Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999–2008 (WARNING TO Neurosurgeons and Ophthalmologists)
Volume 15, Number 2–February 2009 Research
Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999–2008
Tsuyoshi Hamaguchi, Moeko Noguchi-Shinohara, Ichiro Nozaki, Yosikazu Nakamura, Takeshi Sato, Tetsuyuki Kitamoto, Hidehiro Mizusawa, and Masahito Yamada Author affiliations: Kanazawa University Graduate School of Medical Science, Kanazawa, Japan (T. Hamaguchi, M. Noguchi-Shinohara, I. Nozaki, M. Yamada); Jichi Medical University, Shimotsuke, Japan (Y. Nakamura); Kohnodai Hospital, Ichikawa, Japan (T. Sato); Tohoku University Graduate School of Medicine, Sendai, Japan (T. Kitamoto); Tokyo Medical and Dental University, Tokyo, Japan (H. Mizusawa); and Creutzfeldt-Jakob Disease Surveillance Committee, Japan (Y. Nakamura, T. Sato, J. Mizusawa, T. Kitamoto, M. Yamada)
Suggested citation for this article
Abstract To elucidate the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), we analyzed medical procedures (any surgical procedure, neurosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan during 1999–2008. We conducted an age-stratified case–control study with 753 sCJD patients and 210 controls and a study of patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. Although the control group was relatively small, no evidence was found that prion disease was transmitted through the investigated medical procedures before onset of sCJD. After onset of sCJD, 4.5% of the sCJD patients underwent operations, including neurosurgical for 0.8% and ophthalmic for 1.9%; no special precautions against transmission of prion diseases were taken. Fortunately, we have not identified patients with prion disease attributed to these operations. Our findings indicate that surgical procedures or blood transfusion had little effect on the incidence of sCJD.
snip...
Discussion In this case–control study, we found no evidence of increased sCJD risk associated with patient's history of surgical procedures or blood transfusions. In the previous case–control study and in our study, receipt of a blood transfusion was not shown to be a significant risk for CJD (2–10). However, whether surgical procedures contribute to the risk for sCJD has been controversial. Our results, in which any operation was not a significant risk for sCJD, were consistent with results of 2 previous large case–control studies (8,9) and a reanalysis of results of 3 case–control studies (10). Even in the studies with positive results, some different results were provided when the surgical procedures were categorized by affected organ. One previous case–control study indicated significant risk for sCJD after neurosurgical procedures (3), but no significant risk was shown in other studies (5,6,8–10). Ophthalmic surgery was reported as causing significant risk for sCJD in a case–control study in Australia (4) but not in other studies (5,6–10). In a recent study in the United Kingdom (6), the increased risk associated with having undergone surgical procedures was restricted to the category "other surgery," which included such procedures as sutures to skin, and the association largely disappeared when the whole of the other-surgery category was excluded. These different results may show little possibility for transmission of infectious PrP through surgical procedures, although we cannot exclude the possibility that such transmission occurs occasionally because iatrogenic CJD exists.
The conflicting results in case–control studies, including ours, may be explained by differences in the area, race, period in which studies were performed, number of patients, and methods as discussed below. Our study, which attempted to determine when medical procedures were associated with an increased risk for sCJD, had the largest number of sCJD patients in case–control studies to date. The relatively small number of controls is a potential limitation. In case–control studies, methods of obtaining data from controls should be the same as those from patients. In our study, patients in the groups "prion diseases definitely denied" or "prion diseases probably denied" in our CJD surveillance, who had no or little possibility of having prion disease, were used as the controls. Therefore, data from controls could be collected at the same level of precision as those from the sCJD cases. Because the ages of the sCJD patients and controls were significantly different, age-stratified analysis was required in our study. A recent study reported that some methodologic differences might partially explain conflicting data regarding the association between surgical procedures and CJD (17). The report suggested that the use of controls from the community would be preferable to using those from the hospital because community-based controls are often more representative and would result in a more valid comparison (17). Furthermore, using proxy informants for controls may be advisable for the purpose of comparability with case-patients, although this practice does not necessarily offset biases in data ascertainment (17). In our case–control study, we used proxy informants for controls who were recruited from hospitals under the same condition as the sCJD case-patients.
Regarding the 5 sCJD patients with a history of neurosurgical or ophthalmic surgical procedures at hospitals where other patients with prion disease had previously undergone such procedures, we consider that the possibility of transmission through these procedures was extremely limited because the intervals between procedures and the acquisition of sCJD had been >3 years for all patients. According to the Incident Panel in the United Kingdom, most instruments that have gone through 10 cycles of use and decontamination are unlikely to pose a substantial risk (15). We assume that all instruments had gone through >10 cycles of use during the 3-year interval, and almost no infectivity remained on the instruments. In Japan, a large number of dCJD patients have been recognized with no other types of iatrogenic CJD (11,12); this study confirmed that no surgically transmitted cases occurred among patients with sCJD.
