Are cheetahs on the run from prion-like amyloidosis?

Are cheetahs on the run from prion-like amyloidosis?

Byron Caughey* and Gerald S. Baron* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 598940

The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease. Prions are protein-based infectious agents or elements of inheritance that, unlike conventional pathogens, lack agent-specific nucleic acid genomes (5, 6). Prions have been described in both mammals (e.g., bovine spongiform encephalopathy and Creutzfeldt–Jakob disease) and fungi ([URE3], [PSI
], and [Het-s]). Replication of prions requires a self-propagating modification of an otherwise non-prion host protein. Usually the mechanism involves the recruitment of the normal form of the protein into a growing amyloid-like prion aggregate. In many cases the presence of prions is a disease state, but some prions play normal physiological roles (7). Although amyloid-like protein aggregation is typical of many important protein misfolding diseases, including Alzheimer’s disease and type 2 diabetes, most of these diseases are not known to be naturally transmissible or heritable because of transfer of the amyloid. However, experimental inoculations of amyloid preparations can enhance amyloidosis in nai¨ve mice that are strongly primed for the development of amyloidosis (8, 9). This suggests that there is potential for amyloidoses, in general, and AA amyloidosis specifically, to be transmissible and, hence, prion-like. For such transmissions to be significant in the real world, there must be practical routes of transmission and the potential for inducing disease in natural, rather than artificially primed, hosts. The shedding of AA amyloid into the feces of cheetahs suggests a potential route of transmission (Fig. 1) (4). Although the fecal amyloid can promote amyloidosis on i.v. inoculation into mice, this is only true in mice that were primed for amyloidosis by injections of an inflammatory chemical (silver nitrate) that dramatically boosts serum SAA levels. The silver nitrate treatment alone causes spontaneous amyloidosis in these mice, albeit at a slower pace than when the mice are inoculated with exogenous amyloid. Thus, it remains to be determined whether fecal amyloid can actually initiate, rather than enhance, amyloidosis in either mice or cheetahs and, if so, by what route of inoculation. One possible mode of entry would be oral because AA amyloid can be active in primed mice when administered orally as well as intravenously (9, 10). Another potential route would be direct inoculation of fecal amyloid into the blood stream through cuts or abrasions. It should be noted that Zhang et al. (4) inoculated mice with highly concentrated preparations of fecal amyloid. Hence, it is unknown whether amyloid concentrations in feces would allow transmission to nai¨ve recipients by any peripheral route. If fecal amyloid can be transmitted to other captive cheetahs, what makes these animals so susceptible to AA amyloidosis? The fact that mice can be primed for AA amyloidosis by inflamm tory stimuli raises the possibility that inflammation is also important in cheetahs. Indeed, inflammatory diseases are prominent in captive cheetahs with AA amyloidosis, and a number of precipitating factors, including chronic infections, diet, and stress, have been identified (2, 3). Other possibilities include genetic predispositions of cheetahs to AA amyloidosis because of their SAA sequence or expression level. Interestingly, a gene polymorphism has been identified in captive cheetahs that flanks the SAA1 gene and strongly affects its transcriptional induction in response to inflammation (11). Expression of other proteins can also profoundly enhance susceptibility of animals to AA amyloidosis, as shown by modulation of pentraxin levels in hamsters (12). The genetic homogeneity of captive cheetahs may enhance these susceptibility problems (11, 13), but does not appear to be the sole issue (3). The very factors that might make cheetahs susceptible to exogenous AA amyloid ‘‘infections’’ should also potentiate spontaneous AA amyloidosis in these animals. There is precedent for this in the spontaneous amyloidosis that occurs in silver nitrate-primed mice. By analogy, it remains possible that the high incidence of AA amyloidosis in cheetahs is caused by spontaneous disease exacerbated by the inflammatory stimuli, stresses, and inbreeding of captivity rather than exposure to fecal amyloid. Further studies will be required to resolve these questions. AA amyloidosis susceptibility issues may have serious implications for cheetah conservation efforts. If the objective is to rescue the wild cheetah population by releasing cheetahs bred in captivity, then it will be important to know the impact of releasing amyloidotic animals into the wild. Will AA amyloidosis continue to progress and affect the survival of released cheetahs? Can the disease be spread to wild cheetahs? One encouraging observation is that, relative to captive cheetahs, wild Namibian cheetahs are remarkably free of disease, including inflammatory diseases such as AA amyloidosis and gastritis (3). Perhaps lower chronic levels of inflammation, and hence serum SAA levels, make them less susceptible than captive cheetahs to AA amyloid shed by other animals. Although major questions remain about the etiology of AA amyloidosis in captive cheetahs, it may be wise to take measures to limit exposure of cheetahs to potential sources of amyloid ‘‘infectivity.’’ The demonstration that cheetah AA amyloid is active in mice indicates that there is cross-species promiscuity in its amyloid-inducing capacity. This promiscuity might also work in reverse, rendering cheetahs susceptible to AAamyloid- laden tissues of other species that might be fed to them. Interestingly, foie gras was recently shown to contain AA amyloid that could accelerate amyloidosis when fed to mice (9). Thus, consideration of a variety of potential sources of exposure for cheetahs seems warranted. Furthermore, if chronic inflammation enhances disease susceptibility, then anti-inflammatory therapies may be helpful. Is AA amyloidosis in cheetahs a prion disease? The answer depends on whether AA amyloidosis in captive cheetahs is caused by spontaneous disease or transmission of amyloid between animals. Environmental influences on AA amyloidosis epidemiology could be due to the presence of either ‘‘infectious’’ amyloid, a prion-like etiology, or to factors that enhance the incidence of spontaneous disease, i.e., a non-prion etiology. Even if transfer of AA amyloid between cheetahs enhances AA amyloidosis, the question would remain as to whether the transferred amyloid initiates the disease de novo or merely accelerates ongoing disease. The latter scenario would place AA amyloidosis into a gray area with respect to the basic prion concept. In this instance, prion transmission would affect the kinetics of the disease without actually initiating it. Regardless of prion semantics, there could be practical consequences of such kinetic phenomena in both animals and humans. For instance, recent studies have shown that in ection of
-amyloid can enhance Alzheimer’s-like amyloidosis in transgenic mice (14). This raises the possibility that inadvertent transfer of
-amyloid from one person to another could accelerate the neurodegenerative process to the point where it becomes Alzheimer’s disease as opposed to normal aging. In this example, as well as in cheetah AA amyloidosis and many other protein misfolding diseases, the basic problem is likely the outpacing of an organism’s protein quality control mechanisms. This may sometimes be more a problem of the rate, rather than of the instigation, of protein misfolding.

Fig. 1. Diagram of AA amyloid formation and the potential prion-like transmission of AA amyloidosis by fecal shedding and oral uptake of the amyloid. The photo shows an example of Congo red-stained AA amyloid fibril deposits in hamster liver tissue (courtesy of John Coe, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases).

ACKNOWLEDGMENTS. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. 1. Balch WE. Morimoto RI, Dillin A, KellyJW(2008) Adapting proteostasis for disease intervention. Science 319:916–919. 2. Papendick RE, Munson L, O’Brien TD, Johnson KH (1997) Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus). Vet Pathol 34:549–556. 3. MunsonL, et al. (2005) Extrinsic factors significantly affect patterns of disease in free-ranging and captive cheetah (Acinonyx jubatus) populations. J Wildl Dis 41:542–548. 4. Zhang B, et al. (2008) Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci USA 105:7263–7268. 5. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383. 6. Wickner RB, et al. (2004) Prion genetics: New rules for a new kind of gene. Annu Rev Genet 38:681–707. 7. Coustou V, Deleu C, Saupe S, Begueret J (1997) The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc Natl Acad Sci USA 94:9773–9778. 8. Kisilevsky R, Boudreau L (1983) Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy. Lab Invest 48:53–59. 9. Solomon A, et al. (2007) Amyloidogenic potential of foie gras. Proc Natl Acad Sci USA 104:10998–11001. 10. Lundmark K, et al. (2002) Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci USA 99:6979–6984. 11. Zhang B, et al. (March 28, 2008) Characterization of the cheetah serum amyloid A1 gene: Critical role and functional polymorphism of a cis-acting element. J Hered, 10.1093/jhered/esn015. 12. Coe JE, Ross MJ (1990) Amyloidosis and female protein in the Syrian hamster: Concurrent regulation by sex hormones. J Exp Med 171:1257–1267. 13. O’Brien SJ, et al. (1985) Genetic basis for species vulnerability in the cheetah. Science 227:1428 – 1434. 14. Meyer-Luehmann M, et al. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784. 7114  www.pnas.org
cgi
doi
10.1073
pnas.0803438105 Caughey and Baron

http://www.pnas.org/cgi/reprint/0803438105v1?etoc


Monday, May 12, 2008

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

http://betaamyloidcjd.blogspot.com/2008/05/fecal-transmission-of-aa-amyloidosis-in.html


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/2008/03/10-million-baby-boomers-to-have.html


Original Paper

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c

http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html


Sunday, April 27, 2008 re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Greetings,

I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand.

http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html


Draft Factual Account #5

10. On 28 June 1986 Mr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo.(S Jeffrey para 6; YB86/7.8/1.1 ) This examination, and subsequent consideration of the report, are described in the CVL DFA.

51. On 10 June 1987 Mr Bradley sent a BSE update to Dr Watson. It discussed, amongst other things, the nyala case and subsequent paper, the work of Mr Wilesmith, the upcoming BCVA meeting and the work of Dr Kimberlin.(YB 87/6.10/1.1 )

63. On 22 June 1987 Mr Bradley sent a memo to Mr Wells detailing actions taken to date. It noted that publication has been discussed with the CVO and halted and that there were now at least 9 suspect herds and a case in a gemsbok at Marwell.(YB 87/6.22/2.1 )

74. On 1 July 1987, Mr Bradley wrote to Mr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/6.29/3.1; YB87/7.1/2.1; YB87/7.1/3.1-3.10 ) This is further discussed in the CVL DFA.

153. On 11 December 1987, Mr Jeffrey's paper on the nyala was submitted for publication in the journal Veterinary Pathology. The paper had first been drafted the paper in autumn 1986. (S 64 Jeffrey para 10) The title of the paper was changed from 'A scrapie-like disorder in a nyala' to 'A spongiform encephalopathy in a nyala.' Other references to scrapie were also amended.( S Jeffrey para 10; S 65 Wells para 55; YB87/11.11/2.1; YB87/11.17/3.1; YB87/11.23/2.1. )

Spongiform encephalopathy in a nyala (Tragelaphus angasi).

Vet Pathol 1988 Sep;25(5):398-9 Jeffrey M, Wells GA Lasswade Veterinary Laboratory, Midlothian.

166. In January 1988, Mr Wilesmith was informed of the June 1987 case of SE in the gemsbok. He discovered from the Winchester VIC that both the >nyala and the gemsbok had received rations containing MBM and this provided further support for his hypothesis.( S Wilesmith para. 37)

Draft Factual Account #4

28. On 28 June 1986 Dr Jeffrey examined tissue sections taken from the brain of a nyala which had been kept at Marwell Zoo. (S Jeffrey para 6; YB86/7.8/1.1 ) The nyala had shown unusual nervous symptoms two weeks prior to being put down on welfare grounds. These symptoms included 'weaving with the head and neck, holding the head on its side and frequent nibbling near the tailbone.'(YB86/6.23/1.1 ) The sections were originally necropsied by Mr Geoff Holmes at the Winchester VIC.(YB86/5.29/1.1; YB86/6.18/1.1 ) The nyala (tragelaphus angasi) is not an antelope but belongs to the same family (species group) as cattle.

29. Dr Jeffrey observed that the brain showed taxonomic lesions of spongiform encephalopathy and that the similarity of the lesions to natural sheep scrapie was striking, and indeed he thought that in comparison to natural sheep scrapie the lesions were particularly florid.(YB86/7.2/1.1; S Jeffrey para 9 ) The sites (neuroanatomical location) and cellular location (grey matter neuropil and neuronal cytoplasmic vacuolation) were distinctive and characteristic of the TSEs. Dr Jeffrey sent a slide of the nyala brain to Dr Richard Kimberlin at the NPU in the latter quarter of 1986 who 'vividly recollect[ed] seeing the results down the microscope because the pathology was so striking'.(YB 98/11.18/1.1 )

30. Following a field visit to Marwell Zoo on 21 July 1986,(YB86/7.24/1.1 ) a report was compiled by Mr Holmes at Winchester VIC and a scientific paper prepared for publication in a journal.(S Jeffrey para 10 ) Dr Jeffrey conferred with Mr Wells, his line manager at the CVL, in the preparation of the paper.(S Jeffrey para 9; S Wells 1st para 55 ) Dr Jeffrey was not sure of the exact date he submitted the paper to the Animal Health and Veterinary Group (AHVG) for publication but said it was some time in Autumn 1986.(S Jeffrey para 10; YB86/11.00/1.1 ) Dr Jeffrey did not form any conclusions about the origins of the disease in this animal, but he discussed the case with the CVL Epidemiology Department, and they agreed to keep a 'watching brief' on the situation.(S Wilesmith para 11)

89. On 17 June 1987 the Annual Report of the CVO for 1986 was published, having been submitted for publication on 1 June 1987.( M24 Tab 2 at 69 ) The Report described the discovery of a 'Scrapie-like disease in a captive nyala' and noted that 'Transmissible spongiform encephalopathies have been reported in man, sheep and goats (scrapie), mule deer and mink.'

91. On 19 June 1987 Mr Bradley sent Dr Watson a BSE Update. Amongst other things it was noted:(YB 87/6.19/3.1-3.2 )

"The final draft Vet Rec paper has been prepared and submitted for authority to publish. This has been rejected by CVO whilst scrapie is mentioned. For this and other reasons the paper is temporarily withdrawn until further information is available"

92. On 19 June 1987 Dr S.H. Done diagnosed spongiform encephalopathy in a gemsbok from Marwell Park.(YB87/6.19/3.2; YB876.8/3.1; YB87/6.10/3.1; YB87/6.25/1.1 ) This was the zoo was from which the SE-infected nyala had come. While the nyala was from the same species group as cattle, the gemsbok is an African antelope.

100. On 1 July 1987 Mr Bradley wrote to Dr Jeffrey to tell him that his article on spongiform encephalopathy in a nyala was not authorised for publication, and that while he made comparisons with scrapie, the CVO was unlikely to give his approval.(YB87/7.1/3.2; YB87/6.29/3.1; YB87/7.1/2.1 ) The initial title of the paper was 'Scrapie-like disorder in a nyala'.( S Jeffrey para 12 ) At the request of Tolworth, the title of the paper was eventually changed to 'Spongiform encephalopathy in a nyala'.( YB87/11.00/1.1 ) Because of the original references to the scrapie-like nature of the disorder the paper was delayed for publication and was not published until September 1988.( J/VP/25/398 ) Dr Jeffrey told the BSE Inquiry that he resisted the move to alter his paper because it 'would have been negligent to try and publish that without a reference to scrapie'.(T25 at 32 )

157. On 17 November 1987 Mr Bradley minuted Dr Jeffrey noting that the title to his nyala paper was likely to be unacceptable to "senior management" for "veterinary political reasons". He also recommended that where comparisons were made with scrapie the emphasis ought to be altered.(YB 87/11.17/1.1 )

433. On 23 October 1989 Dr Watson told Mr Wells that the CVL were to supply material from the kudu and nyala to the NPU for transmission to mice. Dr Watson said this was an important transmission experiment designed to establish the relationship between the disease in zoo animals and cattle.(S Watson 1st para 134 ) Mr Bradley provided Dr Watson with a list of tissues that were to be sent to the NPU on 24 November 1989.(YB89/10.24/4.1 )

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BSE Inquiry site Draft Factual Account 13 extracts related to zoo animals:

19. On 24 January 1990 Mr Bradley sent to Dr Watson a summary of the main points of a meeting held with the Minister the same day.(20) The minute noted: "The Minister played Devil's advocate in relation to: ... 5. MBM exports unethical. All should be labelled & a letter should be sent to all countries to which MBM was exported should be sent." [No such letter was sent.]

28. By 12 February 1990 the nyala and kudu tissues and the placenta had been inoculated into mice at the NPU.(33) After his investigations into the alimentary tract, ... Mr Bradley said in a minute dated 12 February 1990 that:(36) "It is very clear that it is important to initiate studies now in a much wider range of tissues and in multiple specimens than can be accommodated in the annual quota of 30 for the next two years." Mr Bradley attached a table showing the progress of infectivity studies:..fixed nyala brain, fixed kudu brain, buffy coat.

