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Mortality from Creutzfeldt–Jakob disease and related disorders in Europe, Australia, and Canada A. Ladogana, MD; M. Puopolo, DStat; E.A. Croes, MD, PhD; H. Budka, MD; C. Jarius, MD; S. Collins, MD, FRACP; G.M. Klug, BSc(Hons); T. Sutcliffe, BA; A. Giulivi, MD, FRCP; A. Alperovitch, MD; N. Delasnerie-Laupretre, MD; J.-P. Brandel, MD; S. Poser, MD; H. Kretzschmar, MD, FRCPath; I. Rietveld, MD; E. Mitrova, MD; J. de Pedro Cuesta, MD, PhD; P. Martinez-Martin, MD, PhD; M. Glatzel, MD; A. Aguzzi, MD, PhD; R. Knight, FRCP(Ed); H. Ward, MRCP, FFPH; M. Pocchiari, MD; C.M. van Duijn, PhD; R.G. Will, MD, FRCP; and I. Zerr, MD Abstract—Background: An international study of the epidemiologic characteristics of Creutzfeldt–Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. Methods: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. Results: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. Conclusions: This study has established overall epidemiologic characteristics for Creutzfeldt–Jakob disease (CJD) of all types in a multinational population–based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases. NEUROLOGY 2005;64:1586–1591 Creutzfeldt–Jakob disease (CJD) is one of the transmissible spongiform encephalopathies (TSEs), or prion diseases, which include the animal diseases scrapie and bovine spongiform encephalopathy (BSE). CJD occurs in a number of distinct etiologic subtypes.1 Sporadic CJD (sCJD) occurs worldwide and is of unknown etiology. Genetic forms of human TSE (gTSE), including genetic CJD, Gerstmann– Stra¨ussler–Scheinker syndrome (GSS), and fatal familial insomnia (FFI), are linked to mutations of the prion protein gene (PRNP) (although whether the mutations are causal remains uncertain). Iatrogenic CJD (iCJD) is caused by the transmission of infection from person to person in the course of medical treatment, for example, cadaveric human pituitary growth hormone and human dura mater grafts. Vari- Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article. From the Istituto Superiore di Sanità (Drs. Ladogana, Puopolo, and Pocchiari), Department of Cell Biology and Neurosciences–ISS, Rome, Italy; Department of Epidemiology and Biostatistics (Drs. Croes, Rietveld, and van Duijn), Erasmus Medical College, Rotterdam, the Netherlands; Austrian Reference Centre for Human Prion Diseases (OERPE) and Institute of Neurology (Drs. Budka and Jarius), Vienna, Austria; Australian National CJD Registry (Dr. Collins and G.M. Klug), Department of Pathology, University of Melbourne, Victoria, Australia; Blood Safety Surveillance and Health Care Acquired Infections Division (Dr. Giulivi and T. Sutcliffe), Centre for Infectious Disease Prevention and Control, Ottawa, Ontario, Canada; U.360 INSERM (Drs. Alperovitch, Delasnerie- Laupretre, and Brandel), Hopital de la Salpetriere, Paris, France; Department of Neurology (Drs. Poser and Zerr), Georg-August-Universität Göttingen, Germany; Institute of Neuropathology (Dr. Kretzschmar), University of Munich, Germany; Institute of Preventative and Clinical Medicine (Dr. Mitrova), National Reference Centre of Slow Virus Neuroinfections, Bratislava, Slovakia; Instituto de Salud Carlos III (Drs. de Pedro Cuesta and Martinez-Martin), Departamento de Epidemiologia Aplicada, Centro Nacional de Epidemiologia, Madrid, Spain; Swiss National Reference Centre for Prion Diseases (Drs. Glatzel and Aguzzi), University Hospital of Zurich, Switzerland; and National CJD Surveillance Unit (Drs. Knight, Ward, and Will), Western General Hospital, Edinburgh, UK. Funded through an EU Concerted Action (BIOMED2 contract no. BMH4-CT97-2216). The Australian National CJD Registry is funded by the Commonwealth Department of Health and Ageing. The Canadian Surveillance System is funded by Health Canada. The German Surveillance System is funded by the Federal Ministry of Health (BMG, 325-4471-02/15). The surveillance of CJD in Italy is funded by the Ministry of Health and the Istituto Superiore di Sanità. CJD surveillance in the Netherlands is funded by the Dutch Ministry of Health, Welfare, and Sports. The Slovak Surveillance System is funded by the Slovak Ministry of Health. The Swiss Reference Center for Prion Diseases is funded by the Swiss Federal Office of Public Health. The UK CJD Surveillance System is funded by the Department of Health and the Scottish Executive Health Department. Also supported by the Kanton of Zurich and by grants from the European Union. Received February 27, 2004. Accepted in final form January 17, 2005. Address correspondence and reprint requests to Dr. R.G. Will, National CJD Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, UK; e-mail: r.g.will@ed.ac.uk 1586 Copyright © 2005 by AAN Enterprises, Inc. ant CJD (vCJD) is a novel form of human TSE, which has been