It is noteworthy that 4.5% of the sCJD patients underwent some types of surgical procedures after the disease onset, including neurosurgical (0.8%) and ophthalmic procedures (1.8%). Through surgical instruments, neurosurgical operations may transmit high infectivity from the brain tissues of sCJD patients, and ophthalmic operations may transmit moderate infectivity of the eye tissues in cases of cataracts (15). In this study, all these neurosurgical and ophthalmic procedures were performed without suspicion of prion diseases or special precautions to reduce the risk for secondary transmission of prion infection through the instruments. These findings suggest that delayed diagnosis of sCJD would be linked to increased risk for secondary transmission of prion diseases through surgical instruments. In neurosurgical procedures, the symptoms of sCJD were misdiagnosed as those of other neurologic diseases, and operations were performed near the time of disease onset. In terms of ophthalmic surgery, all patients underwent operations for cataracts, and 7 (50%) of 14 patients had visual disturbances as an initial symptom of sCJD. These data are similar to those in a report from the United Kingdom (18). Visual disturbances might prompt ophthalmic surgery. More seriously, 3 patients underwent operations >8 months after sCJD onset. In this study, all surgeons who provided information reused the surgical instruments with incomplete sterilization, and the potential for infection was the same as in our previous study of ophthalmic surgery (19).
Neurosurgeons and ophthalmologists should become better informed about prion diseases and the necessity of using disposable instruments whenever possible. Furthermore, a more sensitive method for early diagnosis of sCJD is needed because clinical diagnosis is sometimes difficult, particularly in atypical sCJD cases, such as MM2, MV2, VV1, or VV2 types (20–23), according to 6 phenotypes of sCJD divided by codon 129 polymorphisms of PrP (methionine/valine) and type of infectious PrP by Western blotting (24). Even neurologists may misdiagnose the initial stage of the atypical sCJD cases as being another neurodegenrative disease such as Alzheimer disease and progressive supranuclear palsy (20). Moreover, patients who have undergone surgical procedures with possibly contaminated instruments need to undergo a risk assessment with long-term follow-up after careful ethical consideration. Since June 2004, we have identified and monitored all patients who underwent neurosurgical procedures with possibly contaminated instruments, CJD has developed in none of those patients.
In conclusion, we did not demonstrate any evidence of increased risk for sCJD associated with a history of surgery or blood transfusion in the Japanese surveillance system. However, the fact that some patients had surgeries, including neurosurgery, even after the onset of sCJD indicates that we cannot deny any possibility of transmission of prion diseases by medical procedures. Neurosurgeons, ophthalmologists, and other surgeons need to focus more attention on prion diseases to reduce the iatrogenic risk, as well as realize that prolonged, careful surveillance of prion diseases is necessary.
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http://www.cdc.gov/eid/content/15/2/265.htm
Thursday, October 23, 2008 Creutzfeldt-Jakob Disease Associated with Cadaveric Dura Mater Grafts – Japan, 1979-2008 : UPDATE
http://creutzfeldt-jakob-disease.blogspot.com/2008/10/creutzfeldt-jakob-disease-associated.html
Wednesday, August 20, 2008 Tonometer disinfection practice in the United Kingdom: A national survey Eye (2008) 22, 1029–1033; doi:10.1038/sj.eye.6702831; published online 20 April 2007
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/tonometer-disinfection-practice-in.html
Tuesday, August 12, 2008 Biosafety in Microbiological and Biomedical Laboratories Fifth Edition 2007 (occupational exposure to prion diseases)
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/biosafety-in-microbiological-and.html
Saturday, July 26, 2008 Creutzfeldt-Jakob Disease in Recipients of Corneal Transplants Creutzfeldt-Jakob Disease in Recipients of Corneal Transplants.