57. On 17 September 1990 Mr Bradley circulated a minute with regards to an offer by Dr Schellekers of the Netherlands to collaborate on attempting to transmit BSE to chimpanzees.(YB90/9.17/1.1) Mr Wells and Dr Rosalind Ridley, who was conducting the marmoset experiment, told Mr Bradley that they did not feel there was any greater justification for an attempted transmission in chimpanzees than marmosets.(S Bradley 3rd para 40 ) Mr Bradley passed on this view to the CVO.(YB90/9.23/1.1; YB90/9.26/3.1 ). [This is ignorant beyond belief.]

67. In Spring 1991 Mr McGill performed a review of 200 brains that had, using the obex histopathological method, been deemed BSE-negative.(110) This diagnostic approach, that had been developed for use within the VIS, used a single section from the medulla to look for spongiform change. In his review Mr McGill examined other parts of the brain.(111) In his statement to the BSE Inquiry Mr McGill said:

Upon closer examination, three of the 200 'BSE-negative' brains proved positive for spongiform changes diagnostic of BSE.(112) This represents an overall diagnostic accuracy of 99.85%, exceeding the 99.6% previously published for the same standard diagnostic technique. Despite this, at the behest of MAFF managers, the emphasis of the study and its provisional title had to be changed, from accurately representing the whole negative 10%, to a study examining this 10% minus any mention whatsoever of BSE-affected cattle going undiagnosed. I therefore had to reluctantly locate and analyse three new BSE-negative suspect brains.(113)

76. In mid-1991 it was decided that a proposed survey of 300 deer brains would proceed.(124) As with the hound survey, there were difficulties in collecting the material in a manner optimal for histopathological examinations.(See YB92/11.4/2.1) During the period 1986 to 1996, 26 deer brains were referred for examination to the Consultant Pathology Unit at the CVL, but none of these showed evidence of an SE.

103. On 16 July 1992 a meeting was held at CVL to discuss the research proposals relating to the studies on SEs in a greater kudu at a zoo. (S Bradley 3rd para 65 ) Three main experiments were proposed: to determine the distribution of agent in tissues; to study the epidemiology; and to strain type isolates from a brain of a new case of spongiform encephalopathy. Formal proposals were later drawn up and Mr Bradley became the Project Officer for the experiments.

108. Mr Bradley and Mr Dawson met staff at London Zoo on 23 March 1993 to discuss tissue selection for the proposed transmission studies on BSE-infected kudu material.(166) The Zoo did not want to keep the kudu, but moving them to the CVL was ruled out because of inadequate facilities to care for them. The investigations into the distribution of the SE agent in various tissues began in June 1993.

121. On 9 October 1993 Mr Wilesmith and others published a paper on the additional cases of TSE in the herd of greater kudu at London Zoo.(S Wilesmith 2nd para 95 ) On the basis of feeding histories, the authors concluded that horizontal transmission had occurred. However, subsequent investigations based at the zoo revealed that the affected animals were most likely to have been infected from the feedborne source.

143. On 3 July 1994 Mr Bradley was informed that two more kudu were to be culled.( Bradley 3rd para 86 ) He visited the London Zoo on 21 July 1994 to review the progress of the studies on TSEs in zoo animals. Necropsies were to be carried out on the kudu and tissues collected for further transmission studies. At this stage the mice that had been inoculated with kudu tissues in August and September 1993 had not succumbed to spongiform encephalopathy. The Zoo authorities wanted to move the kudu because of the possibility of bad publicity.(YB95/2.10/1.6) This was discussed at a SEAC meeting on 2 February 1995. The meeting agreed that the risk to Zoo visitors was minuscule or non-existent. Mr Bradley's case control study indicated that infected feed was the most probable cause of the BAB kudu SE cases.

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46. On 28 June 1990 Mr Bradley informed Mr Wells that a survey of hounds was to commence.(68) The hound survey arose because the Tyrrell Committee had recognised that domestic pets might prove susceptible to the unconventional agent of BSE and recommended monitoring the health of animals fed offal, carcases or meat and bone meal.(M11a Tab 8 )

47. A total of 444 hound brains of mixed breeds from 101 kennels across the United Kingdom were collected and examined. Histopathological changes consistent with a florid spongiform encephalopathy similar to that reported in cats was not observed. However, the report of the survey identified serious flaws in the survey's design. Mr Wells said in a minute to Mr Bradley in October 1991 that 'the survey as designed has little to offer scientifically'.(YB91/10.17/1.1)

54. On 20 August 1990 Mr Wells confirmed the parenteral transmission of BSE to a pig.(YB90/7.20/2.1) The pig was inoculated in February/March of 1989 and was slaughtered in July 1990.(S Wells 2nd para 40) An interim report was prepared for SEAC(84) and a press conference was held on 24 September 1990 to announce the parenteral transmission of BSE to pigs.(85) The transmission of BSE to pigs was a major factor in the ban on SBOs being extended to all animal feed. Experiments were also conducted by orally dosing pigs with BSE infected material but when the pigs were killed after seven years they were not found to be incubating the disease.(S Wells 2nd para 40 )

55. By August 1990 a total of 10 cases of FSE in domestic cats had been confirmed.(S Wilesmith 2nd para 109 ) Mr Wilesmith designed a questionnaire to be completed by the veterinarians who clinically identified FSE for the purposes of an epidemiological investigation. In addition to this investigation, the University of Bristol was subsequently granted a MAFF contract for a study in collaboration with the NPU to ascertain whether the condition in cats was transmissible to mice and, if so, to undertake strain typing of the agent.(S Wells 2nd para 104; YB 92/6.19/5.1 ) Mr Wells was appointed Project Officer to monitor the study. When the study was completed it showed that the disease in cats was transmissible and that similarities in the biological characteristics of FSE and BSE on transmission to mice indicated that the two diseases probably arose from a common source.(J/VR/134/449 )

64. In February 1991 Mr Mark Robinson began studies on the transmission of BSE to mink.(S Wilesmith 2nd paras 117-118 ) This study was done in collaboration with the United States Department of Agriculture (USDA), the Agricultural Research Service (ARS), and the Department of Veterinary Science at the University of Wisconsin, USA. The results of this study were discussed at the 10th CVL/NPU BSE R&D meeting held on 27 April 1993.(YB93/4.27/1.1) The results indicated that mink were susceptible to BSE, and in contrast to previous attempts to transmit scrapie to the species, were susceptible by the oral route of challenge.(J/JVIR /75/2151)

99. On 11 April 1992 Mr Bradley prepared a paper for the Lamming Expert Committee on Animal Feedingstuffs.(153) Some of the areas covered in the paper were tallow, the danger of BSE to pigs, the effect of the species barrier, tissue infectivity of lambs and calves, scrapie incidence and the danger of dogs developing SEs.

116. In July 1993 studies involving the oral exposure of pigs to scrapie were started the CVL.(179) Such studies were recommended by the expert committee on feedingstuffs chaired by Professor Lamming, because it was found that pigs had been orally exposed not only to BSE but also to scrapie. The pigs were orally exposed to scrapie-infected brain material in November 1993 and while the experiment remains in progress, no pigs have been shown to have developed the disease to date.

123. In December 1993 Dr Ken Charlton of the Animal Disease Research Institute, Nepean, Ontario, Canada, visited the CVL bringing material from a suspect case of BSE in Canada. The CVL confirmed that the case was a BSE case and reported it to the Canadian authorities.(189) in 1994.

152. On 13-16 February 1995 ... ...BSE to pigs - Further work to clarify the finding of non-specific vacuolation in the brains of control pigs was needed.

...BSE to chickens - Sub-passage in chickens and mice of various tissues from experimentally infected birds was needed to clarify the findings of neurological signs without neuropathology in inoculated birds.

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

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

Beiru Zhang*†, Yumi Une‡, Xiaoying Fu*, Jingmin Yan*, FengXia Ge*, Junjie Yao*§, Jinko Sawashita*, Masayuki Mori*, Hiroshi Tomozawa¶, Fuyuki Kametani
, and Keiichi Higuchi*‡** *Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, and ¶Division of Laboratory Animal Research, Research Center for Human and Environmental Science, Shinshu University, 3-1-1, Asahi, Matsumoto 390-8621, Japan; †Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China; ‡Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 229-8501, Japan; §The Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 183-8508, Japan; and
Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Tokyo 156-8585, Japan Edited by Reed B. Wickner, National Institutes of Health, Bethesda, MD, and approved April 1, 2008 (received for review January 16, 2008)

AA amyloidosis is one of the principal causes of morbidity and mortality in captive cheetahs (Acinonyx jubatus), which are in danger of extinction, but little is known about the underlying mechanisms. Given the transmissible characteristics of AA amyloidosis, transmission between captive cheetahs may be a possible mechanism involved in the high incidence of AA amyloidosis. In this study of animals with AA amyloidosis, we found that cheetah feces contained AA amyloid fibrils that were different from those of the liver with regard to molecular weight and shape and had greater transmissibility. The infectious activity of fecal AA amyloid fibrils was reduced or abolished by the protein denaturants 6 M guanidine
HCl and formic acid or by AA immunodepletion. Thus, we propose that feces are a vehicle of transmission that may accelerate AA amyloidosis in captive cheetah populations. These results provide a pathogenesis for AA amyloidosis and suggest possible measures for rescuing cheetahs from extinction. feces  transmissibility

The amyloidoses are a group of protein misfolding disorders characterized by the accumulation of amyloid fibrils formed from a variety of proteins that, under normal physiological conditions, are harmless and soluble. Currently,
25 amyloid diseases have been identified, such as the prion diseases, Alzheimer’s disease, type 2 diabetes, and various systematic amyloidoses (1). Although the various proteins that can polymerize into amyloid fibrils have unrelated sequences, they can all form fibrils with a similar ultrastructural appearance. Among them, prion diseases such as transmissible spongiform encephalopathy (TSE), including scrapie in sheep, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) of deer and elk, are highly infectious (2). In these diseases, prion (PrPSc), an abnormal form of the host cellular prion protein (PrPC), induces the conformational change of PrPC to the PrPSc and causes a detectable phenotype or disease in the affected individual. AA amyloidosis, known as reactive or secondary amyloidosis, is generally recognized as the predominant form of systemic amyloidosis that occurs in domestic animals and the animal kingdom (3). This disease is characterized by the systemic deposition of extracellular fibrils composed of amyloid A protein, primarily in the spleen; liver; and, to a lesser extent, in other organs. In most species, AA amyloidosis occurs sporadically and is typically secondary to chronic inflammation, infection, or neoplasia. Intriguing recent data suggest that AA amyloidosis could be transmitted by a prion-like infectious process through a seeding-nucleation mechanism (4–7). Thus, the fibrillar nuclei formed by the aggregation of misfolded protein monomers (rich in
-sheet structures) act as seeds to induce and stabilize conversion of the native monomeric protein (8–9). This mechanism provides a plausible explanation for the transmissible nature of AA amyloidosis. AA amyloidosis can be easily induced when mice are given an extract from AA amyloid-laden tissue (10, 11) or synthetic amyloid-like fibrils (12, 13), providing further evidence for transmissibility. The cheetah species (Acinonyx jubatus) is in danger of extinction and is included on The World Conservation Union list of vulnerable species. Although efforts have been made in wildlife sanctuary parks and zoos worldwide to prevent extinction, a steady increase in the size of the cheetah population is hampered by the high prevalence of certain diseases in captive cheetahs. In particular, systemic AA amyloidosis is regarded as an increasingly important cause of morbidity and mortality in captive cheetahs as prevalence increased from 20% in pre-1990 reported necropsies to an unusual 70% of necropsied cheetahs in 1995 (14). Despite much effort, the pathogenesis for AA amyloidosis in cheetahs is still only partially understood. Inflammatory diseases, especially chronic lymphoplasmacytic gastritis, found in 100% of cheetahs with AA amyloidosis (14), and genetic homogeneity have been considered as causes for the increased incidence of AA amyloidosis (15). However, environmental epidemiological studies indicate that breeding conditions have a prominent effect on the incidence of AA amyloidosis. A high rearing density is always associated with early age of onset, and with the high incidence and severity of AA amyloidosis, findings similar to sheep scrapie and cervid CWD. Thus, sustained epidemics of sheep scrapie and cervid CWD appear to be principally due to horizontal (animal to animal) transmission, although the routes of natural transmission remain to be clarified (16, 17). The propagation of AA amyloidosis among captive cheetah populations may also depend on a horizontal transmission pathway. Identification of the mode of transmission is a prerequisite for disease control. In this study, we show that the feces from a cheetah with AA amyloidosis can act as a possible transmission origin to accelerate the transmission of AA amyloidosis.

Results

snip...

Discussion It is currently accepted that systemic AA amyloidosis is an increasingly important cause of morbidity and mortality in captive cheetah populations (14). For conservation of this species, therefore, it is critical to elucidate the etiology of AA amyloidosis. As with sheep scrapie and cervid CWD, the routes of transmission are among the most debated and intriguing issues. InfectiousCWDprions in saliva have been identified to be involved in transmission in high-density captive situations (19, 20). Recently, available evidence indicates that an environmental reservoir of infectivity contributes to the continuation of these diseases in affected populations. These infectious agents can be transmitted by flesh flies (21) or hay mites (22) and can directly enter the environment from decomposing carcasses of infected animals (23). Environmental contamination by excreta from infected cervids has also seemed the most plausible explanation for the dissemination of CWD (24). Scrapie-infected hamsters and Creutzfeldt–Jakob disease (CJD) patients were reported to excrete urinary protease-resistant PrP isoform (25), indicating that urinary excretion from infected animals may provide a vector for horizontal transmission. However, there are studies that are not consistent with these findings (26, 27). Perhaps unrecognized nephritic conditions may underlie these discrepant observations, because it has been reported that urinary prion excretion is found only in scrapie-infected mice with lymphocytic nephritis (28). In this study, we observed several bands with high molecular weights that reacted with anti-cheetah AA antiserum in the whole urine sample, but not in the urine pellet in whichAAamyloid fibrils should be recovered. We thought that the possibility for a transmission pathway through urine might be low, but it could not be ruled out. In addition to urine, the alimentary shedding route has been considered as a possible transmission pathway (29). Abnormal prion protein is present in gut-associated lymphoid tissues of mule deer infected with CWD, consistent with an alimentary shedding route (30). In this study, we showed that the fecal fraction from a cheetah with amyloidosis had AA amyloid fibrils and possessed high transmissibility. In mouse AApoAII amyloidosis, regarded recently as another transmissible amyloidosis (5–7), we also demonstrated that the feces could serve as an agent to induce amyloidosis in recipient mice (31). These results shed new light on the etiology involved in the high incidence of AA amyloidosis in cheetahs. In this study, we unexpectedly found that the amyloid fibril fraction from feces had smaller amyloid fibrils and higher sensitivity to denaturation treatment than the liver amyloid fibril fraction. In mammalian prion, it has been demonstrated that there is a very strong correlation between seeding capability and amyloid fibril conformation (32, 33). Similarly, in yeast prion, it also has been indicated that [PSI] with stronger infectivity typically have less stable fibrils in vivo than strains with weaker infectivity (34), and the prion strain with relatively smaller prion particles is always associated with greater frangibility and increased sensitivity to denaturants (35). The enhanced frangibility is presumably involved in the increase in seeding efficiency and prion infectivity, while the high sensitivity probably results from structural differences in inter-molecular contacts and a shorter, less stable amyloid core. The divergent ultrastructure between the fecal and the liver fibrils identified by transmission electron microscopy may be responsible for the different characteristics of transmissibility and sensitivity to denaturation treatment, analogous to prion protein. It has been reported that AA amyloidosis can be experimentally induced by i.v. or i.p. administration of AA amyloid fibrillar extracts in recipient mice (10). A few recent studies have shown that AA-containing extracts also had amyloid-inducing activity when administered orally to mice (36, 37). In AApoAII amyloidosis, we ported that an oral administration of AApoAII amyloid fibrils induced amyloidosis in recipient mice (38). Thus, it is plausible that oral ingestion of AA-containing fecal matter caused amyloid deposition in the cheetah population. At this juncture, the manner in which fecal matter is initially absorbed by the cheetahs is not clear. This may occur during mutual grooming (licking of the fur contaminated by fecal matter). Recently it was shown that a prion agent could bind to whole soil and common soil minerals and retain infectivity for a prolonged period (23, 39). Thus, soil may act as a reservoir capable of contaminating both food and fur. It is also unknown how AA fibril proteins enter the feces. Because AA amyloidosis was also in the small intestines of AA amyloidosis cheetahs, it is possible that AA proteins enter the feces through exfoliated mucosa. In conclusion, we found that cheetahs with amyloidosis pass fecal matter that had strong seeding efficiency and should be regarded as a transmission medium. To control the incidence of AA amyloidosis and reduce the likelihood of the animal’s extinction, prevention of the transmission with excretion from cheetahs with amyloidosis should be considered along with reduction of precursor SAA levels.

snip... full text pdf ;

http://www.pnas.org/cgi/reprint/0800367105v1


Greetings,

I have two comments ;

To control the incidence of AA amyloidosis and reduce the likelihood of the animal’s extinction, prevention of the transmission with excretion from cheetahs with amyloidosis should be considered along with reduction of precursor SAA levels.<<<

considering AA amyloidosis in humans, should we consider this same risk factor for humans, i.e. 'extinction' and 'prevention of transmission with excretion' and Alzheimer's ?