linked to transmission of BSE to the human population.2 The probability that vCJD represents the first zoonotic transmission of a TSE to the human population has political, economic, and social implications, not least because of the potential threat to public health in the United Kingdom and other countries. In 1993, a system was established to coordinate the epidemiologic surveillance in a number of European countries with the primary aim of identifying any change in the characteristics of CJD that might be attributable to the BSE epidemic.3 In 1996, a new form of CJD, vCJD, was identified in the UK, and the hypothesis that this disease might be causally linked to BSE exposure has been supported by subsequent evidence.4,5 The occurrence of a new form of CJD in one country, the United Kingdom, and not, initially, in other countries with similar surveillance methodologies was an important component of the argument in favor of a link with BSE, and this depended on the systematic study of the incidence and case characteristics of CJD of all types in participating countries. This article reviews the data from the European, Australian, and Canadian CJD surveillance systems from 1993 to 2002 and addresses a number of important questions: What is the distribution of CJD by etiologic subtype, and does this vary by country? Is the pattern of occurrence of vCJD consistent with a link with BSE? Does analysis of the temporal trends in the characteristics of sCJD, including intercountry comparisons, suggest a change in the characteristics of sCJD that may be linked to BSE? Methods. The European Union collaborative study of CJD was carried out from 1993 to 2002 by France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. National Creutzfeldt–Jakob disease registry surveillance methods for these participating countries have been reported in detail previously.3 In 1997, the study was enlarged to other European and non- European countries where similar registers and surveillance methods were set up: Australia in 1993, Austria, Spain, and Switzerland in 1996, and Canada in 1998. The aim was to monitor CJD and the occurrence of vCJD in Europe and in countries where exposure to BSE is likely to have been minimal. The annual mortality rates and the standardized mortality ratios (SMRs) were calculated using data collected from 1999 to 2002 when the surveillance system was well established in all countries. Cases were classified according to shared diagnostic criteria3 updated from January 1998 with the introduction of the 14-3-3 CSF test.6 Cases classified as definite (neuropathologically confirmed) or probable that died between January 1, 1993, and December 31, 2002, have been included in the analyses. For each case, a data set including diagnostic classification, etiologic subtype, year of diagnosis, age at onset and death, results of investigations, and, when available, PRNP analysis and the brain prion protein type were established using standard methods.7 The data set was checked for accuracy and consistency by all participants. Statistical analysis. Crude and age- and sex-specific incidences or mortality rates were calculated using as denominator population data for 1998 provided from the national or federal statistics bureau of participating countries. For Canada, population data (2001) were taken from the Canadian Statistics Web site. Six age-interval classes (10 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80) were defined for the analyses. Differences in mortality from sCJD and gTSE among the countries were assessed by calculation of the SMR based on the overall age- and sex-specific mortality rates for the period 1999 to 2002. SMRs with 95% CIs that did not include 1.0 were considered to be significant. The CIs were calculated under the assumption that the observed number of cases followed a Poisson distribution. Results. There were 4,441 deaths from CJD included in the study in the period 1993 to 2002. Of these 4,441 deaths, 66% of cases were classified as definite CJD and 34% as probable CJD. The overall proportion of cases classified as definite or probable did not change over time. The percentage of human TSE diseases with autopsy, EEG, measurement of 14-3-3 in the CSF, and PRNP analysis for the period 1999 to 2002 in each country is given in figure E-1 on the Neurology Web site (www.neurology.org). Postmortem examination was performed in 66% of all cases, ranging from 100% in Slovakia to 49% in Germany. In all countries, the EEG was available in the majority of patients except in Canada (7%). CSF 14-3-3 protein analysis was performed in 86% of all patients, ranging from 52% in Slovakia and Canada to 99.6% in Germany. PRNP analysis was carried out in 67%, ranging from 32% in Australia and the Netherlands to 97% in Slovakia. The large number of cases collected