Case Report
http://creutzfeldt-jakob-disease.blogspot.com/2008/07/creutzfeldt-jakob-disease-in-recipients.html
Monday, December 08, 2008 vCJD & dental treatment Advice
http://creutzfeldt-jakob-disease.blogspot.com/2008/12/vcjd-dental-treatment.html
Wednesday, January 14, 2009 6 acquitted in French trial over hormone deaths
14 Jan 2009, 1858 hrs IST, AP
http://creutzfeldt-jakob-disease.blogspot.com/2009/01/6-acquitted-in-french-trial-over.html
http://creutzfeldt-jakob-disease.blogspot.com/
Friday, October 24, 2008 CBER 2007 Annual Report Assessing the Potential Risk of variant Creutzfeldt-Jakob Disease from Blood Products
http://creutzfeldt-jakob-disease.blogspot.com/2008/10/cber-2007-annual-report-assessing.html
Saturday, August 02, 2008
WARNING OVER SECOND WAVE OF CJD CASES
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/warning-over-second-wave-of-cjd-cases.html
Thursday, April 17, 2008 Use of Materials Derived From Cattle in Human Food and Cosmetics [Docket No. 2004N-0081] RIN 0910-AF47 [Federal Register: April 17, 2008 (Volume 73, Number 75)] [Rules and Regulations] [Page 20785-20794] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr17ap08-7]
http://cjdmadcowbaseoct2007.blogspot.com/2008/04/use-of-materials-derived-from-cattle-in.html
Saturday, January 24, 2009 Bovine Spongiform Encephalopathy h-BSE ATYPICAL USA 2008 Annual Report Research Project: Study of Atypical Bse
Location: Virus and Prion Diseases of Livestock
2008 Annual Report
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
http://bse-atypical.blogspot.com/2009/01/bovine-spongiform-encephalopathy-h-bse.html
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
Saturday, January 24, 2009
Research Project: Detection of TSE Agents in Livestock, Wildlife, Agricultural Products, and the Environment Location: 2008 Annual Report
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
TSS
Wednesday, January 28, 2009 TAFS1 Position Paper on BSE in small ruminants (January 2009)
http://scrapie-usa.blogspot.com/2009/01/tafs1-position-paper-on-bse-in-small.html
The Diagnostic Utility of Brain Biopsy Procedures in Patients With Rapidly Deteriorating Neurological Conditions or Dementia
Josephson SA, Papanastassiou AM, Berger MS, et al. J Neurosurg. 2007;106:72–75. Josephson and colleagues1
Josephson and colleagues1 reviewed case records of all brain biopsy procedures at a tertiary care center in an effort to better characterize the diagnostic sensitivity of brain biopsy procedure for patients with rapidly worsening neurologic conditions, including dementia. Patients with HIV immunosuppression, and known nonlymphomatous tumors were excluded from analysis, resulting in a cohort of 171 identified patients. A surprisingly large number of these patients (n = 90, 53% of the initial cohort) were excluded from subsequent analysis because of the absence of “documentation of a complete history or neurological examination.” An additional 15 patients were excluded for other reasons, leaving 64 patients in the final analysis. The most common diagnoses made at biopsy are shown in Table 1. In the group of 10 patients found to have CJD (Table 1), the most common symptom categories included motor/pyramidal (90%), cognitive (80%), behavioral/psychiatric (80%), extrapyramidal (60%), and cerebellar (40%). Nine of the 10 patients had symptoms involving 2 of the first 3 groupings. Prominent individual symptoms included memory loss (50%), confusion/disorientation (50%), depression (40%), headache (40%), and sleep disturbances (40%). Cerebrospinal fluid (CSF) examination was performed in 8 of the 10 patients, and none had a CSF pleocytosis. Overlap of symptoms between patients with CJD and primary CNS lymphoma was high, and it was not clearly possible to separate these groups on clinical, serologic, or CSF criteria alone. Unfortunately, information was not provided as to the neuroimaging findings in these 2 groups, which would likely be distinctive. NIH Public Access Author Manuscript Rev Neurol Dis. Author manuscript; available in PMC 2009 January 2. Published in final edited form as: Rev Neurol Dis. 2007 ; 4(3): 168–172. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript The authors reported that the overall diagnostic sensitivity of brain biopsy was 65%. However, given the numerous exclusions from analysis, this high sensitivity must be viewed with caution. Prior reports have generally suggested that sensitivity of brain biopsy in neurodegenerative disorders is only 20%.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2613287&blobtype=pdf
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.
In short, a great deal of further work will need to be done before the phenotypic features and prevalence of atypical BSE are understood. More than a single strain may have been present from the beginning of the epidemic, but this possibility has been overlooked by virtue of the absence of widespread Western blot confirmatory testing of positive screening test results; or these new phenotypes may be found, at least in part, to result from infections at an older age by a typical BSE agent, rather than neonatal infections with new "strains" of BSE. Neither alternative has yet been investigated.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
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]
http://pro-med.blogspot.com/2007/11/proahedr-prion-disease-update-2007-07.html
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,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.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
sporadic Fatal Familial Insomnia
http://sporadicffi.blogspot.com/
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000166/!x-usc:mailto:flounder@wt.net
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?
http://www.neurology.org/cgi/eletters/60/2/176#535
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9
June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
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.
http://www.thepathologicalprotein.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
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, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT
http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
2 January 2000 British Medical Journal U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
http://www.bmj.com/cgi/eletters/320/7226/8/b#6117
15 November 1999 British Medical Journal vCJD in the USA * BSE in U.S.
http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
USA PRION UNIT BLOG
http://prionunitusaupdate2008.blogspot.com/
Sunday, April 20, 2008 Progress Report from the National Prion Disease Pathology Surveillance Center April 3, 2008
Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.
see full text ;
http://prionunitusaupdate2008.blogspot.com/2008/04/progress-report-from-national-prion.html
CJD TEXAS (cjd clusters)
http://cjdtexas.blogspot.com/
USA WRITTEN CJD QUESTIONNAIRE ???