In particular, systemic AA amyloidosis is regarded as an increasingly important cause of morbidity and mortality in captive cheetahs as prevalence increased from 20% in pre-1990 reported necropsies to an unusual 70% of necropsied cheetahs in 1995 (14).<<<

hmmm, big increase, and key word here is 'CAPTIVE'. WHAT WERE THESE CHEETAHS FED ? i.e. dead stock downers maybe ?

These cheetahs are reported elsewhere to have been fed cattle delicacies such as split spinal cords, whole necks, whole skulls, and split skulls from which the knacker had "removed" CNS material, as late as 1993.

Switcheroo -- MAFF web site mysteries 19 Apr 99 webmaster correspondence with MAFF "help" desk The MAFF staff actually responds helpfully to substantative question about material on their Web site though delays occur. The webmaster wrote MAFFon 16 April 1999 thanking them for their 15 Apr 99 update on animals that have succumbed to confirmed TSE and asking for dates of death on unpublished cases in tigers, ocelots, pumas, and bison that are listed on their site. These animals died some years back but nothing has ever appeared. On 17 Apr 99, the webmaster wrote again about something very puzzling: an allusion to cheetahs on line 15 and 29 whereas no such line numbers existed on the web page. Evidently they were holding back a line-by-line database of animals that would be very useful to scientists and conservationists around the world.. Very ominiouly, the cheetah lines went up to 29 whereas they showed "only" 5 British cheetahs (at Marwell and Whipsnade) plus 4 exported cheetahs [not furnished but Fota, Pearle Coast, and Safari de Peugres x 2]. There is nothing special about cheetahs and BSE other than they have a shorter incubation time than some of the other felids.

These cheetahs are reported elsewhere to have been fed cattle delicacies such as split spinal cords, whole necks, whole skulls, and split skulls from which the knacker had "removed" CNS material, as late as 1993. No cheetah has ever been autopsied that did not display clinical signs of TSE; 11 cheetahs died at Marwell alone in the mid-90's but apparently were incinerated without autopsy or freezing samples despite the zoo's track record.

The response to my polite inquiry: none. Well, actually there was a response: the MAFF webmaster quietly deleted any mention of the database. The switheroo occured on Mon, Apr 19, 1999 10:59 AM GMT according to Netscape 'document info', taking the site back to an earlier version of the document not mentioning line 15 and 29 and deleting the name of Marwell Zoo (the cheetah BSE factory).

However, I had saved the original page to disk. Here is what the deleted top secret MAFF page actually said:

"Not included above are two cheetahs at zoos in Australia and the Republic of Ireland. Both were apparently litter mates and exported from Marwell zoo, where the cheetahs on lines 15 and 29 were born. Two cases in cheetahs were also confirmed in France, one in January 1997, in an animal born at Whipsnade zoo in 1989. Details are awaited for the second case, but it is reported to have been born in Britain*." *Why don't they just ring up the French team and find out -- they published the abstract 8 months ago in August of 1998. They gave a presentation at the Chester Zoo published in the Proceedings of the EAZWV on May 24-24, 1998.

MAFF came through (somewhat) on 13 May 1999. Though the names of the zoos could not be supplied and the cheetah line 29 business could not be explained, birth and death dates of zoo BSE animals supplement the published record.

http://www.mad-cow.org/zoo_cites_annotated.html


New BSE-like disease found in cheetah 06/09/2007 - 17:52:28

A cheetah at a zoo in Nuremberg has died after contracting an illness similar to mad cow disease, becoming the first confirmed case in Germany of feline spongiform encephalopathy (FSE), city authorities said today.

Lulu, a female cheetah born in 1998, had suffered for six weeks from problems that included trouble balancing and weakness in her hind legs, the Nuremberg city government said in a statement.

The animal eventually was put to sleep, and tests by Bavarian and federal labs were positive for FSE, it added.

It was unclear how and when Lulu became infected with the disease, which has a several-year incubation period, but Nuremberg authorities said it likely happened in the Netherlands, where she was born.

Lulu moved to Germany at the age of 15 months, returned to the Netherlands five years later and arrived at the Nuremberg zoo in March 2006.

http://www.breakingnews.ie/world/mhcwgbqlkfcw/


http://www.eveningecho.ie/news/bstory.asp?j=230658672&p=z3x659378&n=230659432


http://www.live-pr.com/en/bse-like-disease-detected-in-german-zoo-s-r1048136284.htm


GREETINGS,

interesting to say the least. how could this cheetah have contracted FSE?

feed with FSE ?

casual contact with FSE in zoo ?

remember the man and his cat whom both had sporadic CJD;

In October 1998 the simultaneous occurrence of spongiform encephalopathy in a man and his pet cat was reported. The report from Italy noted that the cat did not display the same clinical features as FSE cases previously seen. Indeed, the presence of a new type of FSE was suggested. The man was diagnosed as having sporadic CJD, and neither case (man nor cat) appeared to be affected by a BSE-related condition.

http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html:


Image] Research letters Volume 352, Number 9134 [Image] 3 October1998[Previous] [Next] [Image][Image] Simultaneous occurrence of spongiform encephalopathy in a manand his cat in Italy

[Image] Gianluigi Zanusso, Ettore Nardelli, Anna Rosati, GianMaria Fabrizi, SergioFerrari, Antonella Carteri, Franco De Simone, Nicola Rizzuto, SalvatoreMonaco

Transmissible spongiform encephalopathies (TSE) encompass inherited,acquired, and sporadic mammalian neurological disorders, and arecharacterised by the conversion of the cellular prion protein (PrP) in aninsoluble and protease-resistant isoform (PrPres). In human TSE, four typesof PrPres have been identified according to size and glycoform ratios, whichmay represent different prion strains. Type-1 and type-2 PrPres areassociated with sporadic Creutzfeldt-Jakob disease (CJD), type 3 withiatrogenic CJD, and type 4 with variant CJD.1,2 There is evidence thatvariant CJD is caused by the bovine spongiform encephalopathy (BSE)-prionstrain.2-4 The BSE strain has been identified in three cats with felinespongiform encephalopathy (FSE), a prion disease which appeared in 1990 inthe UK.5 We report the simultaneous occurrence of sporadic CJD in a man anda new variety of FSE in his cat. A 60-year-old man, with no unusual dietary habits, was admitted in November,1993, because of dysarthria, cerebellar ataxic gait, visual agnosia, andmyoclonus. An electroencephalogram (EEG) showed diffuse theta-deltaactivity. A brain magnetic resonance imaging scan was unremarkable. 10 dayslater, he was speechless and able to follow only simple commands. RepeatEEGs showed periodic triphasic complexes. 2 weeks after admission, he wasmute, akinetic, and unable to swallow. He died in early January, 1994. His 7-year-old, neutered, female shorthaired cat presented in November,1993, with episodes of frenzy, twitching of its body, and hyperaesthesia.The cat was usually fed on canned food and slept on its owner's bed. Nobites from the cat were recalled. In the next few days, the cat becameataxic, with hindquarter locomotor dysfunction; the ataxia got worse andthere was diffuse myoclonus. The cat was killed in mid-January, 1994. No pathogenic mutations in the patient's PrP gene were found. The patientand the cat were methionine homozygous at codon 129. Histology of thepatient's brain showed neocortical and cerebellar neuronal loss,astrocytosis, and spongiosis (figure A). PrP immunoreactivity showed apunctate pattern and paralleled spongiform changes (figure B). The cat'sbrain showed mild and focal spongiosis in deeper cortical layers of all fourlobes (figure C), vacuolated cortical neurons (figure D), and mildastrogliosis. The cerebellar cortex and the dentate nucleus were gliosed.Immunoreactive PrP showed a punctate pattern in neocortex, allocortex, andcaudate nucleus (figure E). Western blot analysis of control and affectedhuman and cat brain homogenates showed 3 PrP bands of 27-35 kDa. Afterdigestion with proteinase K and deglycosylation, only samples from theaffected patient and cat showed type-1 PrPres, with PrP glycoform ratioscomparable to those observed in sporadic CJD1 (details available fromauthor). [Image] Microscopic sections of patient and cat brains A: Occipital cortex of the patient showing moderate spongiformdegeneration and neuronal loss (haematoxylin and eosin) and B: punctateperineuronal pattern of PrP immunoreactivity; peroxidaseimmunohistochemistry with monoclonal antibody 3F4. C: cat parietal cortexshowing mild spongiform degeneration (haematoxylin and eosin).D:vacuolated neurons (arrow, haematoxylin and eosin), E: peroxidaseimmunohistochemistry with antibody 3F4 shows punctate perineuronaldeposition of PrP in temporal cortex. This study shows a spatio-temporal association between human and felineprion diseases. The clinical features of the cat were different frompreviously reported cases of FSE which were characterised by gradual onsetof behavioural changes preceding locomotor dysfunction and ataxia.5Neuropathological changes were also at variance with the diffuse spongiosisand vacuolation of brainstem neurons, seen in FSE.5 The synaptic pattern ofPrP deposition, similar in the cat and in the patient, was atypical for aBSE-related condition. Evidence of a new type of FSE was further provided bythe detection of a type-1 PrPres, other than the BSE-associated type 4.2Taken together, our data suggest that the same agent strain of sporadic CJ as involved in the patient and in his cat. It is unknown whether these TSE occurred as the result of horizontaltransmission in either direction, infection from an unknown common source,or the chance occurrence of two sporadic forms.

1 Parchi P, Castellani R, Capellari S, et al. Molecular basis of phenotypicvariablity in sporadic Creutzfeldt-Jakob disease. Ann Neurol 1996; 39:767-78 [PubMed]. 2 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis ofprion strain variation and the aetiology of 'new variant' CJD. Nature 1996;383: 685-90 [PubMed]. 3 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[PubMed]. 4 Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJDand BSE. Nature 1997; 389: 448-50 [PubMed]. 5 Pearson GR, Wyatt JM, Henderson JP, Gruffydd-Jones TJ. Feline spongiformencephalopathy: a review. Vet Annual 1993; 33: 1-10. ------------------------------------------------------------------------ Sezione di Neurologie Clinica, Dipartimento di Scienze Neurologiche e dellaVisione, Università di Verona, Policlinico Borgo Roma, 37134 Verona, Italy(S Monaco; e mail rizzuto@Gorgorna.univr.it); and Istituto ZooprofilatticoSperimentale della Lombardia e dell' Emilia, Brescia =========================================TSS indeed there have been 4 documented cases of TSE in Lions to date. Lion 32 December 98 Born November 86 Lion 33 May 1999 (euthanased) Born November 81. Lion 36 Euthanased August 2000 Born July 87. Deteriorating hind limb ataxia. Lion 37 Euthanased November 2001 Male, 14 years. Deteriorating hind limb ataxia since September 2001. (Litter mate to Ref. 36.) http://www.defra.gov.uk/animalh/bse/index.html go to the url above, on the bar at the top, click on _statistics_, then in middle of next page, click on_other TSEs_. or go here;

http://www.defra.gov.uk/animalh/bse/bse-statistics/level-3-tsestat.html:


and http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html:


http://www.bseinquiry.gov.uk/files/yb/1992/11/13001001.pdf:


also; Reports on the clinical symptoms presented by these cats give a relatively homogeneous picture: Affected cats show a lack of coordination with an ataxia mainly of the hind limbs, they often fall and miss their target when jumping. Fear and increased aggressiveness against the owner and also other animals is often seen. They do not longer tolerate to be touched (stroked) and start hiding. These behavioural chances might be the result of a hypersensibility to touch and noise, but also to increased fear. Excessive salivation is another more frequently seen symptom. Cats with FSE in general show severe behavioural disturbances, restlessness and depression, and a lack of coat cleaning. Symptoms in large cats in general are comparable to those in domestic cats. A report on FSE (in german) has been presented in 2001 in the Swiss FVO Magazin. A paper on the first FSE case in a domestic cat in Switzerland is currently in press in the Journal Schweizer Archiv für Tierheilkunde (SAT).

http://www.neurocenter-bern.ch/tse_e.shtml:


Article Posted: 04/15/2007 9:16:48 PM

Human and Animal Food Poisoning with Mad Cow a Slow Death

an editorial by Terry S. Singeltary Sr.

HUMAN AND ANIMAL FOOD POISONING WITH MAD COW DISEASEs A SLOW DEATH

WITH all the pet food deaths mounting from tainted pet food, all the suffering not only the animals are going through, but there owners as well, why are owners of these precious animals not crying about the mad cow tainted animal carcasses they poison there animals with everyday, and have been for decades, why not an uproar about that? well, let me tell you why, they don't drop dead immediately, it's a slow death, they simply call it FELINE and or CANINE ALZHEIMER'S DISEASE, DEMENTIA OR MAD CAT/DOG DISEASE i.e. FSE and they refuse to document CSE i.e.Canine Spongiform Encephalopathy, but it's there and there is some strange pathological findings on that topic that was convientantly swept under the rug. Sadly, this happens everyday with humans, once again confidently swept under the rug as Alzheimer's and or dementia i.e. fast Alzheimer's. Who wants to spend money on an autopsy on an old dog or cat? Sadly, it's the same with humans, you get old and demented your either die or your family puts you in an old folks home and forgets about you, then you die, and again, no autopsy in most cases. Imagine 4.5 annually with Alzheimer's, with and estimated 20+ million dieing a slow death by 2050, and in reality it will most likely be much higher than that now that the blood supply has been infiltrated with the TSE agent, and we now know that blood is another route and source for this hideous disease. It's hell getting old now a days.

NOW, for the ones that don't believe me, well mad cow has been in the USA for decades undetected officially, but the late Richard Marsh documented way back, again, swept under the rug. Then in 2003 in December, the first case of BSE was finally documented, by accident. Then you had the next two cases that were documented in Texas and Alabama, but it took an act of Congress, literally, to get those finally documented, and when they were finally documented, they were atypical BSE or Bovine Amyloid Spongiform Encephalopathy (BASE), which when transmitted to humans is not vCJD or nvCJD, but SPORADIC CJD. Now you might ask yourself what about that mad cow feed ban of August 4, 1997, the year my mother died from the Heidenhain Variant of Creutzfeldt Jakob Disease (confirmed), well that ruminant to ruminant was merely a regulation on paper that nobody enforced. Just last month there was 10+ PLUS MILLION POUNDS OF BANNED BLOOD TAINTED MBM DISPERSED INTO COMMERCE, and there is no way the FDA will ever recover it. It will be fed out again. 2006 was a banner year for FDA mad cow protein fed out into commerce. Looks like 2007 will be also. Our federal Government has failed us at every corner when it comes to food safety. maybe your dog, your cat, your mom, your dad, your aunt, or your uncle, but again, who cares, there old and demented, just put them down, or put them away. It's hell getting old. ...END

http://www.swnebr.net/newspaper/cgi-bin/articles/articlearchiver.pl?160273


http://newhopetoday.blogspot.com/2007/04/article-posted-04152007-91648-pm-human.html


http://www.emaxhealth.com/forums/showthread.php?t=12779


FELINE AND CANINE ALZHEIMER'S OR MAD CAT/DOG DISEASE AND PET FOOD ... ...TSS Name: Terry S. Singeltary Sr. Date: Jan 26, 2007 Dear Terry S. Singeltary Sr. ... specifically dry dog food, some of which was reported to have been ... [url]www.kxmb.com/getArticle.asp?ArticleId=113652[/url] - 107k -

http://www.kxmb.com/getForumPost.asp?ArticleId=113652


FELINE AND CANINE ALZHEIMER'S OR MAD CAT/DOG DISEASE AND PET FOOD ... ...TSS Name: Terry S. Singeltary Sr. Date: Jan 26, 2007 Dear Terry S. Singeltary ... so that the dog food will not mistakenly be mixed into cattle or other ... [url]www.kxnet.com/t/schools/113652.asp[/url] - 107k -

http://www.kxnet.com/getForumPost.asp?ArticleId=113652


Crushed heads (which inevitably involve brain and spinal cord material) are used to a limited extent but will also form one of the constituent raw materials of meat and bone meal, which is used extensively in pet food manufacturer...

http://www.bseinquiry.gov.uk/files/yb/1989/03/17004001.pdf


QUESTION, IS U.S.A. FOOD PRODUCTION SYSTEM POISONING US ?