in the database and the accuracy in terms of etiologic classification allowed analysis of incidence and mortality rates according to the classification as gTSE, sCJD, iCJD, and vCJD. Eighty-four percent of cases were classified as sporadic, 10% as genetic (including genetic CJD, FFI, and GSS), 3% as iatrogenic, and 3% as vCJD. The number of cases by country according to the etiologic subtype is shown in table 1. The highest number of deaths from sCJD was reported in Germany (n 827), reflecting the largest population by country, whereas Slovakia reported only 18 deaths from sCJD. The number of genetic cases was highest in Italy, France, Germany, the United Kingdom, Spain, and Slovakia. The number of deaths due to iCJD varied markedly by country, with a peak of 82 cases in France and 33 in the United Kingdom related mainly to cases of CJD in human growth hormone recipients (n 105; human dura mater recipients: n 32; corneal graft recipient: n 1). There were no such cases in Slovakia, Austria, or Switzerland. vCJD cases were identified during this study period (1993 to 2002) only in the UK (n 121), France (n 6), and Canada (n 1). When the clinical subtypes were analyzed by year of death, apart from the yearly increase in the absolute number of deaths in each subtype related to new countries joining the study, the emergence of variant cases is the most striking feature (see table E-1). Analysis of the age at death in each etiologic subtype confirmed previous observations on differences in the age distribution between the four subtypes: The vCJD and iCJD cases were mainly in the age class younger than 39 years, the genetic forms mostly distributed between age groups 50 to 59 and 60 to 69, and sporadic cases predominantly in age groups 60 to 69 and 70 to 79 (see figure E-2). The overall yearly number of deaths from TSE (including all subtypes) ranged from 209 cases in 1993 to 621 in 2001 with an average yearly mortality rate of 1.67 cases per million for the period 1999 to 2002 (pooled data from all countries). The distribution of the etiologic subtypes is shown in an analysis of yearly mortality rates from CJD by European country (figure 1). The mortality rates from sCJD were relatively homogeneous, whereas high mortality rates from gTSE were reported in Austria, Italy, Slova- May (1 of 2) 2005 NEUROLOGY 64 1587 kia, and Spain and from iCJD in France (0.12 case per million) and United Kingdom (0.05). Moreover, it is clear that vCJD is predominantly a disease occurring in the United Kingdom (0.38). The distribution of genotypes at codon 129 of PRNP for all types of TSE is shown in table 2. Overall, about 68% of cases were methionine (M) homozygotes, with 67% of sCJD cases and 100% of vCJD cases exhibiting this genotype. In iCJD and GSS, the relative excess of methionine homozygotes was less marked, and in iCJD, the distribution of codon 129 genotypes was different between France (61% MM) and the UK (5% MM).8 There was no significant difference in the distribution of codon 129 genotypes by country in sCJD. sCJD. The SMRs and the 95% CI of SMRs for the countries in the study, for 1999 to 2002, are reported in table 3. In this period, France and Switzerland reported an observed number of deaths higher than expected (n 397 and 57), whereas Slovakia and the UK reported an observed number of deaths lower (n 9 and 241). The incidence and mortality rates for sCJD are similar because of the short mean duration of disease, and data are therefore presented in terms of mortality rates. The overall annual mortality rate from sCJD in the period 1999 to 2002 is 1.39 cases per million (pooled data from all countries). The rates in individual countries range from 0.48 in Slovakia to 2.23 in Switzerland, while most of the countries showed similar rates (figure 2A). Table 1 CJD in Europe, Australia, and Canada 1993–2002: Number of cases by clinical subtype and country Country Population, 10 y old Sporadic CJD Genetic TSE Iatrogenic CJD Variant CJD Total Total With PRNP analysis Australia 16,361,803 189 34 22 4 — 215 Austria*† 7,165,559 77 30 13 — — 90 Canada‡ 27,317,369 169 54 16 3 1 189 France 51,904,469 766 571 84 82 6 938 Germany 73,693,100 827 690 68 5 — 900 Italy 51,868,080 544 303 115 3 — 662 Netherlands 13,698,715 136 24 3 3 — 142 Slovakia 4,683,900 18 18 41 — — 59 Spain*† 35,488,954 380 96 44 5 — 429 Switzerland* 6,384,109 84 45 1 — — 85 UK 52,001,000 530 279 48 33 121 732 Total (%) 340,567,058 3,720 (83.8) 2,144 (57.6) 455 (10.2) 138 (3.1) 128 (2.9) 4,441 * Since 1996. † Including retrospective cases from 1993. ‡ Since 1998, including retrospective cases from 1994. CJD Creutzfeldt–Jakob disease; TSE transmissible spongiform encephalopathy. Figure 1. Yearly mortality rates from human transmissible spongiform encephalopathy (TSE) in Europe by clinical subtype (1999 to 2002). CJD Creutzfeldt–Jakob disease. Table 2 Codon 129 distribution by disease type Human TSE Codon 129 polymorphism, % Total Met/Met Met/Val Val/Val Sporadic CJD 67.2 16.4 16.5 2,339 Genetic CJD 69.4 23.8 6.8 294 FFI 71.4 28.6 — 63 GSS 51.6 32.3 16.1 31 Iatrogenic CJD 54.0 26.5 19.5 113 Variant CJD 100 — — 119 Total 68.1 17.3 14.6 2,959 CJD Creutzfeldt–Jakob disease; FFI fatal familial insomnia; GSS Gerstmann–Stra¨ussler–Scheinker syndrome. Met methionine; Val valine. 