http://cjdquestionnaire.blogspot.com/
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.html
Attending Dr.: Date / Time Admitted : 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report
FINAL AUTOPSY DIAGNOSIS Autopsy' Office (409)772-2858
FINAL AUTOPSY DIAGNOSIS
I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.
http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzfeldt-jakob.html
Alzheimer's and CJD and should it matter in terms of the surgical and medical arena safety of transmission
FC4.3
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
please see full text ;
Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
http://betaamyloidcjd.blogspot.com/
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
http://betaamyloidcjd.blogspot.com/
TSS
Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999–2008
Tsuyoshi Hamaguchi, Moeko Noguchi-Shinohara, Ichiro Nozaki, Yosikazu Nakamura, Takeshi Sato, Tetsuyuki Kitamoto, Hidehiro Mizusawa, and Masahito Yamada Author affiliations: Kanazawa University Graduate School of Medical Science, Kanazawa, Japan (T. Hamaguchi, M. Noguchi-Shinohara, I. Nozaki, M. Yamada); Jichi Medical University, Shimotsuke, Japan (Y. Nakamura); Kohnodai Hospital, Ichikawa, Japan (T. Sato); Tohoku University Graduate School of Medicine, Sendai, Japan (T. Kitamoto); Tokyo Medical and Dental University, Tokyo, Japan (H. Mizusawa); and Creutzfeldt-Jakob Disease Surveillance Committee, Japan (Y. Nakamura, T. Sato, J. Mizusawa, T. Kitamoto, M. Yamada)
Suggested citation for this article
Abstract To elucidate the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), we analyzed medical procedures (any surgical procedure, neurosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan during 1999–2008. We conducted an age-stratified case–control study with 753 sCJD patients and 210 controls and a study of patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. Although the control group was relatively small, no evidence was found that prion disease was transmitted through the investigated medical procedures before onset of sCJD. After onset of sCJD, 4.5% of the sCJD patients underwent operations, including neurosurgical for 0.8% and ophthalmic for 1.9%; no special precautions against transmission of prion diseases were taken. Fortunately, we have not identified patients with prion disease attributed to these operations. Our findings indicate that surgical procedures or blood transfusion had little effect on the incidence of sCJD.
snip...
Discussion In this case–control study, we found no evidence of increased sCJD risk associated with patient's history of surgical procedures or blood transfusions. In the previous case–control study and in our study, receipt of a blood transfusion was not shown to be a significant risk for CJD (2–10). However, whether surgical procedures contribute to the risk for sCJD has been controversial. Our results, in which any operation was not a significant risk for sCJD, were consistent with results of 2 previous large case–control studies (8,9) and a reanalysis of results of 3 case–control studies (10). Even in the studies with positive results, some different results were provided when the surgical procedures were categorized by affected organ. One previous case–control study indicated significant risk for sCJD after neurosurgical procedures (3), but no significant risk was shown in other studies (5,6,8–10). Ophthalmic surgery was reported as causing significant risk for sCJD in a case–control study in Australia (4) but not in other studies (5,6–10). In a recent study in the United Kingdom (6), the increased risk associated with having undergone surgical procedures was restricted to the category "other surgery," which included such procedures as sutures to skin, and the association largely disappeared when the whole of the other-surgery category was excluded. These different results may show little possibility for transmission of infectious PrP through surgical procedures, although we cannot exclude the possibility that such transmission occurs occasionally because iatrogenic CJD exists.
The conflicting results in case–control studies, including ours, may be explained by differences in the area, race, period in which studies were performed, number of patients, and methods as discussed below. Our study, which attempted to determine when medical procedures were associated with an increased risk for sCJD, had the largest number of sCJD patients in case–control studies to date. The relatively small number of controls is a potential limitation. In case–control studies, methods of obtaining data from controls should be the same as those from patients. In our study, patients in the groups "prion diseases definitely denied" or "prion diseases probably denied" in our CJD surveillance, who had no or little possibility of having prion disease, were used as the controls. Therefore, data from controls could be collected at the same level of precision as those from the sCJD cases. Because the ages of the sCJD patients and controls were significantly different, age-stratified analysis was required in our study. A recent study reported that some methodologic differences might partially explain conflicting data regarding the association between surgical procedures and CJD (17). The report suggested that the use of controls from the community would be preferable to using those from the hospital because community-based controls are often more representative and would result in a more valid comparison (17). Furthermore, using proxy informants for controls may be advisable for the purpose of comparability with case-patients, although this practice does not necessarily offset biases in data ascertainment (17). In our case–control study, we used proxy informants for controls who were recruited from hospitals under the same condition as the sCJD case-patients.