What Do We Feed to Food-Production Animals? A Review of Animal Feed Ingredients and Their Potential Impacts on Human Health

Amy R. Sapkota,1,2 Lisa Y. Lefferts,1,3 Shawn McKenzie,1 and Polly Walker1 1Johns Hopkins Center for a Livable Future, Bloomberg School of Public Health, Baltimore, Maryland, USA; 2Maryland Institute for Applied Environmental Health, College of Health and Human Performance, University of Maryland, College Park, Maryland, USA; 3Lisa Y. Lefferts Consulting, Nellysford, Virginia, USA

snip...

Table 1. Animal feed ingredients that are legally used in U.S. animal feeds

Animal

Rendered animal protein from Meat meal, meat meal tankage, meat and bone meal, poultry meal, animal the slaughter of food by-product meal, dried animal blood, blood meal, feather meal, egg-shell production animals and other meal, hydrolyzed whole poultry, hydrolyzed hair, bone marrow, and animal animals digest from dead, dying, diseased, or disabled animals including deer and elk Animal waste Dried ruminant waste, dried swine waste, dried poultry litter, and undried processed animal waste products

snip...

Conclusions

Food-animal production in the United States has changed markedly in the past century, and these changes have paralleled major changes in animal feed formulations. While this industrialized system of food-animal production may result in increased production efficiencies, some of the changes in animal feeding practices may result in unintended adverse health consequences for consumers of animal-based food products. Currently, the use of animal feed ingredients, including rendered animal products, animal waste, antibiotics, metals, and fats, could result in higher levels of bacteria, antibioticresistant bacteria, prions, arsenic, and dioxinlike compounds in animals and resulting animal-based food products intended for human consumption. Subsequent human health effects among consumers could include increases in bacterial infections (antibioticresistant and nonresistant) and increases in the risk of developing chronic (often fatal) diseases such as vCJD. Nevertheless, in spite of the wide range of potential human health impacts that could result from animal feeding practices, there are little data collected at the federal or state level concerning the amounts of specific ingredients that are intentionally included in U.S. animal feed. In addition, almost no biological or chemical testing is conducted on complete U.S. animal feeds; insufficient testing is performed on retail meat products; and human health effects data are not appropriately linked to this information. These surveillance inadequacies make it difficult to conduct rigorous epidemiologic studies and risk assessments that could identify the extent to which specific human health risks are ultimately associated with animal feeding practices. For example, as noted above, there are insufficient data to determine whether other human foodborne bacterial illnesses besides those caused by S. enterica serotype Agona are associated with animal feeding practices. Likewise, there are insufficient data to determine the percentage of antibiotic-resistant human bacterial infections that are attributed to the nontherapeutic use of antibiotics in animal feed. Moreover, little research has been conducted to determine whether the use of organoarsenicals in animal feed, which can lead to elevated levels of arsenic in meat products (Lasky et al. 2004), contributes to increases in cancer risk. In order to address these research gaps, the following principal actions are necessary within the United States: a) implementation of a nationwide reporting system of the specific amounts and types of feed ingredients of concern to public health that are incorporated into animal feed, including antibiotics, arsenicals, rendered animal products, fats, and animal waste; b) funding and development of robust surveillance systems that monitor biological, chemical, and other etiologic agents throughout the animal-based food-production chain from farm to for, to human health outcomes; and c) increased communication and collaboration among feed professionals, food-animal producers, and veterinary and public health officials.

REFERENCES...snip...end

Sapkota et al. 668 VOLUME 115 NUMBER 5 May 2007 Environmental Health Perspectives

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1867957&blobtype=pdf


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf


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/2008/03/10-million-baby-boomers-to-have.html


Original Paper

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c

http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html


Sunday, April 27, 2008 re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Greetings,

I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand.

http://betaamyloidcjd.blogspot.com/2008/04/re-association-between-deposition-of.html


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

re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Greetings,

I thought this most important research by Aguzzi et al 'Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease' most important, and thought further reading of this study should be at hand. It seems that more research is further showing that the infamous 'one-in-a-million' diagnosis of CJD that was and is quoted all the time, and or the recently revised guess of 'one case per 9000 in adults age 55 and older', is dreadfully low and inaccurate, thus causing the potential for further exposure and transmission via the medical, surgical, and dental routes. for this reason it is paramount that all TSE be made reportable of all age groups, in every state. it must be made reportable nationally and internationally. also, I think it most important to further research the transmission of Alzheimer's disease, and find out if there is a risk of transmission via the proven routes as the TSE i.e. consumption, medical, surgical, dental, and if so, there may be a need to make Alzheimer's disease a reportable disease as well. ...TSS

PLEASE note, in my ignorance, and my machines, a few LETTERS/SYMBOLS describing B -amyloid (A B ) and apolipoprotein E e 4 will not be displayed properly i.e. the 'B' and the 'e' ...TSS

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Laura Debatin a Johannes Streffer b Markus Geissen c Jakob Matschke c Adriano Aguzzi a Markus Glatzel a, c

a Institute of Neuropathology, and b Division of Psychiatry Research, University Hospital Zurich, Zurich , Switzerland; c Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg , Germany

Copyright © 2008 S. Karger AG, Basel

Abstract

Background: Alzheimer’s disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, B -amyloid (A B ), which deposits in AD, and the abnormal form of the prion protein, PrP Sc , which deposits in sCJD. Methods: We have characterized sCJD patients (n = 14), AD patients (n = 5) and nondemented controls (n = 5) with respect to the deposition of PrP Sc and A B morphologically, biochemically and genetically and correlated these findings to clinical data. Results: sCJD-diseased individuals with abundant deposits of A B present with a specific clinicopathological profile, defined by higher age at disease onset, long disease duration, a genetic profile and only minimal amounts of PrP Sc in the cerebellum. Conclusion: The co-occurrence of pathological changes typical for sCJD and AD in combination with the inverse association between accumulation of A B and PrP Sc in a subgroup of sCJD patients is indicative of common pathways involved in the generation or clearance of A B and PrP Sc in a subgroup of sCJD patients.

Copyright © 2008 S. Karger AG, Basel

Introduction

snip...

Discussion

In a wide range of dementias, generation and subsequent deposition of abnormally processed proteins is thought to be causally involved in the pathophysiology of the disease and assessment of protein deposition can be employed as a diagnostic tool for the classification of these entities [28]. AD and CJD are two examples of this group of diseases, where generation and deposition of abnormally processed proteins, PrP Sc in the case of sCJD and A B in the case of AD, are involved in the pathophysiology. Coexistence of AD-type neuropathology in sCJD has been repeatedly reported, yet the interpretation of these findings is highly controversial. Some investigators surmise unspecific age-related changes [11] , others assume that this points to similarities in the pathogenesis of AD and CJD [29] . In this study, we characterized deposition of A B in sCJD patients by immunohistochemistry, Western blotting, ELISA and genetic investigations. Using biochemical methods we were able to identify a subgroup of sCJD patients, which is defined by high cerebral A B 42 loads. These patients were on average more than 6 years older than those with minimal or no depos-

its of A B 42 , presented with significantly longer disease durations, were more likely to carry an uncommon polymorphism on PRNP codon 129 or deposit PrP Sc type 2 [30] and had a high likelihood to carry at least one allele of apolipoprotein E e 4. Interestingly, these patients harbor only minimal amounts of PrP Sc in the cerebellum. This clinicopathological signature suggests that this group of patients represents a subgroup of sCJD.

A study focusing on the assessment of genetic profiles of sCJD demonstrated that the apolipoprotein E e 4 allele is an independent risk factor for developing sCJD [31, 32] . In this study, we provide evidence that the apolipoprotein E e 4 status may be linked to the development of a subtype of sCJD. The above-mentioned study did not investigate A B loads in apolipoprotein E e 4-positive sCJD patients. One could hypothesize that patients identified by van Everbroeck et al. [32] belong to the subgroup of sCJD patients characterized by abundant A B and scarce PrP Sc deposits.

A study focusing on the influence of PrP C expression on A B plaque formation suggested that overexpression of PrP C promotes A B plaque formation [15] . Given the fact that PrP C expression is unchanged during the course of prion disease [33] , PrP C upregulation is an unlikely explanation for enhanced A B deposition in certain sCJD patients. Since accumulation of malprocessed proteins in the brain is the result of the differential between its de novo generation and its clearance, it is conceivable that A B deposition in sCJD may be the result of a saturation of common clearance mechanisms [34, 35] . This hypothesis is supported by a wealth of data suggesting that similar processes of protein degradation are in place for PrP Sc and A B [36–38] .

In an attempt to delineate possible molecular pathways explaining the abundant generation of A B 42 in a subset of sCJD patients, we measured central nervous system expression of B -secretase, a key protease for the generation of A B [27] . Several studies have shown that B -secretase activity and protein expression are increased in the cortex of patients suffering from AD [26, 39, 40] . Furthermore, BACE activity seems to be increased in the cerebrospinal fluid of sCJD patients [41] . The fact that we did not find any significant differences in BACE expression is in agreement with published studies and may indicate alternative pathways for A B generation in these patients [41] .

The group of sCJD patients with high cerebral levels of A B 42 showed minimal deposits of PrP Sc . PrP Sc profiling allowed us to directly compare PrP Sc levels between sCJD cohorts [22] . PrP Sc levels showed the most drastic differences in the cerebellum. PrP Sc levels in low A B 42 patients uniformly showed high cerebellar PrP Sc loads, whereas PrP Sc levels in high A B 42 patients uniformly showed low or nondetectable cerebellar PrP Sc levels. Interestingly, cerebellar involvement is a rarity in AD [42] . It has been speculated that the descriptive classification

of AD may camouflage CJD [43] . Although one could argue that the subgroup of sCJD we have identified could have been misdiagnosed as AD, thus supporting the above-mentioned hypothesis, the sCJD typical clinical presentation of these patients argues against the theory that sCJD is commonly misdiagnosed as AD. Taking into account that the majority of cerebral proteinopathies are characterized by deposition of more than one abnormally processed protein [28] , neuropathological diagnosis of dementia should only be carried out in centers equipped to monitor deposition of all disease-associated proteins.

In conclusion, the present study provides evidence for the existence of a subgroup of sCJD characterized by abundant A B 42 deposits, high age at onset of disease, a specific genetic profile and only marginal deposits of PrP Sc . These data are in line with common molecular mechanisms leading to the deposition of A B and PrP Sc . Their delineation will be the focus of future studies. The fact that this newly defined group of patients harbors only minimal amounts of PrP Sc is intriguing. On the one hand, this represents a challenge to neuropathologists, and on the other hand, the possibility that minimal PrP Sc deposits may go undetected could lead to the misdiagnosis of AD.

snip...full text ;

http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000121389

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

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

To the Editor:

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

Terry S. Singeltary, Sr Bacliff, 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

JOURNAL OF NEUROLOGY

MARCH 26, 2003

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/

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

Notes:

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

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

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

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

-- Communicated by: Terry S. Singeltary Sr. <flounder9@verizon.net>

[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://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

Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)

http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf

The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...

http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf

And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.

http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf

Human BSE

These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.

http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf

IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

From: TSS Subject: CJD or Alzheimer's, THE PA STUDY...full text Date: May 7, 2001 at 10:24 am PST

Diagnosis of dementia: Clinicopathologic correlations

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.

NEUROLOGY 1989;39:76-79

Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261.

January 1989 NEUROLOGY 39 79

snip...

From: TSS (216-119-130-151.ipset10.wt.net) Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: May 8, 2001 at 6:27 pm PST

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de

#### Bovine Spongiform Encephalopathy ####

Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd

To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic. (Arch Neurol. 1992;49:28-31)

"Dementia" is a syndrome characterized by global deterioration of cognitive abilities and is the general term used to describe the symptom complex of intellectual deterioration in the adult. It is associated with multiple causes, although Alzheimer's disease (AD) alone accounts for approximately 60% of cases.1-3...

snip...

Subject: Re: Hello Dr. Manuelidis Date: Fri, 22 Dec 2000 17:47:09 -0500 From: laura manuelidis Reply-To: laura.manuelidis@yale.edu Organization: Yale Medical School To: "Terry S. Singeltary Sr."

References: <39B5561A.87B84A28@wt.net> <39B64574.A4835745@yale.edu> <39B680D8.3872535B@wt.net> <39B66EF1.4CE25685@yale.edu> <39BBB812.425109F@wt.net> <39BE84CB.D7C0C16B@yale.edu> <3A3BA197.7F60D376@wt.net>

Dear Terry,

One of our papers (in Alzheimer's Disease Related Disord. 3:100-109, 1989) in text cites 6 of 46 (13%) of clinical AD as CJD. There may be a later paper from another lab showing the same higher than expected incidence but I can't put my hands on it right now. We also have a lot of papers from 1985 on stating that there are likely many silent (non-clinical) CJD infections, i.e. much greater than the "tip of the iceberg" of long standing end-stage cases with clinical symptoms. Hope this helps.

best wishes for the new year laura manuelidis

end...

======================= *********2008************* =======================

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

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

10 Million Baby Boomers to have Alzheimer's in the coming decades

2008 Alzheimer’s disease facts and figures

Alzheimer’s Association*

Abstract Alzheimer’s disease is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years. More than 5 million Americans are estimated to have Alzheimer’s disease. Every 71 seconds someone in America develops Alzheimer’s disease; by 2050 it is expected to occur every 33 seconds. During the coming decades, baby boomers are projected to add 10 million people to these numbers. By 2050, the incidence of Alzheimer’s disease is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million persons. Significant cost implications related to Alzheimer’s disease and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (eg, caregiver lost wages and out-of-pocket expenses, decreased business productivity) costs. Not included in these figures are the estimated 10 million caregivers who annually provide $89 billion in unpaid services to individuals with Alzheimer’s disease. This report provides information to increase understanding of the public health impact of Alzheimer’s disease, including incidence and prevalence, mortality, lifetime risks, costs, and impact on family caregivers.


snip...


7.2. Impact of future reductions in deaths from other causes
As discussed in the Mortality section, the number of
deaths due to heart disease, cancer, and stroke, the three
leading causes of death, is decreasing. As a result, unless
there are new treatments to prevent Alzheimer’s and other
dementias, the remaining lifetime risk of Alzheimer’s and
dementia will increase substantially in the future because
the decreasing number of deaths from heart disease, cancer,
and stroke means that more people live long enough to
develop Alzheimer’s and other dementias.

7.3. Implications for baby boomers

The baby boomers are people living in the United States
now who were born from 1946 through 1964. In 2008, the
oldest baby boomers, people born in 1946, will be 62. The
youngest baby boomers, people who were born in 1964, will
be 44. The remaining lifetime risks of Alzheimer’s disease and
dementia shown in Figs. 9 and 10 apply to baby boomers
who are already age 55 or older. The remaining lifetime
risks of Alzheimer’s and other dementias also apply to baby
boomers who are younger than 55, assuming that they live
to be at least 55. The baby boomer group now includes about
78 million Americans, of whom 27 million are ages 55 to 62 and 51
million ages 44 to 54. Applying the proportions in Figs. 9
and 10, the Alzheimer’s Association estimates that 10 million
of these baby boomers can expect to develop Alzheimer’s
disease in their remaining lifetime (Appendix 16).
Similarly, about 14 million baby boomers can expect to
develop dementia, including Alzheimer’s disease.
As noted earlier, these figures are conservative because
of the relatively high threshold for including an individual
as a person with dementia in the Framingham Heart Study,
which is the source of the lifetime risk estimates (Appendix
16). True lifetime risk for baby boomers will probably be
greater for this reason. True lifetime risk for baby boomers
will also be greater because deaths from heart disease,
cancer, and stroke will probably continue to drop, increasing
the life span during which the boomers could develop
Alzheimer’s or other dementias.