1588 NEUROLOGY 64 May (1 of 2) 2005 Data on age at death and sex were available in 3,716 patients with sCJD, and the age- and sex-specific rates are shown in figure E-3A. The distribution of the yearly ageand gender-specific mortality rates for sCJD showed a low rate in the under-50 age group, a peak in mortality in the 60 to 79 age group, and a decline in the 80 and older age group. This observation is consistent between countries. A slightly higher rate of deaths among men was observed for patients ages 70. The age distribution of cases was similar in all countries, with the exception of a peak mortality in the 60 to 69 age group in Slovakia. Analysis of pooled data from Australia, Austria, France, Germany, Italy, the Netherlands, Slovakia, Spain, and the United Kingdom for the three time periods (1993 to 1995, 1996 to 1998, and 1999 to 2002) showed mortality rates from sCJD increasing with the time in all age groups, most prominently in patients over age 60 (see figure E-4). The distribution of codon 129 genotypes in sCJD by year of death is shown in figure E-5. The distribution with time shows an overall slight decrease in the proportion of cases of sCJD with an MM genotype (2 test for linear trend, p 0.01). Prion protein type is available in 865 (23%) cases of sCJD. Combining the two prion protein types (type 1 or type 2A) and the three codon 129 genotypes allows cases of sCJD to be classified into six subgroups, with the MM/type 1 cases representing the majority of cases (see table E-2) of clinically "typical" sCJD. About 6% of cases have both type 1 and type 2A in the brain. Eighty-eight percent of MM cases are associated with PrPSc type 1, whereas 82% of valine/valine (VV) and 62% of MV cases are PrPSc type 2A (2 test, p 0.0001). Table E-3 shows the number of MM/type 1 and MV/type 2 sCJD cases in the four countries with available information. We did not observe any significant (after Bonferroni correction for multiple testing) temporal trend for patients with MM/type 1 sCJD (2 test for linear trend, France, p 0.03; Germany, p 0.12; Italy, p 0.27; UK, p 0.91) or MV/type 2 (France, p 0.02; Germany, p 0.08; Italy, p 0.32; UK, p 0.75). gTSE. The SMRs and the 95% CIs of SMRs for gTSE in 1999 to 2002 are reported in table 3. In Italy (n 62) and Slovakia (n 20), there was a relative excess of genetic cases, whereas in Germany, the Netherlands, and the United Kingdom, there was a relatively low number. The overall annual mortality rate in the period 1999 to 2002 for gTSE is 0.17 case per million. However, the analysis of the incidence and mortality rates for gTSE by countries showed marked differences (see figure 2B). The yearly mortality rates in individual countries ranged from 0.02 in the Netherlands (1999 to 2002) to 1.07 in Slovakia (1999 to 2002). Data on age at death and sex were available in 455 patients with gTSE, and the age- and sexspecific rates overall (pooled data from all countries) are shown in figure E-3B. The distribution of the yearly ageand gender-specific mortality rates was different from that Table 3 SMRs and 95% CIs of sporadic Creutzfeldt–Jakob disease and genetic TSE in Europe, Australia, and Canada, 1999–2002 Country Sporadic Genetic TSE SMR 95% CI SMR 95% CI Australia 1.11 0.89–1.37 0.85 0.39–1.61 Austria 0.80 0.54–1.13 1.59 0.69–3.14 Canada 0.87 0.72–1.04 0.71 0.38–1.22 France 1.34* 1 1.21–1.47* 1.00 0.71–1.38 Germany 0.93 0.84–1.03 0.69* 2 0.49–0.95* Italy 0.95 0.84–1.06 1.60* 1 1.23–2.05* Netherlands 0.82 0.62–1.07 0.11* 2 0.00–0.60* Slovakia 0.44* 2 0.20–0.83* 6.84* 1 4.18–10.56* Spain 1.03 0.89–1.18 1.30 0.89–1.84 Switzerland 1.61* 1 1.22–2.08* 0.22 0.01–1.21 UK 0.83* 2 0.73–0.94* 0.41* 2 0.23–0.67* * Significant increase (1) or decrease (2) in mortality rates with respect to the estimates for overall Europe. SMR standardized mortality ratio; TSE transmissible spongiform encephalopathy. Figure 2. Yearly mortality rates from sporadic Creutzfeldt–Jakob disease (CJD) (A) and genetic transmissible spongiform encephalopathy (TSE) (B) by country (1999 to 2002). May (1 of 2) 2005 NEUROLOGY 64 1589 of sCJD cases, with higher rates in the 50 to 59 and 60 to 69 age groups and a decline in the over-70 age groups. A slightly higher rate of deaths among women was observed. There was no increase in mortality from gTSE over the 10-year period in any of the age groups under