave biologically like those isolated from humans with sporadic CJD with type 2 PrPSc. The transmission properties of prions associated with type 2 PrPSc from BSE-inoculated 129MM Tg35 mice are being investigated by serial passage. We consider these data inconsistent with contamination of some of the 129MM Tg35 mice with sporadic CJD prions. These transmission studies were performed according to rigorous biosafety protocols for preparation of inocula and both the inoculation and care of mice, which are all uniquely identi®ed by sub-cutaneous transponders. However, crucially, the same BSE inocula have been used on 129VV Tg152 and 129MM Tg45 mice, which are highly sensitive to sporadic CJD but in which such transmissions producing type 2 PrPSc were not observed. Furthermore, in an independent experiment, separate inbred lines of wild-type mice, which are highly resistant to sporadic CJD prions, also propagated two distinctive PrPSc types on challenge with either BSE or vCJD. No evidence of spontaneous prion disease or PrPSc has been seen in groups of uninoculated or mock-inoculated aged 129MM Tg35 mice. While distinctive prion isolates have been derived from BSE passage in mice previously (designated 301C and 301V), these, in contrast to the data presented here, are propagated in mice expressing different prion proteins (Bruce et al., 1994). It is unclear whether our ®ndings indicate the existence of more than one prion strain in individual cattle with BSE, with selection and preferential replication of distinct strains by different hosts, or that `mutation' of a unitary BSE strain occurs in some types of host. Western blot analysis of single BSE isolates has not shown evidence of the presence of a proportion of monoglycosylated dominant PrPSc type in addition to the diglycosylated dominant pattern (data not shown). Extensive strain typing of large numbers of individual BSE-infected cattle either by biological or molecular methods has not been reported. Presumably, the different genetic background of the different inbred mouse lines is crucial in determining which prion strain propagates on BSE inoculation. The transgenic mice described here have a mixed genetic background with contributions from FVB/N, C57BL/6 and 129Sv inbred lines; each mouse will therefore have a different genetic background. This may explain the differing response of individual 129MM Tg35 mice, and the difference between 129MM Tg35 and 129MM Tg45 mice, which are, like all transgenic lines, populations derived from single founders. Indeed, the consistent distinctive strain propagation in FVB and C57BL/6 versus SJL and RIIIS lines may allow mapping of genes relevant to strain selection and propagation, and these studies progress. That different prion strains can be consistently isolated in different inbred mouse lines challenged with BSE prions argues that other species exposed to BSE may develop prion diseases that are not recognizable as being caused by the BSE strain by either biological or molecular strain typing methods. As with 129MM Tg35 mice, the prions replicating in such transmissions may be from naturally occurring prion strains. It remains of considerable concern whether BSE has transmitted to, and is being maintained in, European sheep ¯ocks. Given the diversity of sheep breeds affected by scrapie, it has to be considered that some sheep might have become infected with BSE, but propagated a distinctive strain type indistinguishable from those of natural sheep scrapie. ... The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002 6358 ãEuropean Molecular Biology Organization http://embojournal.npgjournals.com/cgi/reprint/21/23/6358 J Neuropsychiatry Clin Neurosci 17:489-495, November 2005 This study characterizes the type and timing of CONCLUSIONS Historically, psychiatric manifestations have been http://neuro.psychiatryonline.org/cgi/content/abstract/17/4/489 Personal Communication -------- Original Message -------- Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge. Variant Creutzfeldt-Jakob disease (vCJD) is a unique clinicopathological and molecular phenotype of human associated with infection with bovine spongiform prions. Here, we found that generation of this required expression of human prion protein (PrP) with Expression of human PrP with valine 129 resulted in a remarkably, persistence of a barrier to transmission of subpassage. Polymorphic residue 129 of human PrP distinct prion strains after BSE prion infection. Thus, human infection with BSE-derived prions may result in novel phenotypes in addition to vCJD, depending on the source and the recipient. snip... 3 DECEMBER 2004 VOL 306 SCIENCE http://www.sciencemag.org derived from bovine spongiform encephalopathy transmissions to inbred mice ...........snip............end..............TSS TSS
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