References

snip... see full text 24 pages ;

© 2008 The Alzheimer’s Association. All rights reserved.


http://www.alzheimersanddementia.org/webfiles/images/journals/jalz/JALZ_739.pdf


Friday, March 21, 2008

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000121389


see full text Alzheimer's and CJD i.e. TSE, aka mad cow disease

http://betaamyloidcjd.blogspot.com/

http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html


TSS

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Friday, March 21, 2008

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease Original Paper

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, Adriano Aguzzia, Markus Glatzela, c

aInstitute of Neuropathology, and bDivision of Psychiatry Research, University Hospital Zurich, Zurich, Switzerland; cInstitute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Address of Corresponding Author

Neurodegenerative Dis (DOI: 10.1159/000121389)

---------------------------------------------------------------------------- ----

Key Words

Sporadic Creutzfeldt-Jakob disease Alzheimer's disease Deposition of -amyloid Prion protein

---------------------------------------------------------------------------- ----

Abstract

Background: Alzheimer's disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, -amyloid (A), which deposits in AD, and the abnormal form of the prion protein, PrPSc, which deposits in sCJD. Methods: We have characterized sCJD patients (n = 14), AD patients (n = 5) and nondemented controls (n = 5) with respect to the deposition of PrPSc and A morphologically, biochemically and genetically and correlated these findings to clinical data. Results: sCJD-diseased individuals with abundant deposits of A present with a specific clinicopathological profile, defined by higher age at disease onset, long disease duration, a genetic profile and only minimal amounts of PrPSc in the cerebellum. Conclusion: The co-occurrence of pathological changes typical for sCJD and AD in combination with the inverse association between accumulation of A and PrPSc in a subgroup of sCJD patients is indicative of common pathways involved in the generation or clearance of A and PrPSc in a subgroup of sCJD patients.

Copyright © 2008 S. Karger AG, Basel

---------------------------------------------------------------------------- ----

Author Contacts

Markus Glatzel Institute of Neuropathology, University Medical Center Hamburg-Eppendorf Martinistrasse 52, DE-20246 Hamburg (Germany) Tel. +49 40 42 803 2218, Fax +49 40 42 803 4929 E-Mail mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:m.glatzel@uke.uni-hamburg.de




http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000121389




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

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

To the Editor:

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

Terry S. Singeltary, Sr Bacliff, 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




JOURNAL OF NEUROLOGY

MARCH 26, 2003

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




Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)




http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf




snip...

The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...

snip...




http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf




And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.




http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf




Human BSE

snip...

These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES


http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf


Subject: Re: Hello Dr. Manuelidis Date: Fri, 22 Dec 2000 17:47:09 -0500 From: laura manuelidis <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:laura.manuelidis@yale.edu> Reply-To:laura.manuelidis@yale.edu Organization: Yale Medical School To: "Terry S.Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:flounder@wt.net>

References: < manuelidis ="=" href=" http://neurotalk.psychcentral.com/thread13175.html


http://neurotalk.psychcentral.com/showthread.php?p=156015


More Evidence Mad Cow Same As CJD And Alzheimer's

1-24-3

To: Terry S. Singletary Sr From Cindy B. Date: Friday, Jan 24 2003

Subj: CJD $ Alzheimer's

Hi,

I read your article on CJD on www.rense.com and was wondering when they are going to alert the population of this and start testing all these animals that are being consumed by humans.

I have also read other articles that relate Alzheimer's, ALS, Parkinson's disease among others that have been linked to BSE/Mad Cow.

Assuming all this is true (which I have no doubt it is), wouldn't everyone have to get tested to see if they have contracted any of these or their variants?

I am really bothered by this whole thing and the lies that have been perpetuated by their many fronts in our government.

Also, when they talk about "downers", does that refer to sick animals? And that even these sick animals are given as feed to the other animals?

One last thing, I have information that an individual has "mad cow" who was in surgery here in our local hospital. The individual that told me says they are keeping it under tight wraps.

Thanks for your work and the very informative article,

Cindy Bouthillier Greeley, Colorado

Date: Fri, 24 Jan 2003 From: Terry S. Singeltary Sr.

Subject: Re: CJD $ Alzheimer's

Hello Cindy,

Thank you for your kind words. I have posted some data below on CJD and Alzheimer's that you may find interest in.

Yes, there are about 200,000 downers annually in the USA. This involves cattle that go down for one reason or another and that includes prion/CNS disorder cattle of all sorts and yes, you are feeding dead doggy and kitty cat (and the chemicals used to euthanize old pets, dead downer cattle, 'roadkill' which includes scrapie infected sheep and CWD/mad deer infected deer and elk. It's just and endless cycle of greed.

I would be interested to know more about the case of CJD and the hospital/surgical arena. This will be a major vector (of transmission) for prions.

OH...and don't start looking for rapid TSE/prion testing in sufficient numbers to find TSEs/mad cow in US cattle anytime soon, because if you don't look...you don't find. Thus, you keep the 'gold card' of 'BSE/TSE FREE' status in US cattle. Of course, we know different...

Kind regards, Terry

Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)


http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf


snip...

The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf


And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.


http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf


Human BSE

snip...

These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf


=====================================================

From: TSS (216-119-130-123.ipset10.wt.net)

Subject: CJD or Alzheimer's, THE PA STUDY...

full text Date: May 7, 2001 at 10:24 am PST

Diagnosis of dementia: Clinicopathologic correlations

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.

NEUROLOGY 1989;39:76-79

Several recent papers and reports have addressed the problem of improving the clinician's ability to diagnose dementia. Notable among those reports are the diagnostic criteria for dementia of the American Psychiatric Association, known as DSM III,1 as well as the clinical and neuropathologic criteria for the diagnosis of Alzheimer's disease (AD).2,3 Other researchers have published guidelines for the differentiation of various types of dementia4 and for antemortem predictions about the neuropathologic findings of demented patients.5

Most studies on the accuracy of clinical diagnosis in patients with dementia, especially AD, have used clinicopathologic correlation,6-15 and have found a percentage of accuracy ranging from 43% to 87%. Two recent reports, however,16,17 have claimed an accuracy of 100%. These two reports are based on relatively small series and have consisted of very highly selected patient samples. In our own recent experience, several cases of dementia have yielded unexpected neuropathologic findings,18 and we hypothesized that, in larger series, there would be a significant number of discrepancies between clinical diagnoses and autopsy findings. The present paper reviews the neuropathologic diagnosis of 54 demented patients who were autopsied consecutively at the University of Pittsburgh over a 7-year period, and reports the ability of clinicians to predict autopsy findings.

Material and methods. We independently reviewed the pathologic data and clinical records of 54 consecutive patients who had had an autopsy at the University of Pittsburgh (Presbyterian University Hospital [PUH] and the Pittsburgh (University Drive) Veterans Administration Medical Center [VAMC]), between 1980 and 1987.

The 54 cases included all those where dementia was diagnosed clinically but for which an obvious etiology, such as neoplasm, trauma, major vascular lesions, or clinically evident infection had not been found. The brains, evaluated by the Division of Neuropathology of the University of Pittsburgh, were obtained from patients cared for in different settings at their time of death.

On the basis of the amount of information available in each case, we divided the patients into three groups. Group 1 included 12 subjects who had been followed for a minimum of 1 year by the Alzheimer Disease Research Center (ADRC) of the University of Pittsburgh. ADRC evaluations include several visits and neurologic and neuropsychological testing as well as repeated laboratory tests, EEG, and CT.19,20

Group 2 included 28 patients who had been seen in the Neurology Service of PUH, of the VAMC, or in geriatric or psychiatric facilities of the University of Pittsburgh or at Western Psychiatric Institute and Clinic. All patients were personally evaluated by a neurologist and received a work-up to elucidate the etiology of their dementia.

Group 3 included 14 patients seen in other institutions; in most cases, they had also been seen by a neurologist and had had laboratory studies that included CT of the head. In three of the 14 cases, however, the information could be gathered only from the clinical summary found in the autopsy records.

Many of these subjects were referred for autopsy to the ADRC because of a public education campaign that encourages families to seek an autopsy for their relatives with dementia.

Pathologic data. All brains were removed by a neuropathologist as the first procedure of the autopsy at postmortem intervals of between 4 and 12 hours. The unfixed brain was weighed and the brainstem and cerebellum were separated by intercollicular section. The cerebral hemispheres were sectioned at 1-cm intervals and placed on a glass surface cooled by ice to prevent adhesion of the tissue to the cutting surface. The brainstem and cerebellum were sectioned in the transverse plane at 6-mm intervals. Brain sections were fixed in 10% buffered formalin. Selected tissue blocks for light microscopy were obtained from sections corresponding as exactly as possible to a set of predetermined areas used for processing brains for the ADRC protocol; additional details of the neuropathologic protocol have been previously published.18,21 Following standard tissue processing and paraffin embedding, 8-um-thick sections stained with hematoxylin and eosin and with the Bielschowsky ammoniacal silver nitrate impregnation were evaluted. Additional stains were used when indicated by the survey stains, including the Bielschowsky silver technique as previously reported.21

Clinical data. The medical history, as well as the results of examinations and laboratory tests, were obtained from the medical records libraries of the institutions where the patient had been followed and had died. We supplemented these data, when appropriate, with a personal or telephone interview with the relatives.

One neurologist (O.L.L.) recorded the information to be evaluated on two forms. The first form included sex, age, handedness, age at onset, age at death, course and duration of the disease, education, family history, EEG, CT, NMR, medical history, and physical examination as well as examination of blood and CSF for factors that could affect memory and other cognitive functions. The form also listed the results of neuropsychological assessment, and the characteristics and course of psychiatric and neurologic symptoms. The form provided details on the presence, nature, and course of cognitive deficits and neurologic signs. The second form was a 26-item checklist derived from the NINCDS-ADRDA Work Group Criteria for probable Alzheimer's disease.2 The forms did not include the patient's identity, the institution where they had been evaluated, the clinical diagnosis, or the pathologic findings.

Each form was reviewed independently by two other neurologists (F.B. and J.M.), who were asked to provide a clinical diagnosis. In cases of probable or possible AD, the two neurologists followed the diagnostic criteria of the NINCDS/ ADRDA work group.2

The results were tabulated on a summary sheet filled out after the two neurologists had provided their diagnosis on each case. The sheet included the diagnosis reached by the two neurologists and the diagnosis resulting from the autopsy.

Table 1. Pathologic diagnosis in 54 patients with dementia

N %

Alzheimer's disease alone 34 62.9

Alzheimer's disease and 2 3.7 Parkinsons's disease

Alzheimer's disease with 2 3.7 multi-infarct dementia

Alzheimer's disease with amyotrophic lateral sclerosis 39 72.2

Total Alzheimers disease 39 72.2

Multi-infarct dementia 4 7.4

Multi-infarct dementa 1 1.8 with Parkinson's disease

Parkinson's disease 2 3.7

Progressive subcortical gliosis 2 3.7

Creutzfeldt-Jakob disease 3 5.5

Progressive supranuclear palsy 1 1.8

Huntington's disease 1 1.8

Unclassified 1 1.8

Total other disease 15 27.7

Total all cases 54

Table 2. Clinical diagnosis

Clinical diagnosis Clinician #1 --- #2

Probable AD 29 21

Probable AD and MID 3 0

Probable AD and thyroid disease 1 2

Probable AD and PD 3 1

Probable AD and ALS 1 0

Probable AD and 0 1 olivopontocerebellar degeneration

Total probable AD 37 25 (68.5%) (46.2%)

Possible AD 3 2

Possible AD and MID 2 2

Possible AD and alcoholism 0 1

Possible AD and depression 1 0

Possible and thyroid disease 0 3

Possible AD and traumatic 1 2 encephalopathy

Possible AD and PD 3 6

Total Possible AD 10 16 (18.5%) (29.6%)

Atypical AD 0 1

Atuypical AD and MID 0 1

MID 2 4

MID and PD 3 0

Dementia syndrome of depression 0 1

HD 1 1

Wernicke-Korsakoff syndrome 1 0

Dementia of unknown etiology 0 5

Total 54 54

Results. The subjects included 26 women and 28 men who ranged in age from 30 to 91 years (mean, 72.2; SD, 10.7).

Autopsy findings. Table 1 shows that 39 (72.2%) of the 54 cases fulfilled histologic criteria for AD, with or without other histopathologic findings. The remaining 15 cases (27.7%) showed changes corresponding to other neurodegenerative disorders, cerebrovascular disease, or Creutzfeldt-Jakob disease (CJD). Seven cases met the histopathologic criteria for multi-infarct de-mentia (MID). Five cases (9.2%) showed changes associated with Parkinson's disease (PD).

Twenty-two of the 39 AD patients (56%) were age 65 or greater at the time of the onset of the disease. Seven of the 15 patients in the group with other diseases (47%) were age 65 or older at the time of disease onset.

Clinical diagnosis. There was a general adherence to the criteria specified by McKhann et al.2 However, the two clinicians in this study considered the diagnosis of probable AD when the probability of AD was strong even if a patient had another disease potentially associated with dementia that might or might not have made some contribution to the patient's clinical state (table 2).

Accuracy of the clinical diagnosis (table 3). Group 1 (N = 12). There were six men and six women. Ten cases (83.3%) met the histologic criteria for AD. In nine cases (75.0%), the diagnosis of both clinicians agreed with the pathologic findings; in the other case (8.3%), one clinical diagnosis agreed with the histologic findings. The remaining two cases (16.6%) had histopathologic diagnoses of CJD and progressive supranuclear palsy (PSP), respectively. Both cases were incorrectly diagnosed by both clinicians.

Group 2 (N = 28). There were 11 women and 17 men. Eighteen cases (64.2%) had the histopathologic features for AD with or without additional findings. Sixteen of these cases (57.1%) were correctly diagnosed by both clinicians, one case by one of them, and both incorrectly diagnosed one case. The remaining ten cases (35.7%) included two with CJD; two with subcortical gliosis (SG); two with PD, one of which was associated with MID; one case of Huntington's disease (HD); two cases with MID; and one unclassifed. Only one, the HD case (3.5%), was correctly diagnosed by both observers, and four cases (14.2%), two MID and two PD, one associated with MID, were correctly diagnosed by one clinician.

Group 3 (N = 14). In this group there were nine women and five men. Eleven cases (78.5%) met the histopathologic criteria for AD with or without additional findings. Eight of these cases (57.1%) were correctly diagnosed by both clinicians, two cases by one of them, while both were incorrect in one case. Of the remaining three cases (21.4%), only one was correctly diagnosed (7.1%) by one clinician. Both missed the two other cases of MID.

There was no statistically significant difference in diagnostic agreement across patient groups in which the amount of clinical information was different (X2 = 1.19; p > 0.05).

Table 3. Accuracy of the clinical diagnosis by two clinicians

Both One Neither Correct Correct Correct

Group 1 (N = 12) 9 1 2(16.6%)

Group 2 (N = 28) 17 5 6(21.4%)

Group 3 (N = 14) 8 3 3(21.4%)

Table 4. Previously reported studies of clinicopathologic correlation in demented patients*

Agreement %

Number of cases AD

Retrospective studies

Todorov et al, 1975(7) 776 43

Perl et al, 1984(9) 26 81

Wade et al, 1987(12) 65 85

Alafuzoff et al, 1987(13) 55 63

Kokmen at al, 1987(14) 32 72

Joachim et al, 1987(15) 150 87

Prospective studies

Sulkava et al, 1983(8) 27 82

Molsa et al, 1985(10) 58 71

Neary et al, 1986(11) 24 75

Martin et al, 1987(16) 11 100

Morris et al, 1987(17) 25 100

* Certain differences in methodology need clarification. Some authors7,8,10,11,12,13,16,17 tabulated patients with AD alone, and others9,14,15 included patients with AD plus other diseases, eg, Parkinson's disease and MID. We have combined AD alone and AD plus MID and other neurodegenerative diseases.

Discussion. Our results indicate that in a population of patients with dementias of varied etiology, the diagnosis could be correctly inferred by at least one of two clinicians in approximately 80% of cases. For one observer, the sensitivity of clinical diagnosis for AD was 85% and the specificity was 13%, and for the other, it was 95% and 33% respectively.

In the cases with a discrepancy between the clinical diagnosis and the neuropathologic findings, the great majority of patients had atypical clinical courses and findings. The three cases with autopsy findings of CJD had a much longer course than is usually seen with that condition and failed to show the usual EEG abnormalities. The patient with autopsy findings of PSP did not show the disorder in the extraocular movements usually associated with that condition. An atypical course was also present for two AD cases and two MID cases that did not have any feature suggestive of vascular disease. In one MID case, the CT did not show any focal lesions, while in the other it was not available. With regard to the two patients with SG, the pathologic diagnosis is so unusual and so infrequently recorded that clear clinical correlates are not evident.18 The third category of possible error is the patient listed as unclassified, for whom no specific neuropathologic diagnosis could be reached.22

The small number of neuropathologic diagnoses of Parkinson's disease reflects that, for the purpose of this series, the diagnosis of PD was made only when there were both a clear-cut clinical history and the neuropathologic findings characteristic of the disease, such as Lewy bodies, neuronal loss, globose neurofibrillary tangles, astrocytosis, and extraneuronal melanin pigment in substantia nigra and locus ceruleus.