Regarding the 5 sCJD patients with a history of neurosurgical or ophthalmic surgical procedures at hospitals where other patients with prion disease had previously undergone such procedures, we consider that the possibility of transmission through these procedures was extremely limited because the intervals between procedures and the acquisition of sCJD had been >3 years for all patients. According to the Incident Panel in the United Kingdom, most instruments that have gone through 10 cycles of use and decontamination are unlikely to pose a substantial risk (15). We assume that all instruments had gone through >10 cycles of use during the 3-year interval, and almost no infectivity remained on the instruments. In Japan, a large number of dCJD patients have been recognized with no other types of iatrogenic CJD (11,12); this study confirmed that no surgically transmitted cases occurred among patients with sCJD.
It is noteworthy that 4.5% of the sCJD patients underwent some types of surgical procedures after the disease onset, including neurosurgical (0.8%) and ophthalmic procedures (1.8%). Through surgical instruments, neurosurgical operations may transmit high infectivity from the brain tissues of sCJD patients, and ophthalmic operations may transmit moderate infectivity of the eye tissues in cases of cataracts (15). In this study, all these neurosurgical and ophthalmic procedures were performed without suspicion of prion diseases or special precautions to reduce the risk for secondary transmission of prion infection through the instruments. These findings suggest that delayed diagnosis of sCJD would be linked to increased risk for secondary transmission of prion diseases through surgical instruments. In neurosurgical procedures, the symptoms of sCJD were misdiagnosed as those of other neurologic diseases, and operations were performed near the time of disease onset. In terms of ophthalmic surgery, all patients underwent operations for cataracts, and 7 (50%) of 14 patients had visual disturbances as an initial symptom of sCJD. These data are similar to those in a report from the United Kingdom (18). Visual disturbances might prompt ophthalmic surgery. More seriously, 3 patients underwent operations >8 months after sCJD onset. In this study, all surgeons who provided information reused the surgical instruments with incomplete sterilization, and the potential for infection was the same as in our previous study of ophthalmic surgery (19).
Neurosurgeons and ophthalmologists should become better informed about prion diseases and the necessity of using disposable instruments whenever possible. Furthermore, a more sensitive method for early diagnosis of sCJD is needed because clinical diagnosis is sometimes difficult, particularly in atypical sCJD cases, such as MM2, MV2, VV1, or VV2 types (20–23), according to 6 phenotypes of sCJD divided by codon 129 polymorphisms of PrP (methionine/valine) and type of infectious PrP by Western blotting (24). Even neurologists may misdiagnose the initial stage of the atypical sCJD cases as being another neurodegenrative disease such as Alzheimer disease and progressive supranuclear palsy (20). Moreover, patients who have undergone surgical procedures with possibly contaminated instruments need to undergo a risk assessment with long-term follow-up after careful ethical consideration. Since June 2004, we have identified and monitored all patients who underwent neurosurgical procedures with possibly contaminated instruments, CJD has developed in none of those patients.
In conclusion, we did not demonstrate any evidence of increased risk for sCJD associated with a history of surgery or blood transfusion in the Japanese surveillance system. However, the fact that some patients had surgeries, including neurosurgery, even after the onset of sCJD indicates that we cannot deny any possibility of transmission of prion diseases by medical procedures. Neurosurgeons, ophthalmologists, and other surgeons need to focus more attention on prion diseases to reduce the iatrogenic risk, as well as realize that prolonged, careful surveillance of prion diseases is necessary.
snip...end
http://www.cdc.gov/eid/content/15/2/265.htm
Thursday, October 23, 2008 Creutzfeldt-Jakob Disease Associated with Cadaveric Dura Mater Grafts – Japan, 1979-2008 : UPDATE
http://creutzfeldt-jakob-disease.blogspot.com/2008/10/creutzfeldt-jakob-disease-associated.html
Wednesday, August 20, 2008 Tonometer disinfection practice in the United Kingdom: A national survey Eye (2008) 22, 1029–1033; doi:10.1038/sj.eye.6702831; published online 20 April 2007
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/tonometer-disinfection-practice-in.html
Tuesday, August 12, 2008 Biosafety in Microbiological and Biomedical Laboratories Fifth Edition 2007 (occupational exposure to prion diseases)
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/biosafety-in-microbiological-and.html
Saturday, July 26, 2008 Creutzfeldt-Jakob Disease in Recipients of Corneal Transplants Creutzfeldt-Jakob Disease in Recipients of Corneal Transplants.