examination (data not shown). Discussion. This is the largest systematic prospective survey of CJD ever carried out, including detailed information in 3,700 cases of sCJD and 4,400 cases in total. The proportion of cases by etiologic subtype is similar to previous studies3,9,10 with 80% of cases classified as sporadic, but there is marked variation in the incidence of gTSE, iCJD, and vCJD between countries. Overall, there is evidence of an increase in mortality of sCJD with time, but this is not specific to any particular country or countries, and no new subtype of CJD, other than vCJD, has been identified. Any surveillance system depends on a high-level ascertainment to allow meaningful results and for intercountry comparisons to be valid. The efficiency of case identification and data collection should be similar in all participating countries. There is variation in the provision of health care in the countries in our study, for example, in the number of neurologists per country11 and in postmortem rates. However, there is a general consistency in the mortality rates for sCJD in this study between participating countries. Furthermore, the increasing temporal trends in mortality and the changes in the agespecific incidence rates are also very similar between countries, arguing that the efficiency of case ascertainment is similar despite the variations in health care systems and resources available to individual centers. Complete data sets were available for nearly all cases included in this study, and there was a high rate of data consistency, requiring only minor amendments to the original data set. The proportion of cases undergoing postmortem examination was high, at about two-thirds of all cases. PRNP analysis was available in 60% of cases; although there was variation in the proportion of tested cases ranging from 32% in Australia to 97% in Slovakia, in the majority of countries, the proportions tested were comparable (see figure E-1). Although there are uncertainties about the efficiency of case finding of CJD across time and the age range, for example, in the first years of the study and in the elderly, the data in this article suggest that surveillance for all types of CJD has been carried out efficiently and that intercountry comparisons are likely to be valid. One notable finding is the marked variation in the incidence of etiologic subtypes by country with an excess of iatrogenic cases in France and the United Kingdom and an excess of genetic cases in Italy and Slovakia. The great majority of cases of iCJD in this study are related to human growth hormone treatment, and the reason for the excess of cases in particular countries suggests that the treated populations in these countries were exposed to a higher level of infection. It is of note that in France and the UK, human growth hormone was produced locally, whereas in other countries, commercially produced human growth hormone was mainly used.12 Cases of gTSE were found in all participating countries, indicating that the risk of gTSE is widespread, although the excess of gTSE cases in particular countries indicates that this risk is not homogeneous. The variation in mortality rates for gTSEs by country is not directly related to differences in the proportion of cases with available PRNP analysis (see table 1) and is therefore likely to be a real observation. Codon 200 mutations account for about 50% of all PRNP mutations in this series, have been identified in all participating countries, and represent the majority of mutations found in France (55%) and Slovakia (100%) but not in Italy (32%) and Spain (33%). The worldwide dissemination of the codon 200 mutation has previously been studied, with haplotype analysis suggesting a link between the Italian and Spanish families, but no link between families in Slovakia, Germany, and Austria.13 The possibility of genetic isolation and/or consanguinity may explain the high incidence of gTSE in Slovakia14 and perhaps in some Italian cases.15 Previous work from the EuroCJD Group has shown that a family history of a similar disorder is found in only about one-third of all mutation-related cases.16 The widespread geographic occurrence of a range of PRNP mutations may relate to spontaneous mutations in PRNP, similar to those that have previously been identified in association with mutations at codon 178 of PRNP.17 Analysis of SMRs for sCJD by country indicates some variation with time (data not shown). This may represent a variation about a mean; for example, in Austria, a high SMR for sCJD in the period 1993 to 1995 (1.58) was not sustained in subsequent years. There is a possibility that the fluctuations in mortality from sCJD may explain the high incidence of sCJD identified in Switzerland,18 but other explanations must be considered, including a locally