Are these results derived from a sample of 54 patients representative of disease patterns in the community? Generally, the diagnosis of patients reported from major medical centers tend to be biased since the more complicated cases are referred there. In this study, however, this bias may be less important. Due to the major public education campaign about dementia and AD sponsored by the ADRC, there is a widespread awareness in Pittsburgh and in the surrounding regions of Western Pennsylvania of the value of an autopsy for a definitive diagnosis. Therefore, the great majority of cases were referred to us because the family wanted to know the precise etiology of a case of dementia.

The significant improvement in the clinical diagnosis of AD is a recent phenomenon. Due to the publicity and the advances in communication of scientific investigations, most physicians are more likely to consider AD as the main cause of dementia. The current risk of overdiagnosing AD reminds one of what occurred during the 1960s with the diagnosis of "atherosclerotic dementia."6 The high sensitivity and low specificity for AD shown in our study may reflect that possibility.

Because of the varying criteria for "other dementias" in many publications, we chose to analyze the accuracy of clinical diagnosis in terms of the diagnosis of AD alone or AD plus other neuropathologic findings. Several retrospective studies have attempted to point out reliable clinical and pathologic features for diagnosing the dementias, especially AD. The study of Tomlinson et al6 is not included in table 4 because there was no attempt to validate the clinical diagnosis with pathologic findings. The reports surveyed vary considerably in size and methodology. Sample size, for example, ranges from 26 subjects9 to 776 subjects.7 Some studies base the diagnosis on limited clinical information,7'9'14'15 others use widely accepted diagnostic criteria such as those specified in DSM III,13 and one group uses a standardized clinical assessment of patients enrolled in a longitudinal study.12 The reported accuracy of the clinical diagnosis of AD ranges from 43%7 to 87%.15

Recent prospective studies that adhere to strict clinical criteria,10'11'17 those in DSM III8 or those proposed by McKhann et al,16 indicate improved accuracy of clinical diagnosis of the most common causes of dementia, especially AD. In sample sizes ranging from 11 subjects16 to 58 subjects,l0 the accuracy of clinical diagnosis is reported as ranging from 71%10 to 100%16'17' Only two series, both based on small samples, report a 100% accuracy. We consider it unlikely that such accuracy could be confirmed in large series because of some inevitable imprecision in clinical diagnoses and the variability of clinical pictures. Furthermore, although researchers generally agree on the application of uniform criteria in clinical diagnosis of dementia, opinions still differ about specific diagnostic criteria, as well as about the pathologic characterization of dementia. Except for those small series, the results summarized in table 4(7-15) is are remarkably consistent with ours.

In table 3, although there was no statistical difference (p > 0.05) in diagnostic agreement across patient groups, there is a trend toward a lower percentage of diagnostic errors for the patients who had been followed most intensely (16% in group 1 compared with 21% in groups 2 and 3). The difference is not great, and it is, in fact, surprising to find out that in the patients about whom relatively little was known (group 3) the percentage of diagnostic error was the same as among patients seen by neurologists and for whom much more data were available (group 2). These paradoxical findings probably indicate that both clinicians learned to extract essential diagnostic criteria2 in spite of the variations in the amount of information available for consideration. It may well be that clinical, radiographic, and laboratory assessment of patients with dementia is burdened with information that is excessive and unessential for purely diagnostic purposes.

Acknowledgments

We thank Dr. A. Julio Martinez and Dr. Gutti Rao from the Division of Neuropathology for autopsy data. Mrs. Margaret Forbes, Ms. Annette Grechen, and Mrs. Paula Gent helped in the preparation of the manuscript.

References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Organic Dementia Disorders, 3rd ed. Washington DC, APA, 1983:101-161.

2. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Dis-ease. Neurology 1984;34:939-944.

3. Khachaturian Z. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105.

4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston: Butterworths, 1983.

5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7:486-488.

6. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11.205-242.

7. Todorov A, Go R, Constantinidis J, Elston R. Specificity of the clinical diagnosis of dementia. J Neurol Sci 1975;26:81-98.

8. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13.

9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua-tion of banked brain specimens submitted with clinical diagnosis of Alzheimer's disease. In: Wirtman R, Corkin S, Growdon J, eds. Alzheimer's disease: advances in basic research and therapies. Proceedings of the Fourth Meeting of International Study Group on the Treatment of Memory Disorders Associated with Aging. Zurich, January 1984. Cambridge, MA: CBSM, 1984:463. Molsa PK, Paljarvi L, Rinne JO, Rinne UK, Sako E. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 1985;48:1085-1090.

11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn-dromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986;49:163-174.

12. Wade J, Mirsen T, Hachinski V, Fismm~ M, Lau C, Merskey H. The clinical diagnosis of Alzheimer disease. Arch Neurol 1987;44:24-29.

13. Alafuzoff I, Igbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinicalpathological correlation and classification by multivariate data analysis. Acta Neuropathol (Berl) 1987,74:209-225.

14. Kokmen E, Offord K, Okazaki H. A clinical and autopsy study of dementia in Olmsted County, Minnesota, 1980-1981. Neurology 1987;37:426-430.

15. Joachim CL, Morris JH, Selkoe D. Clinically diagnosed Alzheimer's disease: autopsy neuropathological results in 150 cases. Ann Neurol 1988;24:50-56.

16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology 1987;37:1201-1204.

17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann Neurol 1987;22:122.

18. Moossy J, Martinaz J, Hanin I, Rao G, Yonas H, Boiler F. Thalamic and subcortical gliosis with dementia. Arch Neurol 1987;44:510-513.

19. Huff J, Becker J, Belle S, Nebes R, Holland A, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology 1987;37:1119-1124.

20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The neurological examination in patients with probable Alzheimer's disease. Arch Neurol 1987;44:929-932.

21. Moossy J, Zubenko G, Martinez AJ, Rao G. Bilateral symmetry of morphologic lesions in Alzheimer's disease. Arch Neurol 1988;45:251-254.

22. Heilig CW, Knopman DS, Mastri AR, Frey W II. Dementia without Alzheimer pathology. Neurology 1985;35:762-765.

From the Departments of Neurology (Drs. Boller, Lopez, and Moossy), Psychiatry (Dr. Boller), Pittsburgh (University Drive) Veterans Administration Medical Center (Dr. Boller), Department of Pathology (Division of Neuropathology) (Dr. Moossy), and the Pittsburgh Alzheimer Disease Research Center (Drs. Boller, Lopez, and Moossy), University of Pittsburgh Medical School, Pittsburgh, PA.

Supported in part by NIH Grants nos. AG05133 and AG03705, NIMH Grant no. MH30915, by funds from the Veterans Admin., and by the Pathology Education and Research Foundation (PERF) of the Department of Pathology, University of Pittsburgh.

Presented in part at the fortieth annual meeting of the American Academy of Neurology, Cincinnati. OH, April 1988.

Received April 7, 1988. Accepted for publication in final form July 20, 1988.

Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261.

January 1989 NEUROLOGY 39 79

TSS

From: TSS (216-119-130-151.ipset10.wt.net)

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

Date: May 8, 2001 at 6:27 pm PST

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:BSE-L@uni-karlsruhe.de

######### Bovine Spongiform Encephalopathy #########

Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd

· To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic. (Arch Neurol. 1992;49:28-31)

"Dementia" is a syndrome characterized by global deterioration of cognitive abilities and is the general term used to describe the symptom complex of intellectual deterioration in the adult. It is associated with multiple causes, although Alzheimer's disease (AD) alone accounts for approximately 60% of cases.1-3

Interest in the accuracy of the diagnosis of dementia is a relatively recent phenomenon, reflecting both an increase in physicians' awareness of multiple specific causes of dementia and a marked increase in both the incidence and prevalence of dementia associated with the increase in the elderly population.4' The clinical evaluation remains the key to the differential diagnosis, and in most cases dementia can be diagnosed accurately by clinical criteria. However, the definitive diagnoses of AD.1'5'7 Pick's disease,8'10 Creutzfeldt-Jakob disease (CJD),11-16 Binswanger's disease,17'18' and diffuse Lewy body disease19-22 still require histologic examination of the cortex to identify characteristic structural changes.

Brain tissue is almost invariably obtained at autopsy, and the vast majority of pathologic diagnoses are thus made post mortem. Alternatively, an antemortem histologic diagnosis can be provided to the patient and his or her family if a cerebral biopsy is performed while the patient is still alive. Because brain biopsies for dementia are not routinely performed, we sought to define the spectrum of pathologic changes seen in a retrospective unselected series of adult patients undergoing cerebral biopsy for the diagnosis of atypical dementing illnesses and to determine the patient selection criteria most likely to result in a definitive diagnosis.

MATERIALS AND METHODS

Cerebral biopsies performed solely for the diagnosis of dementia in adult patients were identified by a manual search of the patient files of the Division of Neuropathology, Duke University Medical Center Durham, NC, and by a computerized search of discharge diagnoses of patients undergoing brain biopsies. Fourteen cases were identified from the period 1980 to 1989. Patients undergoing biopsies for suspected tumor, inflammation, or demyelinating disease were excluded. A clinical history of dementia was an absolute requirement for inclusion in the study. Diagnosis was based on Dignostic and Statistical Manual of Mental Disorders, Third Edition, and on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for probable AD.23

The published recommendations for handling tissue from patients with suspected CJD were followed in every case.24-26 Briefly, tissue was transported in double containers clearly marked "Infectious Disease Precations." Double gloves, aprons, and goggles were used at all times. Tissue was fixed in saturated phenol in 3.7% phosphate-buffered formaldehyde for 48 hours25 and subsequently hand processed for paraffin embedding. At least 1 cm(to 3 power) of tissue was available for examination from each patient, except for patient 7, who underwent bilateral temporal lobe needle biopsies. Patient 14 underwent biopsy of both frontal and temporal lobes.

One paraffin block was prepared for each biopsy specimen, and sections were routinely stained with hematoxylin-eosin, luxol fast blue, Congo red, alcian blue, periodic acidSchiff, and modified King's silver stain27 in every ease, except for case 7, in which the diagnosis was made by frozen section. Portions of both gray and white matter were primarily fixed in glutaraldehyde and embedded in epoxy resin (Epon). Tissue was examined by electron microscopy if abnormalities, such as neuronal storage or other inclusions, were seen in routine paraffin sections.

Khachaturian's5 National Institute of Neurological and Communicative Disorderers and Stroke/ADRDA criteria for quantitation of senile plaques and the diagnosis of AD were used in all cases after 1985. At the time of our, study, these criteria were also applied retrospectively to cases accessioned before 1985. No attempt was made to grade the severity of other abnormalities (eg, gliosis and spongiform change), and the original pathologic diagnoses were not revised.

RESULTS

The clinical presentations, biopsy findings, and follow-up data, including postoperative complications, are summarized in Table 1 for all 14 patients. Their biopsy findings are summarized in Table 2.

The ages of this unselected group of 14 patients who underwent cerebral biopsies for dementia ranged from 32 to 78 years (mean, 51.6 years). There were seven men and seven women. Duration of symptoms ranged from 1 month to 6 years (mean, 2.3 years). No differences were noted between the group with diagnostic biopsies (cases 1 through 7) and the group with nondiagnostic biopsies (cases 8 through 14) with regard to age at the time of biopsy or duration of symptoms. However, five of seven patients in the nondiagnostic group had hemiparesis, chorea, athetosis, or lower motor neuron signs. None of these findings was present in the patients with diagnostic biopsies. Visual disturbances, abnormal eye movements, and ataxia were present in four of seven cases with diagnostic biopsies but were absent in the group with nondiagnostic biopsies.

In this series of 14 patients, two experienced postoperative complications, one of which was severe. Patient 2 developed an intraparenchymal parietal cortex hemorrhage and was mute after biopsy. Patient 9 developed a subdural hygroma that was treated uneventfully.

Eight patients died 1 month to 9 years after biopsy. An autopsy was performed in five of these eight patients. One of these patients (patient 4) had a firm diagnosis of presenile AD on biopsy, which was confirmed at autopsy. Patient 3 had a biopsy diagnosis of CJD, which was also confirmed at autopsy. Two patients with only white-matter gliosis diagnosed at biopsy had autopsy diagnoses of amyotrophic lateral sclerosis with dementia (patient 8) and CJD (patient 9). One patient in whom a biopsy specimen appeared to be normal had Huntington disease identified at autopsy (patient 14). At the time of this writing, four patients are still alive, two are in clinically stable condition 1 to 2 years after biopsy, and two are severely demented 2 to 3 years after biopsy. Two patients (one with a definite and one with a possible diagnosis of CJD) have been unavailable for follow-up.

COMMENT Our study of patients presenting with atypical dementia reaffirms the diagnostic utility of cerebral biopsy. In selected cases, cerebral biopsy results in a high yield of definitive diagnostic information. A wide variety of disorders may be encountered, including CJD, AD, diffuse Lewy body disease, and storage disorders, such as Niemann-Pick disease.28-30 The diagnosis of Niemann-Pick disease type C was confirmed by assay of cholesterol esterification in cultured fibroblasts31'32' with markedly abnormal results in one patient, who was described in detail elsewhere.33

One example of an unsuspected anaplastic astrocytoma (case 7) was also encountered. This case was unusual in light of currently used sensitive imaging techniques. This patient may have been suffering from gliomatosis cerebri.

Table 1.--Summary of Clinical Presentation and Course*

Case/Age,y/Sex

Duration of Symptoms, y

Clincial Findings

Biopsy

Follow-up ==========

1/60/F

0.1

Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral synchronous discharges

CJD

Unavailable ==========

2/57/M

0.4

Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal EEG

CJD

Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy ==========

3/59/M

2

Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic sharp waves

CJD

Dead at 61 y, autopsy showed CJD =========

4/32/M

1

Dementia, myclonus, ataxia, family history of early-onset dementia

AD

Dead at 40 y, autopsy showed AD =========

5/78/M

6

Dementia, paranoia, agitation, rigidity

Diffuse Lewy body disease

Dead at 78 y, no autopsy =========

6/37/F

6

Dementia, dysarthria, abnormal eye movements, ataxia

Neuronal storage disorder, adultonset N-P type II

Stable at 39 y =========

7/58/F

0.3

Dementia, amnesia, depression, partial complex seizures

Anaplastic astrocytoma

Dead at 58 y, no autopsy ==========

8/37/M

2

Dementia, dysarthria, upper-extremity atrophy and fasciculations

Gliosis

Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter gliosis =========

9/45/F

2

Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis

Gliosis

Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD =========

10/56/F

2

Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic sharp waves

Consistent with CJD

Unavailable ==========

11/60/F

2

Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic resonance image showing small vessel disease

Plaques, gliosis

stable at 61 y =========

12/52/F

2

Dementia, aphasia, right-sided hemiparesis

Gliosis

Bedridden, severely demented at 54 y =========

13/40/M

0.5

Dementia, mild bifacial weakness, concrete thinking, altered speech

Normal

Stable at 41 y =========

14/52/M

6

Dementia, choreoathetosis, family history of senile dementia, computed tomographic scan showing normal caudate

Normal

Dead at 61y, autopsy showed Huntington's disease, grade II/IV ========== * EEG indicates electroencephalogram; CJD, Creutzfeldt-Jakob disease; AD, Alzheimer's disease; and N-P, Niemann-Pick disease.