Case Report
http://creutzfeldt-jakob-disease.blogspot.com/2008/07/creutzfeldt-jakob-disease-in-recipients.html
Monday, December 08, 2008 vCJD & dental treatment Advice
http://creutzfeldt-jakob-disease.blogspot.com/2008/12/vcjd-dental-treatment.html
Wednesday, January 14, 2009 6 acquitted in French trial over hormone deaths
14 Jan 2009, 1858 hrs IST, AP
http://creutzfeldt-jakob-disease.blogspot.com/2009/01/6-acquitted-in-french-trial-over.html
http://creutzfeldt-jakob-disease.blogspot.com/
Friday, October 24, 2008 CBER 2007 Annual Report Assessing the Potential Risk of variant Creutzfeldt-Jakob Disease from Blood Products
http://creutzfeldt-jakob-disease.blogspot.com/2008/10/cber-2007-annual-report-assessing.html
Saturday, August 02, 2008
WARNING OVER SECOND WAVE OF CJD CASES
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/warning-over-second-wave-of-cjd-cases.html
Thursday, April 17, 2008 Use of Materials Derived From Cattle in Human Food and Cosmetics [Docket No. 2004N-0081] RIN 0910-AF47 [Federal Register: April 17, 2008 (Volume 73, Number 75)] [Rules and Regulations] [Page 20785-20794] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr17ap08-7]
http://cjdmadcowbaseoct2007.blogspot.com/2008/04/use-of-materials-derived-from-cattle-in.html
Saturday, January 24, 2009 Bovine Spongiform Encephalopathy h-BSE ATYPICAL USA 2008 Annual Report Research Project: Study of Atypical Bse
Location: Virus and Prion Diseases of Livestock
2008 Annual Report
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
http://bse-atypical.blogspot.com/2009/01/bovine-spongiform-encephalopathy-h-bse.html
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
Saturday, January 24, 2009
Research Project: Detection of TSE Agents in Livestock, Wildlife, Agricultural Products, and the Environment Location: 2008 Annual Report
http://bse-atypical.blogspot.com/2009/01/research-project-detection-of-tse.html
TSS
Wednesday, January 28, 2009 TAFS1 Position Paper on BSE in small ruminants (January 2009)
http://scrapie-usa.blogspot.com/2009/01/tafs1-position-paper-on-bse-in-small.html
The Diagnostic Utility of Brain Biopsy Procedures in Patients With Rapidly Deteriorating Neurological Conditions or Dementia
Josephson SA, Papanastassiou AM, Berger MS, et al. J Neurosurg. 2007;106:72–75. Josephson and colleagues1
Josephson and colleagues1 reviewed case records of all brain biopsy procedures at a tertiary care center in an effort to better characterize the diagnostic sensitivity of brain biopsy procedure for patients with rapidly worsening neurologic conditions, including dementia. Patients with HIV immunosuppression, and known nonlymphomatous tumors were excluded from analysis, resulting in a cohort of 171 identified patients. A surprisingly large number of these patients (n = 90, 53% of the initial cohort) were excluded from subsequent analysis because of the absence of “documentation of a complete history or neurological examination.” An additional 15 patients were excluded for other reasons, leaving 64 patients in the final analysis. The most common diagnoses made at biopsy are shown in Table 1. In the group of 10 patients found to have CJD (Table 1), the most common symptom categories included motor/pyramidal (90%), cognitive (80%), behavioral/psychiatric (80%), extrapyramidal (60%), and cerebellar (40%). Nine of the 10 patients had symptoms involving 2 of the first 3 groupings. Prominent individual symptoms included memory loss (50%), confusion/disorientation (50%), depression (40%), headache (40%), and sleep disturbances (40%). Cerebrospinal fluid (CSF) examination was performed in 8 of the 10 patients, and none had a CSF pleocytosis. Overlap of symptoms between patients with CJD and primary CNS lymphoma was high, and it was not clearly possible to separate these groups on clinical, serologic, or CSF criteria alone. Unfortunately, information was not provided as to the neuroimaging findings in these 2 groups, which would likely be distinctive. NIH Public Access Author Manuscript Rev Neurol Dis. Author manuscript; available in PMC 2009 January 2. Published in final edited form as: Rev Neurol Dis. 2007 ; 4(3): 168–172. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript The authors reported that the overall diagnostic sensitivity of brain biopsy was 65%. However, given the numerous exclusions from analysis, this high sensitivity must be viewed with caution. Prior reports have generally suggested that sensitivity of brain biopsy in neurodegenerative disorders is only 20%.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2613287&blobtype=pdf
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.
In short, a great deal of further work will need to be done before the phenotypic features and prevalence of atypical BSE are understood. More than a single strain may have been present from the beginning of the epidemic, but this possibility has been overlooked by virtue of the absence of widespread Western blot confirmatory testing of positive screening test results; or these new phenotypes may be found, at least in part, to result from infections at an older age by a typical BSE agent, rather than neonatal infections with new "strains" of BSE. Neither alternative has yet been investigated.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
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]
http://pro-med.blogspot.com/2007/11/proahedr-prion-disease-update-2007-07.html
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,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.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
sporadic Fatal Familial Insomnia
http://sporadicffi.blogspot.com/
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000166/!x-usc:mailto:flounder@wt.net
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?
http://www.neurology.org/cgi/eletters/60/2/176#535
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9
June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
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.
