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From: TSS ()
Colorado Surveillance Program for Chronic Wasting Disease Transmission to Humans Lessons From 2 Highly Suspicious but Negative Cases C. Alan Anderson, MD; Patrick Bosque, MD; Christopher M. Filley, MD; David B. Arciniegas, MD; B. K. Kleinschmidt-DeMasters, MD; W. John Pape, BS; Kenneth L. Tyler, MD Objective To describe 2 patients with rapidly progressive dementia and risk factors for exposure to chronic wasting disease (CWD) in whom extensive testing negated the possible transmission of CWD. Design/Methods We describe the evaluation of 2 young adults with initial exposure histories and clinical presentations that suggested the possibility of CWD transmission to humans. Patients A 52-year-old woman with possible laboratory exposure to CWD and a 25-year-old man who had consumed meat from a CWD endemic area. Interventions Clinical evaluation, neuropathological examination, and genetic testing. Results Neuropathological and genetic assessment in the 2 patients proved the diagnoses of early-onset Alzheimer disease and a rare genetic prion disease. Conclusion No convincing cases of CWD transmission to humans have been detected in our surveillance program. http://archneur.ama-assn.org/cgi/content/abstract/64/3/439?ct > Results Neuropathological and genetic assessment in the 2 patients proved the > diagnoses of early-onset Alzheimer disease and a rare genetic prion disease very interesting, and something to ponder here for sure ; AS implied in the Inset 25 we must not _ASSUME_ that snip... http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf and i think this would apply to CWD to humans as well. > rare genetic prion disease would be interesting to know the exact genetic TSE they are speaking of. GSS, FFI, Familial/Genetic CJD, and or the sporadic FFI that is not genetic, and don't ask me why ??? does not make sense to me either. it's either genetic or not. like i have said many times, the diagnostic criteria differentiating the different human and animal TSE is missing something. but if you have a strain of genetic/familial TSE i.e. FFI, and then you classify a sub-type of that strain that use to be gentic to sporadic, then you have either gone back to sCJD, or the complete damn diagnostic criteria is wrong. you just have well named the damn thing ; Parchi-Capellari-Chin-Schwarz-Schecter-Butts-Hudkins-Burns-Powers-Gambetti-DISEASE. ...TSS Subject: Alzheimer-type neuropathology in a 28-year old patient with iatrogenic CJD after dural grafting HUMAN-04 Alzheimer-type neuropathology in a 28-year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting M Preusser1, T Stroebel1, E Gelpi1, 2, M Eiler3, G Broessner4, E Schmutzhard4, H Budka1, 2 1 Institute of Neurology, Medical University Vienna, Austria; 2 Austrian Reference Centre for Human Prion Diseases (OERPE), General Hospital Vienna, Austria; 3 Department of Neurology, LKH Rankweil, Austria; 4 Department of Neurology, Medical University Innsbruck, Austria We report the autopsy case of a 28-year old male patient who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of diseaseassociated prion protein (PrPsc) in a synaptic pattern and western blot analysis identified PrPsc of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer´s disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease-specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents 1. the iCJD case with the longest incubation time after dural grafting reported so far, 2. the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, 3. the first description of Alzheimer type-changes in iCJD, and 4. the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma. some other things to ponder ; Alzheimer's and Transmissible Spongiform Encephalopathies http://neurotalk.psychcentral.com/showthread.php?t=13175 ------------------------------------------------------------ HUMAN and ANIMAL TSE Classifications i.e. mad cow TSEs have been rampant in the USA for decades in many SOURCES Creutzfeldt-Jakob disease ratio of protease-resistant prion protein (PrPSc), and type 2 PrPSc display unglycosylated core fragments of acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to K cleavage sites. These antibodies, which were Findings We studied 114 brain samples from 70 patients Every patient classified as CJD type 2, and all variant cerebellum and other PrPSc-rich brain areas, with a Interpretation The regular coexistence of multiple electrophoretic PrPSc mobilities as surrogates for classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? Detection of Type 1 Prion Protein in Variant Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,? Fred G. van Zijderveld,? Moira E. Bruce,? James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease (CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151-157; DOI: 10.2353/ajpath.2006.050766) In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component brain. Western blot analysis of PrP in a sample of of vCJD during digestion with proteinase K is shown. are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). probed with 3F4, which detects both type 1 and type 2 which detects type 1. The insert shows a shorter course study from a separate experiment also probed included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Figure 7. A minority type 1-like PrPSc is found in vCJD to mice and in BSE. Western blot analysis of PrPSc in a sample of tonsil from a case of vCJD (Tonsil), in a of a wild-type mouse (C57BL) infected with vCJD and in BSE brain (BSE) is shown. Tissue extracts were digested Duplicate blots were probed with either 3F4 or 6H4, type 1 and type 2 PrPSc, and with 12B2, which detects included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this on vCJD, where type 1 is present in all samples but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the signature" of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative and that any mechanistic explanation of prion replication and the molecular basis of agent strain must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments AJP January 2006, Vol. 168, No. 1 ...TSS http://ajp.amjpathol.org/cgi/content/abstract/168/1/151maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1136646133963_237&FIRSTINDEX=0&volume=168&issue=1&journalcode=amjpathol
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