Table 2.--Pathologic Findings at Biopsy *

Case Site of Biopsy Type of Biopsy Tissue Examined Spongiform Change Neuritic Plaques per X 10 Field Tangles White Matter Gliosis Other

1 R temporal Open 1 cm3 + 0 0 0 0 =====

2 L temporal Open 1 cm3 + 0 0 0 0 =====

3 R temporal Open 1 cm3 + 0 0 0 0 =====

4 R frontal Open 1 cm3 0 >100 + + Amyloid angiopathy =====

5 R temporal Open 1 cm3 0 9 0 0 Lewy bodies =====

6 R temporal Open 1 cm3 0 0 0 0 Neuronal storage =====

7 R temporal/L temporal Needle/needle 1 X 0.3 X 0.3 cm / 1 X 0.3 X 0.1 cm 0/0 0/0 0/0 +/0 0/anaplastic astrocytoma =====

8 R frontal Open 1 cm3 o o o + 0 =====

9 L parietal Open 1 cm3 0 0 ± + 0 =====

10 R temporal Open 1 cm3 ± 0 0 0 0 =====

11 L temporal Open 1 cm3 0 23 0 + 0 =====

12 L temporal Open 1 cm3 0 0 0 + 0 =====

13 r frontal Open 1 cm3 0 0 0 0 0 =====

14 L temporal/L frontal Open/open 1 cm3/ 1 cm3 0/0 0/0 0/0 0/0 0/0 ===== * Plus sign indicates present; zero, absent; and plus/minus sign, questionably present

Positron emission tomography showed multiple areas of increased uptake, even though the magnetic resonance image was nondiagnostic and showed only subtle increased signal intensity on review. Bilateral temporal lobe needle biopsies yielded abnormal findings. Biopsy of the right side showed only reactive gliosis, which may have been adjacent to tumor. Biopsy of the left side, performed 3 days later, was diagnostic for anaplastic astrocytoma. Unfortunately, permission for an autopsy was refused, and complete evaluation of the underlying pathologic process thus must remain speculative.

The high incidence of definite and probable CJD in our series indicates that it is imperative that appropriate precautions are taken to prevent the transmission 0f disease to health care workers when biopsy tissue from patients with dementia is handled.24-26

At our institution, cerebral biopsy for the diagnosis of dementia is reserved for patients with an unusual clinical course or symptoms that cannot be diagnosed with sufficient certainty by other means. In most instances, cerebral biopsy is unnecessary and is clearly not a procedure to be proposed for routine diagnostic evaluation. In all cases, extensive clinical, metabolic, neuropsychological and radiologic evaluations must be performed before cerebral biopsy is considered. In addition, preoperative consultations among neurologists, neurosurgeons, neuroradiologists, and neuropathologists are necessary to ascertain the optimal biopsy site given the clinical data to ensure that maximal infornmtion is derived from the biopsy tissue.

An optimal biopsy specimen is one that is taken from an affected area, handled to eliminate artifact, and large enough to include both gray and white matter.34 Open biopsy is generally preferred because it is performed under direct visualization and does not distort the architecture of the cerebral cortex. This method also provides sufficient tissue (approximately 1 cm3) to perform the required histologic procedures.

Some physicians question the utility of diagnostic cerebral biopsies in dementia, stating that the procedure is unlikely to help the patient. While it is frequently true that the diagnoses made are untreatable with currently available therapeutic modalities, this is by no means universally true. Kaufman and Catalano35 noted that cerebral biopsy has revealed specific treatable illnesses, such as meningoencephalitis and multiple sclerosis. Our patient with anaplastic astrocytoma (patient 7) underwent radiation therapy, although she quickly died of her disease. Furthermore, when a definitive diagnosis can be made, even of incurable illnesses, such as CJD and AD, it is often possible to give an informed prognosis to the family and to help them plan for the future.

The formulation of indications, for diagnostic cerebral biopsy raises difficult and complex issues. In 1986, Blemond36 addressed the clinical indications and the legal and moral aspects of cerebral biopsy, and his recommendations remain valid today: (1)The patient has a chronic progressixe cerehral disorder with documented dementia. (2) All other possible diagnostic methods have already been tried and have failed to provide sufficient diagnostic certainty. (3) The general condition of the patient permits cerebral biopsy. (4) Several specialists are in agreement regarding the indication. (5) Informed consent is obtained from relatives. (6) Modern diagnostic tools, such as immunocytochemistry and electron microscopy, are used to the fullest capacity in the examination of the material obtained.

As with any intracranial surgical procedure involving the cerebral cortex, the risks of cerebral biopsy include anesthetic complications, hemorrhage, infections, and seizures. Guthkelch37 stated that the mortality associated with brain biopsy is not greater than that associated with general anesthesia. Cerebral biopsy, however can result in substantial morbidity. In our series, two of 14 patients suffered operative complications, intraparenchymal hemorrhage in one patient (patient 2) resulted in aphasia, while another patient (patient 10) developed a subdural hygroma, which was successfully treated, and recovered her baseline status.

The current diagnostic accuracy of cerebral biopsy in the evaluation of dementia is unknown. Most of the larger general series 34'38-41 were reported before computed tomography was available and included many pediatric cases presenting with genetic neurodegenerative disorders that are now more readily diagnosed by other means. For adults with dementia, less information is available. Katzman et al4 recently reviewed the literature concerning the diagnostic accuracy of cerebral biopsy for dementia and concluded that 75% of these procedures result in diagnostic material. Patient selection is very important, and the literature is heavily weighted toward patients with a clinical diagnosis of AD.35'42-44 Our study thus provides documentation of the diagnostic accuracy of cerebral biopsies in unselected patients with atypical dementia.

Autopsy follow-up is imperative in any dementia program,2 as a definitive diagnosis will not be made in a substantial proportion of patients. In our series, three patients died without a diagnosis, and autopsy was performed in all three. The diagnostic features were not present in the cortical area in which the biopsy was performed. In case 8, examination of the spinal cord revealed amyotrophic lateral sclerosis. Diffuse gliosis of the white matter was noted, which was the pathologic basis of the patient's dementia. In case 9. the spongiform change of CJD was focal, according to the pathologist's report; unfortunately, the tissue was not available for our review. In case 14, the diagnosis of Huntington's disease grade II/IV was made after close examination of the caudate nucleus. As one might predict, fewer autopsies were performed in the group with diagnostic biopsies; only two of five deaths in this category were followed by postmortem examinations. The diagnosis of AD was confirmed in case 4. In ease 3, the biopsy diagnosis of CJD was confirmed.

In summary, a series of 14 unselected cerebral biopsies performed for the diagnosis of atypical dementia was reviewed to define the spectrum of pathologic changes seen and to estimate the likelihood of obtaining diagnostic tissue. Histologic diagnoses of CJD, AD, diffuse Lewy body disease, Niemann-Pick disease type C, or anaplastic astrocytoma were made in seven patients. The high incidence of CJD in this population (four of 14 cases) emphasizes the need to use appropriate precautions when tissue from patients with unusual dementing illnesses is handled. Consultation among neurologist, neurosurgeons, neuroradiologists, and neuropathologists is essential to select appropriate patients and to choose the proper biopsy site. Demented patients with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs are unlikely to benefit from cortical biopsy.

This investigation was supported by Clinical Investigator Award PHS AG-00446 from the National Institute on Aging (Dr. Hulette) and by grant PHS SP50AG05128-03 from the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (Drs Earl and Crain). Dr Hulette is a College of American Pathologists Foundation Scholar, Northfield, Ill.

The Authors thank Ms Bonnie Lynch and Ian Sutherland, PhD, for thier assistance.

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7. Wilcock GK, Hope RA, Brooks DN, et al. Recommended minimum data to be collected in research studies on Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1989;52;693-700

8. Esiri MM, Oppenheimer DR. Diagnostic neuropathology. Boston, Mass: Blackwell Scientific publications Inc; 1989;236-239.

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12. Brown P, Rodgers-Johnson P, Cathala L, Gibbs CJ, Gajdusek DC. Creutzfeldt-Jakob disease of long duration; clinicopathologic characteristics, Transmissibility and differential diagnosis. Ann Neurol. 1984;16:295-304.

13. Davanipour Z, Alter M, Sobel E. Creutzfeldt-Jakob disease. Neurol Clin. 1986:4:415-425.

14. Masters CL, Richardson EP: Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease): the nature and progression of spongiform changes. Brain 1978;101:333-344.

15. Neatherlin JS. Creutzfeldt-Jakob disease. J Neurosci Nurs. 1988;20:309-313.

16. Nochlin D, Sumi SM, Bird TD, et al. Familial dementia with Prp-positive amyloid plaques: a variant of Gerstmann-Straussler syndrome. Neurology. 1989;39;910-918

17. Fisher CM. Binswanger's encephalopathy: a review. J Neurol 1989;236;65-79

18. Roman GC. Senile dementia of the Bins-wanger type. JAMA. 1987125811782-1788.

19. Burkhardt CR, Tilley CM, Kleinschmidt-DeMasters BK, de la Monte S, Norenberg MD, Sehneck SR. Diffuse Lewy hody disease and progressive dementia. Neurology. 1988;38:1520-1528.

20. Dickson DW, Davies P, Mayeux R, et al. Diffuse Lewy body disease: neuropathological and biochemical studies of six patients. Acta Neuropathol (Berl). 1987;75:8-15.

21. Gibb WRG. Neuropathelogy in movement disorders. J Neurol Neurosurg Psychiatry. 1989:supl:55-67.

22. Gibb WRG, Luthert PJ, Janota A. Lantos PL. Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry. 1989;52;185-192.

23. MeKhann G. Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimers disease: report of the NINCDS-ADRDA work group. Neurology. 1984;34:939-944.

24. Brown P, Gibbs CJ Jr, Gajdusek DC, Cathala F, LaBauge R. Chemical disinfection of Creutzfeldt-Jakob disease virus. N Engl J Med. 1982;306;1279-1282.

25. Brumbach RA. Routine use of phenolipid formalin in fixation of autopsy brain tissue reduce risk of inadvertent transmission of Creutzfeldt-Jakob disease. N Engl J Med. 1988;319;654.

26. Rosenberg RN, White CL, Brown P, et al. Precautions in handling tissues, fluids and other contaminated materials from patients with documented or suspected Creutzfeldt-Jakob disease. Ann Neurol. 1986;12:75-77.

27. Lloyd B, Brinn N, Burger PC. Silver-staining of senile plaques and neurofibrillary change in paraffin-embedded tissues, J Histotech. 1985;8: 155-156.

28. Brady RO. Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw-Hill International Book Co; 1983:831-841.

29. Cogan DG, Chu FC, Reingold D, Barranger J. Ocular motor signs in some metabolic diseases. Arch Ophthalmol. 1981:99:1802-1808.

30. Lake BD. Lysosomal enzyme deficiencies. In: Adams JH, Corsellis JAN, Duchen LW. eds. Greenfield's Neuropathology. 4th ed. New York, NY:John Wiley & Sons Inc; 1984;491-572.

31. Pentchev PC. Comly ME, Kruth HS, et al. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82;8247-8251.

32. Vanier MT, Wenger DA, Comly ME, Rousson R. Brady RO, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. Clin Genet. 1988;33;331-348.

33. Hulette CM, Earl NL, Anthony DC, Crain BJ. Adult onset Niemann-Pick disease type C: a case presenting with dementia and absent organomegaly. Clin Neuropathol. In press.

31. Pentchev PC, Comly ME, Kruth HS, et al. A defect in cholesterol esterfication in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82;8247-8251

32. Vanier MT, Wenger Da, Comly ME, Rousson R, Brady Ro, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. Clin Genet. 1988;33;331-348

33. Hulette CM, Earl NL, Anthony DC, Crain Bj. Adult onset Niemann-Pick disease type C; a case presenting with dementia and absen organomegaly. Cliln Neuropathol. In Press.

34. Groves R, Moller J. The value of the cerebral cortical biopsy. Acta Neurol Scand. 1966;42;477-482

35. Kaufman HH. Catalano LW. DiaGnostic brain biopsy: a series of 50 cases and a review. NeUROSURGERY. 1979:4:129-136.

36. Blemond A. Indications, legal and moral aspects of cerebral biopsies, In: Proceedings of Fifth International Congress of Neuropathology, Zurich, 1965, Princeton, NJ: Excerpta Medica; 1966:372-375.

37. Guthkelch AN. Brain biopsy in infancy and childhood. Dev Med Child Neurol, 1968;10;107-109.

38. Blackwood W, Cumings JN. The combined histological and chemical aspects of cerebral biopsies. In: Proceeedings of Fifth International Congress of Neuropathology, Zurich, 1965. Princeton, NJ: Excerpta Medica; 1966:364-371.

39. Green MA, Stevenson LD, Fonseca JE, Wortis SB. Cerebral biopsy in patients with presenile dementia. Dis Nerv Syst. 1952;13:303-307.

40. Sim M, Turner E, Smith WT. Cerebral biopsy in the investigation of presenile dementia, I: clinical aspects, Br J Psychiatry. 1966;112:119-125.

41. Turner E, Sim M. Cerebral biopsy in the investigation of presenile dementia, II: pathological aspects, Br J Phychiatry. 1966;112:127-133.

42. Bowen DM, Benton JS, Spillane JA. Smith CCT, Allen SJ. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci. 1982;57:191-202.

43. Neary D, Snowden JS, Bowen DM, et al. Cerebral biopsy in the investigation of presenile dementia due to cerebral atrophy. J Neurol Neurosury Psychiatry. 1986;49:157-162.

44. Neary D, Snowden JS, Mann DMA, et al. Alzheimer's disease: a corelative study. J Neurol Neurosurg Psychiatry. 1986;49:229-237.

=============================

Clinico-Pathological Correlation in Dementias

F. TeixeiraI, E. Alonso2, V. Romerol, A. Ortiz', C. Martinez3, E. Otero4 'Departnents of Experimental Neuropathology and 2Genetics, and the 3Division of Psychology and 4Neurology, National Institute of Neurology and Neurosurgery, Mexico City, Mexico

Submitted: February 22, 1994 Accepted: February 9, 1995

The object of this study is to investigate whether or not there are clinical signs and symptoms in patients with dementia that, by themselves or jointly, can be associated with the pathological diagnosis of Alzheimer's disease. Twelve patients with dementia were studied, in whom the clinical diagnosis of Alzheimer's disease was made according to established criteria. A sample of leptomeninges, cortex and subcortical white matter was obtained from each patient and was processed for light and electron microscopy. In the cases in whom neuritic plaques and neurofibrilary tangles were present, pathological changes were quantified. The diagnosis of Alzheimer's disease was confirmed in 5 cases, whereas in 3 patients spongiform encephalopathy was present. In the remaining patients, the number of neuritic plaques was within normal limits for the age of the subjects. Comparison of the data in Alzheimer (n = 5) and non-Alzheimer (n =7) groups showed an increased, statistically significant incidence of acalculia, abnormalities of judgment, impairment of abstraction and primitive reflexes in the former. Although good fitting models were obtained, none achieved perfect discrimination. The model that included alterations of judgment and acalculia gave the best fit.

Key Words: Alzheimer's disease, dementia

INTRODUCTION

snip...

The sample in this study may be considered small for the purpose of selecting a set of signs and symptoms that can characterize Alzheimer's disease clinically. However, it is not an easy task to obtain the permission to perform a brain biopsy which is of no benefit for the patient when the relative is informed of the risks involved. The definite diagnosis of Alzheimer's disease depends on the microscopical examination of brain tissue, either by autopsy or biopsy. In the USA, the Alzheimer Disease Research Center of the University of Pittsburgh has launched a public campaign to encourage relatives of demented patients to request a postmortem examination of the brain (Boller et al 1989). However, in Mexico, a similar campaign has enjoyed little success so far for several reasons. The patient who suffers from Alzheimer's disease usually dies at home. The relatives, who are already exhausted by the demands of caretaking, obtain a death certificate from the family physician, and proceed quickly to the funeral rites. The few families who do request an autopsy are almost invariably denied admission to the hospital where the patient had been admitted because cadavers without a death certificate must be sent to the police department for autopsy. Many patients die in small towns or villages where there are no pathologists, let alone neuropathologists. Therefore, brain biopsy remains the only possibility for confirming the clinical diagnosis. It is true that there is no benefit derived by the patient from this procedure and that he or she faces surgical and anesthetic risks. In contrast, brain biopsy allows: 1. the development of new diagnostic procedures that might, in the future, replace it; 2. adequate genetic counselling in cases with an autosomal dominant pattern of inheritance, so that family members can take part in studies at the molecular biology level; and 3. the performance of therapeutic trials and of epidemiological surveys in Mexico.

Familiar aggregation has been demonstrated in 40% of cases of Alzheimer's disease. In 15% of these cases, the pattern of inheritance was autosomal dominant (Heston et al 1981). Patient number nine's family is an example of the latter, and showed an early age of onset. Vacuolar change, similar to that present in Jakob- Creutzfeldt disease, has been described in brains of patients with Alzheimer's disease, especially at the medial temporal isocortex, where it has a high, statistically significant association with the presence of large numbers of neurofibrillary tangles and argyrophilic plaques (Smith et al 1987). This study considered the possibility that cases 5 to 7, diagnosed as Jakob-Creutzfeldt disease, could be, in fact, Alzheimer cases with this peculiar vacuolar change. A good method for separating the two entities would be the use of antibodies against prion (Pr-P) proteins (Tateishi et al 1988), which were, unfortunately, not available to the authors. However, none of these cases showed positivity for A4 protein, neither had one single argyrophilic plaque or tangle. Moreover, the biopsies were taken from the frontal regions, which are reported to be free of involvement in instances of Alzheimer's disease with vacuolar changes (Smith et al 1987).