http://www.thepathologicalprotein.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
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, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT
http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
2 January 2000 British Medical Journal U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
http://www.bmj.com/cgi/eletters/320/7226/8/b#6117
15 November 1999 British Medical Journal vCJD in the USA * BSE in U.S.
http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
USA PRION UNIT BLOG
http://prionunitusaupdate2008.blogspot.com/
Sunday, April 20, 2008 Progress Report from the National Prion Disease Pathology Surveillance Center April 3, 2008
Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.
see full text ;
http://prionunitusaupdate2008.blogspot.com/2008/04/progress-report-from-national-prion.html
CJD TEXAS (cjd clusters)
http://cjdtexas.blogspot.com/
USA WRITTEN CJD QUESTIONNAIRE ???
http://cjdquestionnaire.blogspot.com/
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.html
Attending Dr.: Date / Time Admitted : 12/14/97 1228
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report
FINAL AUTOPSY DIAGNOSIS Autopsy' Office (409)772-2858
FINAL AUTOPSY DIAGNOSIS
I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.
http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzfeldt-jakob.html
Alzheimer's and CJD and should it matter in terms of the surgical and medical arena safety of transmission
FC4.3
Transmission of AA-amyloidosis: Similarities with Prion Disorders
Westermark, P Rudbeck laboratory, Department of Genetics and Pathology, Sweden
The systemic amyloidoses are characterized by widely spread amyloid deposits that can affect virtually every organ in the body. The precursor protein, which varies between different forms is produced at one or several locations, circulates with the plasma and is finally deposited as fibrils in the target organs by mechanisms yet to be determined. In one of the more common forms, systemic AA-amyloidosis, the substrate protein serum AA (SAA) is an acute phase reactant, with significant production only when certain proinflammatory signal substances are upregulated. A persistently high plasma concentration of SAA is a prerequisite for AA-amyloidosis to develop. AA-amyloidosis can easily be induced in many strains of mice by an inflammatory challenge, typically after a long lag phase. This phase is dramatically shortened by administration of amyloid fibrils extracted from an amyloidotic mouse, given intravenously, intra-nasally or given in the drinking water. The fibrillar extract is very potent, active down to pg of protein and facilitates amyloid formation even when given several months before an inflammation is induced. Also amyloid-like fibrils, produced in vitro from synthetic peptides have a clear effect, supporting the idea that the active principle is the misfolded and aggregated protein. AA-amyloidosis occurs in many avian and mammalian species. AA-fibrils from some, but not all species seed murine amyloidosis, showing a species barrier. AA-amyloidosis occurs in species, used as human food and may therefore be a risk factor. Consequently, AA-amyloidosis has similarity with prionoses, differing by the need of an upregulated production of the substrate SAA.
P03.139
Cellular Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein
Hooper, NM1; Parkin, ET1; Watt, NT1; Baybutt, H2; Manson, J2; Hussain, I3; Turner, AJ1 1University of Leeds, Institute of Molecular and Cellular Biology, UK; 2Roslin Institute, Neuropathogenesis Unit, UK; 3GlaxoSmithKline, Neurodegeneration Research, UK
Background: The normal cellular function of the prion protein (PrP), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD) in humans, remains enigmatic. Several studies have reported combinations of Alzheimer’s Disease (AD) and CJD neuropathology and the Val/Met129 polymorphism in the PrP gene has been identified as a risk factor for early-onset AD, leading to speculation that there may be some pathogenic connection between these two neurodegenerative conditions. The amyloid ß (Aß) peptides that cause AD are derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by the ß-secretase (BACE1) and the g-secretase complex. Aim: As both APP and PrP are cleaved by zinc metalloproteases of the ADAM family, we investigated whether PrP alters the proteolytic processing of APP. Results: Here we show that expression of PrP in SH-SY5Y cells dramatically downregulated the cleavage of APP by BACE1 and reduced the secretion of Aß peptides into the conditioned medium by >92%. Conversely, siRNA reduction of endogenous PrP in N2a cells led to an increase in secreted Aß. Furthermore, levels of Aß were significantly increased in the brains of PrP null mice as compared with wild type mice. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases, did not inhibit the BACE1 cleavage of APP. To investigate whether the Val/Met129 polymorphism in human PrPC would alter the production of Aß, brains from mice with the human PrP gene with MM or VV 129 genotypes were analysed. In the MM mice there was a significant increase in Aß in the brains as compared with the VV mice. In the brains of two strains (79A and 87V) of scrapie-infected mice there was a significant increase in Aß peptides as compared to uninfected mice. Conclusions: Together these data reveal a novel function for PrP in regulating the processing of APP through inhibition of BACE1. The increase in APP processing in cells expressing disease-associated forms of PrP and in scrapie-infected brains raises the possibility that the increase in Aß may contribute to the neurodegeneration observed in prion diseases. Funded by the Medical Research Council of Great Britain.