efficient surveillance system and underreporting in other countries. This hypothesis has been judged to be implausible in view of the similarities between Switzerland and other countries such as Austria, in which there is no equivalent rise in mortality rates, despite similar population, age structure, and quality of health care. Furthermore, the proportion of cases with results of specialist investigations in Switzerland (see figure E-1) is similar to that in other countries and lower than in Austria. However, the possibility that the variation in mortality rates for sCJD between countries is related to differences in the efficiency of case identification or classification cannot be excluded. It is clear from our study that vCJD occurs predominantly in the United Kingdom with a smaller number of cases in France during the study period, probably linked to a proportionally lower human exposure to BSE.19 The single vCJD case in Canada most likely occurred as a consequence of exposure in the United Kingdom. The hypothesis that improved 1590 NEUROLOGY 64 May (1 of 2) 2005 identification of atypical cases of CJD, rather than BSE, may explain the occurrence of vCJD20 is not supported by our data. Despite evidence of efficient surveillance for all forms of CJD in participating countries, vCJD was not identified during the study period in a population of 300 million over 4 to 7 years. Single cases of vCJD have subsequently been identified in Italy21 and the USA,22 but not in the other countries in the surveillance system. Furthermore, the cases in the USA and Canada had a history of extended residence in the UK during the period when human BSE exposure was maximal, a striking coincidence if these cases had been identified solely as a result of improved case identification. Overall, there has been an increase in mortality from sCJD with time, and it is not possible to be certain whether this is related to improved efficiency of the surveillance system with time or some other cause such as a new environmental source of infection. However, the increased mortality is related mainly to increasingly mortality rates in the elderly, rather than the younger age groups, and the changes in mortality have been found in all participating countries, including Australia and Canada, in which indigenous BSE exposure is likely to have been negligible. This argues against the possibility that the rise in mortality may be related to BSE infection in humans, resulting in a phenotype indistinguishable from sCJD. Further analyses of trends in subtypes of sCJD do not support the hypothesis that BSE infection might result in an increase in the MM/type 1 subtype of sCJD23 or an increase in the MV/type 2 subtype in relation to a novel form of BSE.24 The proportion of all cases of sCJD with an MM genotype has decreased, if anything, during the period of the study; although data are available in only a minority of cases, there has also been a decrease overall in the proportion of cases with an MM genotype and type 1 prion protein deposition in the brain. If BSE were to result in a novel phenotype of sCJD, this is most likely to occur first and to a greater extent in the United Kingdom than in other countries. The analyses in this study do not suggest a change in the characteristics of sCJD in the United Kingdom compared with other countries. Although the phenotype of BSE infection in individuals with an MV or VV background cannot be predicted, to date there is no evidence of a novel phenotype of sCJD in Europe related to BSE infection. Acknowledgment The authors thank the following for their assistance and participation: in Australia, C.L. Masters, A. Boyd, V. Lewis, and J. Lee; in Austria, Drs. Christa Jarius, Ellen Gelpi, Christine Haberler, Thomas Ströbel, and Till Voigtländer, and Dita Drobna, Helga Flicker, Brigitte Millan-Ruiz, and Monika Richter; in Canada, Drs. C. Bergeron, M. Coulthart, N. Cashman, and D. Westaway; in France, reporting physicians and members of the Reseau National de surveillance de maladies de Creutzfeldt–Jakob et maladies apparentees; in Germany, reporting physicians, Maja Schneider-Dominico for help in coordination of surveillance, and Drs. Otto Windl and Walter Sculz-Schaeffer; in Italy, S. Almonti, V. Mellina, and L. Ingrosso for advice and help with data collection; in the Netherlands, colleagues at the Department of Neurology at the Academic Medical Centre, Amsterdam and the Department of Pathology at the University Medical Centre, Utrecht; in Spain, reporting physicians and members of the Spanish TSE study group at Consejo Interterritorial and co-workers at CNE and ISCIII; in the UK, the staff at the National CJD Surveillance Unit, James Ironside for neuropathologic expertise, and clinicians for their cooperation with the study. References 1. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998;95:13363–13383. 2. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt– Jakob disease in the UK. Lancet 1996;347:921–925. 3. Will RG, Alperovitch A, Poser S, et al. Descriptive epidemiology of Creutzfeldt–Jakob disease in six European countries, 1993–1995. Ann Neurol 1998;43:763–767. 4. Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that "new variant" CJD is caused by the BSE agent. Nature 1997;389: 498–501. 5. Scott MR, Will RG, Ironside J, et al. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci USA 1999;96:15137–15142. 6. World Health Organisation. WHO manual for strengthening diagnosis and surveillance of Creutzfeldt–Jakob disease. Geneva: WHO, 1998:1– 75. 7. Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224–233. 8. Brandel J-P, Preece M, Brown P, et al. A. Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK. Lancet 2003;362:128–130. 9. Brown P, Cathala F, Gajdusek DC. Creutzfeldt–Jakob disease in France: III. Epidemiological study of 170 patients dying during the decade 1968–1977. Ann Neurol 1979;6:438–446. 10. Will RG, Matthews WB. A retrospective study of Creutzfeldt–Jakob disease in England and Wales 1970–79 I: clinical features. J Neurol Neurosurg Psychiatry 1984;47:134–140. 11. Kmietowicz Z. United Kingdom needs to double the number of neurologists. Br Med J 2001;322:1508. 12. Will RG, Alpers MP, Dormont D, et al. Infectious and sporadic prion diseases. In: Prusiner SB, ed. Prion biology and diseases. New York: Cold Spring Harbor Laboratory Press, 1999:465–507. 13. Lee H-S, Sambuughin N, Cervenakova L, et al. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt–Jakob disease. Am J Hum Genet 1999;64:1063–1070. 14. Mitrova E, Bronis M. "Clusters" of CJD in Slovakia: the first statistically significant temporo-spatial accumulations of rural cases. Eur J Epidemiol 1991;7:450–456. 15. D’Alessandro M, Petraroli R, Ladogana A, et al. High incidence of Creutzfeldt–Jakob disease in rural Calabria, Italy. Lancet 1998;352: 1989–1990. 16. Euro-CJD Group. Genetic epidemiology of Creutzfeldt–Jakob disease in Europe. Rev Neurol (Paris) 2001;157:633–637. 17. Dagvadori A, Petersen RB, Lee H-S, et al. Spontaneous mutations in the prion protein gene causing transmissible spongiform encephalopathy. Ann Neurol 2002;53:355–359. 18. Glatzel M, Rogivue C, Ghani A, et al. Incidence of Creutzfeldt–Jakob disease in Switzerland. Lancet 2002;360:139–141. 19. Alperovitch A, Will RG. Predicting the size of the vCJD epidemic in France. CR Biol 2002;325:33–36. 20. Venters GA. New variant Creutzfeldt–Jakob disease: the epidemic that never was. Br Med J 2001;323:858–861. 21. La Bella V, Collinge J, Pocchiari M, et al. Variant Creutzfeldt–Jakob disease in an Italian woman. Lancet 2002;360:997–998. 22. Wiersma S, Cooper S, Knight R, et al. Probable variant Creutzfeldt– Jakob disease in a US resident—Florida 2002. MMWR 2002;51:927– 929. 23. Asante EA, Linehan JM, Desbruslais M, et al. BSE prions propagate as either variant CJD or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 2002;21:6358–6366. 24. Casalone C, Zanusso G, Acutis P. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt–Jakob disease. Proc Natl Acad Sci USA 2004;101: 3065–3070. May (1 of 2) 2005 NEUROLOGY 64 1591 ============================== Greetings, THE sporadic CJD rates in Germany, France, and Italy are phenomenal. WITH the new BASE in cattle in Italy, the TSE in cattle that is NOT similar to nvCJD (vCJD), but very similar to some of the sporadic CJDs, might just explain this. also, with the FRENCH scrapie strain that was very similar to a FRENCH sporadic CJD case, again, shows just how important some of those old studies were, and why they should not have been ignored... >>>Overall, there has been an increase in mortality from sCJD with time, and it is not possible to be certain whether this is related to improved efficiency of the surveillance system with time or some other cause such as a new environmental source of infection. However, the increased mortality is related mainly to increasingly mortality rates in the elderly, rather than the younger age groups, and the changes in mortality have been found in all participating countries, including Australia and Canada, in which indigenous BSE exposure is likely to have been negligible. This argues against the possibility that the rise in mortality may be related to BSE infection in humans, resulting in a phenotype indistinguishable from sCJD. Further analyses of trends in subtypes of sCJD do not support the hypothesis that BSE infection might result in an increase in the MM/type 1 subtype of sCJD23 or an increase in the MV/type 2 subtype in relation to a novel form of BSE.24 The proportion of all cases of sCJD with an MM genotype has decreased, if anything, during the period of the study; although