P03.140
Prion Protein Regulates the ß-Secretase Cleavage of the Alzheimer’s Amyloid Precursor Protein through Interaction with Glycosaminoglycans
Griffiths, HH; Parkin, ET; Watt, NT; Turner, AJ; Hooper, NM University of Leeds, Institute of Molecular and Cellular Biology, UK
Background: Proteolytic processing of the amyloid precursor protein (APP) by ßsecretase, BACE1, is the initial step in the production of the amyloid ß (Aß) peptide which is involved in the pathogenesis of Alzheimer’s disease. We have shown that the cellular prion protein (PrP) inhibits the cleavage of APP by BACE1 in cell and animal models. Aim: To investigate the mechanism by which PrP inhibits the action of BACE1. Results: Neither PrPdeltaGPI, which is not membrane attached, nor PrP-CTM, which is anchored by a transmembrane domain and is excluded from cholesterol-rich lipid rafts, reduced cleavage of APP, suggesting that to inhibit the BACE1 cleavage of APP PrP has to be localised to lipid rafts. Coimmunoprecipitation experiments demonstrated that PrP physically interacts with BACE1. However, PrP did not alter the activity of BACE1 towards a fluorogenic peptide substrate nor perturb the dimerisation of BACE1. Using constructs of PrP lacking either the octapeptide repeats or the 4 residues KKRP at the N-terminus of the mature protein (PrPdeltaN), we demonstrate that the KKRP sequence but not the octapeptide repeats, is essential for regulating the BACE1 cleavage of APP. As the KKRP sequence is known to participate in glycosaminoglycan (GAG) binding, we confirmed that PrPdeltaN did not bind to immobilised heparin. Addition of heparin to SH-SY5Y cells increased the amount of APP cleaved by BACE1 in a concentration-dependent manner and reduced the amount of BACE1 coimmunoprecipitated with PrP, suggesting that GAGs are required for PrP to interact with BACE1 and inhibit APP processing. Of a range of GAGs, including dextran sulphate, hyaluronic acid and chondroitin sulphate, investigated there was complete correlation between those that could restore BACE1 cleavage of APP in PrP expressing cells and those that bound PrP. Conclusion: These data suggest a possible mechanism by which PrP regulates the ßcleavage of APP is through the N-terminus of PrP interacting via GAGs with one or more of the heparin binding sites on BACE1 within a subset of cholesterol-rich lipid rafts, thereby restricting access of BACE1 to APP. Funded by the Medical Research Council of Great Britain.
P04.37
Comparison of the Neuropsychological Profile of Patients with Sporadic Creutzfeldt-Jakob Disease and Patients with Alzheimer’s
Krzovska, M1; Cepek, L1; Ratzka, P2; Döhlinger, S3; Uttner, I1; Wolf, Stefanie4; Irle, Eva4; Mollenhauer, Brit5; Kretzschmar, Hans A.6; Riepe, Matthias7; v. Arnim, Christine1; Otto, Markus1 1University of Ulm, Germany; 2Department of Neurology, Germany; 3University of Goettingen, Germany; 4University of Goettingen, Germany; 5Elena Klinik, Germany; 6LMU, Germany; 7University of Berlin, Germany
Background:To evaluate the neuropsychological profile of sCJD we administered the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) in order to determine if and how the sCJD-Subgroups (Met/Met, Met/Val, Val/Val) have different results in the item analysis of the ADAS-cog. Furthermore, we studied how the scores differ from that of patients with Alzheimer’s disease (AD). Methods:33 sCJD patients (11 with definite CJD and 22 with probable CJD) underwent neuropsychological testing with the ADAS-cog and Mini Mental State Exam (MMSE). Of these 31 were genotyped at the Codon 129 (11 Val/Val, 18 Met/Val and 2 Met/Met). The patients were matched in regards to sex and total ADAS-cog score with AD patients. The scores of the 11 ADAS-cog items were compared between the sCJD and the AD groups as well as between the sCJD-subgroups Met/Val and Val/Val and the AD group. Results:The ADAS-cog total score of the sCJD and AD groups was 22.6+/- 6.5, respectively. Regarding the single Item scores of the sCJD patient group and the AD patient group, there were statistically significant differences in the Items Constructional praxis, Word-finding difficulty in spontaneous speech and Spoken language ability. When comparing the sCJD subtypes with each other no statistically significant difference was found in the items. Conclusion: In the speech domain and constructional praxis there is indication of greater impairment in sCJD patients in general when compared with AD patients. A disturbance of the speech appears to be an important characteristic of the Met/Val and Val/Val subtypes of sCJD, and should therefore be the focus of special attention in future neuropsychological studies.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
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Alzheimer's and CJD
http://betaamyloidcjd.blogspot.com/
Saturday, March 22, 2008
10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures
http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html
http://betaamyloidcjd.blogspot.com/
re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease
http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html
http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html
http://betaamyloidcjd.blogspot.com/
TSS
Labels: CJD, Neurosurgeons, Ophthalmologists, PRION, TSE
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1:36 PM