data are available in only a minority of cases, there has also been a decrease overall in the proportion of cases with an MM genotype and type 1 prion protein deposition in the brain. If BSE were to result in a novel phenotype of sCJD, this is most likely to occur first and to a greater extent in the United Kingdom than in other countries. The analyses in this study do not suggest a change in the characteristics of sCJD in the United Kingdom compared with other countries. Although the phenotype of BSE infection in individuals with an MV or VV background cannot be predicted, to date there is no evidence of a novel phenotype of sCJD in Europe related to BSE infection. <<< SADLY, the cjd surveillance in the USA is as poorly designed and supported as the USA BSE surveillance in cattle. more designed not to find it as the june 2004 enhanced USA BSE cover-up was, except USDA et al could not even get that right. with a USA cjd surveillance in only 35 or so states, and in some of those states only under 55, shows that the old dying of sCJD (which by the way could include nvCJD, the oldest to date was 74 years old), and with the very young dying of sporadic CJD in the USA, with a system such as this, they just don't care about the old, even if it did include any atypical phenotype of TSE in the old. and the lack of a WRITTEN cjd questionnaire, gives more credence to a cover-up. anytime someone wants to speak with me over the phone as opposed to email, a flag automatically goes up, same with this PHONE CALL only cjd questionnaire for the USA CJD surveillance unit. as someone so nicely called it 'THE BIG BROTHER APPROACH'. with the finding of UK BSE in Canada and the USA, with the findings in Mission Texas that indeed USA scrapie to cattle DOES NOT mimic UK BSE, but a very different strain, with cwd rampant, scrapie rampant, all rendered and fed back to humans and animals for decades. why would North American human TSE typically look like UK nvCJD (vCJD)? WHY the increase of sporadic CJD in countries with atypical TSEs in animals consumed for human consumption? what would iCJD from some of these atypical TSEs look like via the medical arena on 2nd or 3rd passage? why did the USA NOT participate in this study?WHY IS THE TRIPLE SSS POLICY of shoot, shovel and shut the hell up ALIVE AND WELL IN TEXAS??? Medical Sciences 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 Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003 (received for review 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. C.C. and G.Z. contributed equally to this work. ||To whom correspondence should be addressed. E-mail: salvatore.monaco@mail.univr.it. www.pnas.org/cgi/doi/10.1073/pnas.0305777101 http://www.pnas.org/cgi/content/abstract/0305777101v1 Adaptation of the bovine spongiform encephalopathy agent to primates THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger ] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible http://www.pnas.org/cgi/content/full/041490898v1 Characterization of two distinct prion strains http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471 -------- Original Message -------- Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD Date: Thu, 28 Nov 2002 10:23:43 -0000 From: "Asante, Emmanuel A" To: Dear Terry, I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention. Thank you for your interest in the paper. In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc. I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask. Best wishes. Emmanuel Asante <> ____________________________________ Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02) New e-mail: e.asante@prion.ucl.ac.uk (active from now) ____________________________________ snip... full text ; http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm 1: J Infect Dis 1980 Aug;142(2):205-8 Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC. Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation. PMID: 6997404 snip... A The Present Position with respect to Scrapie Scrapie is a natural disease of sheep and goats. It is a slow The field problem has been reviewed by a MAFF working group It is clear that scrapie in sheep is important commercially and Recently the question has again been brought up as to whether Whether true or not. the hypothesis that these agents might be snip... 76/10.12/4.6 http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf http://www.bseinquiry.gov.uk/files/yb/1976/10/12002001.pdf CJD CASE 1977 ? (notes) http://www.bseinquiry.gov.uk/files/yb/1977/00/00002001.pdf in the USA, a 16 year old in 1978; (20 year old died from sCJD in USA in 1980 and a 16 year in France, a 19 year old in 1982; in Canada, a 14 year old of UK origin in 1988; in Poland, cases in people aged 19, 23, and 27 were identified in
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