Although the diagnosis of probable Alzheimer's disease was made in all of the patients in this study, according to the criteria established by McKhann et al (1984), this diagnosis was confirmed in only 47.1% of them. This low rate might be the result of several factors. The National Institute of Neurology and Neurosurgery in Mexico City is an institution that concentrates especially on difficult or unusual cases that are referred from all over the country. Therefore, it received a biased sample that included as many as 3 cases of spongiform encephalopathy. In addition, it is important to remember that a small, 1 cubic centimeter sample of cortex and white matter may not be representative of the extent of the damage in other areas of the brain, and so, correlates poorly with the clinical picture. This illustration is particularly true of cases 1 to 4, which did not fit into any of the pathological entities that manifest clinically as dementia. To understand more clearly the relation between damage and clinical impairment, further prospective studies using autopsy material are needed.

REFERENCES

American Psychiatric Association. 1987. Diagnostic and statistical manual of mental disorders. 3rd ed., revised. Washington DC: American Psychiatric Association. 282 Journal of Psychiaty & Neuroscience VoL 20, No. 4,1995 Boller F, Lopez OL, Moossy J. 1989. Diagnosis of dementia: clinicopathologic correlations. Neurology 39:76-79. Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L. 1988. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 38: 1682-1687. De la Monte SM. 1989. Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease. Ann Neurol 25:450-459. Heston LL, Mastri AR, Andersen E, White V. 1981. Dementia of the Alzheimer type. Arch Gen Psychiat 38:1085- 1090. Joachim CL, Morris JH, Selkoe DJ. 1988. Clinically diagnosed Alzheimer's disease: autopsy results in 150 cases. Ann Neurol 24:50-56. Karp HR, Mirra SS. 1986. Dementia in adults. In: Joynt RJ, editor. Clinical neurology. Philadelphia PA: Lippincott. pp 1-74. Khachaturian ZS. 1985. Diagnosis of Alzheimer's disease. Arch Neurol 42:1097-1104. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 1984. Clinical diagnosis of Alzheimer's disease. Neurology 34:939-944. Mosla PK, Paijarvi L, Rinne JO, Rinne UK, Sako E. 1985. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 48:1085-1090. Muller HF, Schwartz G. 1978. Electroencephalograms and autopsy findings in geropsychiatry. J Geront 4:504-513. Nott PN, Fleminger JJ. 1975. Presenile dementia: the difficulties of early diagnosis. Acta Psychiatr Scand 51: 210- 217. Smith TW, Anwer U, DeGirolami U, Drachman DA. 1987. Vacuolar change in Alzheimer's disease. Arch Neurol 44:1225-1228. Sulkava R, Haltia M, Paetau A, Wikstrom JU, Palo J. 1983. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 46:9-13. Tateishi J, Tetsuyuki K, Mashigu Chi M, Shii M. 1988. Gerstmann Straussler-Scheinker disease: immunohistological and experimental studies. Ann Neurol 24:35-40. Todorov A, Go R, Constantinidis J, Eiston R. 1975. Specificity of the clinical diagnosis of dementia. J Neurol Sci 26:81-98. Wade JPH, Mirsen TR, Hachinski VC, Fisman M, Lau C, Merskey H. 1987. The clinical diagnosis of Alzheimer's disease. Arch Neurol 44:24-29.tss

ONE IN A MILLION, OR EVERY 72 SECONDS $$$

Subject: Every 72 seconds someone in America develops Alzheimer’s Date: March 20, 2007 at 5:35 pm PST

Alzheimer’s Disease Prevalence Rates Rise to More than Five Million in the United States Someone develops Alzheimer’s every 72 seconds, according to new Alzheimer’s Association report

The Alzheimer’s Association today reports that in 2007 there are now more than 5 million people in the United States living with Alzheimer’s disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer’s disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.

The greatest risk factor for Alzheimer’s is increasing age, and with 78 million baby boomers beginning to turn 60 last year, it is estimated that someone in America develops Alzheimer’s every 72 seconds; by mid-century someone will develop Alzheimer’s every 33 seconds.

These new estimates, as well as other data concerning the disease and its effects, are issued today as hundreds of advocates from across the country gather in the nation’s capitol for the Alzheimer’s Association’s annual Public Policy Forum. The report titled, 2007 Alzheimer’s Disease Facts and Figures, is being released at a hearing today chaired by Senator Barbara Mikulski. Senators Barbara Mikulski and Christopher Bond and Representatives Edward Markey and Christopher Smith have introduced bipartisan legislation to address problems identified in the Association’s report. The Association’s report details the escalation of Alzheimer’s disease which now is the seventh leading cause of death in the country and the fifth leading cause of death for those over age 65. It also offers numerous statistics that convey the burden that Alzheimer’s imposes on individuals, families, state and federal governments, businesses, and the nation’s health care system. For example:

Without a cure or effective treatments to delay the onset or progression of the Alzheimer’s, the prevalence could soar to 7.7 million people with the disease by 2030, which is more than the population of 140 of the 236 United Nations countries. By mid-century, the number of people with Alzheimer’s is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined. As the prevalence impact of Alzheimer’s grows, so does the cost to the nation. The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart. “Alzheimer’s Disease Facts and Figures clearly shows the tremendous impact this disease is having on the nation; and with the projected growth of the disease, the collective impact on individuals, families, Medicare, Medicaid, and businesses will be even greater,” says Harry Johns, President and CEO of the Alzheimer’s Association. “However there is hope. There are currently nine drugs in Phase III clinical trials for Alzheimer’s several of which show great promise to slow or stop the progression of the disease. This, combined with advancements in diagnostic tools, has the potential to change the landscape of Alzheimer’s.”

According to the latest statistics from the Centers for Disease Control and Prevention, from 2000-2004 death rates have declined for most major diseases -- heart disease (-8 percent), breast cancer (-2.6 percent), prostate cancer (-6.3 percent) and stroke (-10.4 percent), while Alzheimer’s disease deaths continue to trend upward, increasing 33 percent during that period.

“We must make the fight against Alzheimer’s a national priority before it’s too late. The absence of effective disease modifying drugs, coupled with an aging population, makes Alzheimer’s the health care crisis of the 21st century,” Johns said.

Medicare currently spends nearly three times as much for people with Alzheimer’s and other dementias than for the average Medicare beneficiary. Medicare costs are projected to double from $91 billion in 2005 to more than $189 billion by 2015, more than the current gross national product of 86 percent of the world’s countries. In 2005, state and federal Medicaid spending for nursing home and home care for people with Alzheimer’s and other dementias was estimated at $21 billion; that number is projected to increase to $27 billion by 2015.

The new report also highlights the impact that Alzheimer’s has on states with more than 6 in 10 (62%) having double digit growth in prevalence by the end of the decade. In addition, Alaska (+47%), Colorado (+47%), Utah (+45%), Wyoming (+43%), Nevada (+38%), Idaho (+37%), Oregon (+33%), and Washington (+33%) will experience increases ranging from one-third to one-half. The states with the largest numbers of deaths due to Alzheimer’s disease in 2003 were (1) California, (2) Florida, (3) Texas, (4) Pennsylvania, and (5) Ohio.

The Alzheimer’s Association is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer’s. For more than 25 years, the Association has provided reliable information and care consultation; created services for families; increased funding for dementia research; and influenced public policy changes.

Contact: Call our media line at 312.335.4078

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Every 72 seconds someone in America develops Alzheimer’s.


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Alzheimer-type neuropathology 28 year old patient with idCJD

Sun Feb 19, 2006 11:14

71.248.144.164

SHORT REPORT

Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting M Preusser1, T Ströbel1, E Gelpi1,2, M Eiler3, G Broessner4, E Schmutzhard4 and 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, Innsbruck, Austria

Correspondence to: Dr H Budka Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 4J, 1097 Vienna, Austria; mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:herbert.budka@kin.at

ABSTRACT

We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the 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 disease associated 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 (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) 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.

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http://jnnp.bmjjournals.com/


CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegeneradve disorders;

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.


93/01.05/4.1tss


http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf


BSE101/1 0136

IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning funher research to sec if the conditions, as opposed to the partial pathological process, is transmissible.

What are the implications for public health?

3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1-1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed m GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832

121/YdeStss

92/11.4/1.2


http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf


also, see the increase of Alzheimer's from 1981 to 1986


http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf


Regarding Alzheimer's disease

(note the substantial increase on a yearly basistss)


http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf


snip...

The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf


And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.


http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf


Human BSE

snip...

These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.

snip...


http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf


From: terry <[log in to unmask]> Subject: Re: FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE ??? In-Reply-To: <[log in to unmask]>

I have 2 questions for you, terry singeltary. Do you agree with colm kelleher where he states there may be a relationship between vCJD and alzeheimer's in that alzheimers may be misdiagnosed. And is it true that BSE cannot be destroyed by heat or chemical so that any instrument that touches it must be thrown out. Sent wirelessly via BlackBerry from T-Mobile.


http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0612&L=sanet-mg&T=0&P=8525


Sender: Sustainable Agriculture Network Discussion Group

From: "Terry S. Singeltary Sr." <[log in to unmask]> Subject: Re: FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE ??? Comments: To: [log in to unmask]

i have written about this many times and spoke with colm on several occasions when he was writing his book.....

Do you agree with colm kelleher where he states there may be a relationship

between vCJD and alzeheimer's in that alzheimers may be misdiagnosed

NOT JUST vCJD but all human TSE, especially sporadic CJD, there are studies showing ''CJD'' as being misdiagnosed as Alzheimer's (see below).

AND personally i think there is a potential that Alzheimers may be low level TSE. may be something else too, i mean, just what is Alzheimer's???

IN CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

H F BAKER, R M RIDLEY, L W DUCHEN, T J CROW, C J BRUTON

As part of a larger series of experiments designed to assess the transmissibility of various neurodegenerative disease including the spongiform encephalopathies (eg Creutzfeldt-Jakob disease and BSE we injected several marmosets (Callithrix Jacchus) intracerebrally with brain homogenate from :

1) a 56 year old patient with severe Alzheimer's disease - B - amyloid plaques and conogophilic angiopathy (CAA) and neurofibrillary tangles; and

2) a 62 year old patient with Gerstmann-Straussler disease, a spongiform encephalopathy with PrP Plaques and, in this case, B-amyloid plaques and CAA.

These monkeys were killed more than 6 years after inoculation and their brains were found to contain moderate numbers of B-amyloid plaques and CAA but NO neurofibrillary tangles NO PrP. The brains of more than 12 monkeys killed at an older age did not contain these changes. B-amyloid was not found in the brains of monkeys injected with brain material which did not contain B-amyloid. These results suggest that B-amyloidosis is a transmissible process resembling the transmissibility of PrP amyloidosis in transmissible dementia and strengthens the parallels between Alzheimer's disease and Creutzfeldt-Jakob disease.

It should be stressed, however, that we are not claiming to have transmitted Alzheimer's disease because

1) the animals were behaving normally when killed and

2) no neurofibrillary tangles were seen.

We have argued previously that transmission of spongiform encephalopathy, particularly from the genetic cases (GSS and some CJD), does not imply that the donor cases themselves acquired the disease by infection. We would apply the same arguments in this case, particularly in view of the genetic basis of some cases of Alzheimer's disease and the extensive epidemiological data which does not link Alzheimer's disease to infection.

DISCLOSURE

This work is currently under preparation for publication BUT IN VIEW OF PUBLIC CONCERN OVER THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (eg BSE) AND THE HIGH INCIDENCE OF ALZHEIMER'S DISEASE IN THE GENERAL POPULATION, IT IS IMPORTANT THAT THESE FINDINGS ARE NOT DISCUSSED OPENLY BEFORE FULL PUBLICATION.

Furthermore, BEFORE DISCLOSURE, IT IS IMPORTANT THAT INTERESTED PARTIES BE PROPERLY APPRAISED OF THE DATA AND THERE IMPLICATIONS.

Previous attempts to transmit Alzheimer's disease to rodents and large primates have been unsuccessful. It is our belief that post-mortem tissue from these animals still exists and we are anxious that research workers (in the USA) SHOULD NOT RE-EXAMINE this material until our data are published.

SAFETY

At this point we would like to stress again the lack of evidence relating Alzheimer's disease to exposure to brain tissue through neurosurgery or occupation. NEVERTHELESS it is appropriate that proper bodies should consider whether the results of our experiments have any implications for human health.

FURTHER EXPERIMENTS

The interpretation we have made that B-amyloidosis as a self-peretuating process has important implications for understanding the process of neurodegeneration, which are best studied at the level of protein chemistry. However, we can see arguments for some transmission experiments including:

1) serial passage of B-amyloidosis in order to strengthen the evidence of transmissibility;

2) transmission from other cases of Alzheimer's disease in order to establish the generality of this effect;

3) transmission to primates which are allowed to run their full course, ie to see whether the full syndrome of Alzheimer's disease develops including neurofibrillary tangle formation, astrocytosis, neuronal loss and concomitant cognitive decline. (We are already expert in the neuropsychological assessment of marmosets). It should be remembered that, at the present time, only the amyloidosis have been found to be transmissible such that Alzheimer's disease PER SE has not been transmitted;

4) comparison of transmission from cases which contain only CAA and those which contain only B-amyloid plaques. These two forms of amyloid differ very slightly and it is not known whether this difference is preserved on transmission;

5) establishment of the time course of the development of B-amyloidosis. The present experiment suggests that the time course is somewhere between 1-5 years;

6) transmission using larger quantities of purified preparations of B-amyloid. This may reduce the transmission time considerably;

7) transmission using animals of different initial ages to investigate the relationship between transmission time and chronological age, eg transmission into mature animals may decrease transmission time through an interaction between the pathological process and senescence;

8) manipulation of transmission time by treatments which may speed up plaque formation, eg by increasing the production of amyloid precursor protein, or which may slow down plaque formation and protect from disease progression.

The proposal is to inoculate about 25 marmosets in the first instance and to replace them in a 'rolling' experiment as they die or are killed according to the experimental design. The marmosets will be kept in the MRC Marmoset Colony in Cambridge. Additional facilities and personnel are not required over and above that awarded to Dr. Ridley in an MRC Programma Grant.

A preliminary report of our findings will be presented by Professor L W Duchan at the January 1993 meeting of the British Neuropathological Society.


http://www.bseinquiry.gov.uk/


Published online before print June 15, 2007 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0609621104

Neuroscience

Cellular prion protein regulates -secretase cleavage of the Alzheimer's amyloid precursor protein

( lipid raft proteolysis scrapie glycosaminoglycan )

Edward T. Parkin *, Nicole T. Watt *, Ishrut Hussain , Elizabeth A. Eckman ¶, Christopher B. Eckman ¶, Jean C. Manson , Herbert N. Baybutt , Anthony J. Turner *, and Nigel M. Hooper *** *Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom; Neurodegeneration Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom; ¶Mayo Clinic, Jacksonville, FL 32224; and Roslin Institute, Neuropathogenesis Unit, Edinburgh EH9 3JF, United Kingdom

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved May 10, 2007 (received for review October 30, 2006)

Proteolytic processing of the amyloid precursor protein (APP) by -secretase, -site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid (A) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrPC), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and PrPC are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrPC in the proteolytic processing of APP. Cellular overexpression of PrPC inhibited the -secretase cleavage of APP and reduced A formation. Conversely, depletion of PrPC in mouse N2a cells by siRNA led to an increase in A peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, A levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the -secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrPC on the -secretase cleavage of APP required the localization of PrPC to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrPC via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A is regulated by PrPC and may have implications for both Alzheimer's and prion diseases.

--------------------------------------------------------------------------------

Author contributions: E.T.P., J.C.M., and N.M.H. designed research; E.T.P., N.T.W., I.H., E.A.E., C.B.E., and H.N.B. performed research; E.T.P., N.T.W., E.A.E., C.B.E., and N.M.H. analyzed data; I.H., E.A.E., and C.B.E. contributed new reagents/analytic tools; and E.T.P., J.C.M., A.J.T., and N.M.H. wrote the paper.

The authors declare no conflict of interest.

Present address: Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, United Kingdom.

**To whom correspondence should be addressed.

Nigel M. Hooper, E-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:n.m.hooper@leeds.ac.uk


www.pnas.org/cgi/doi/10.1073/pnas.0609621104


http://www.pnas.org/cgi/content/abstract/0609621104v1?etoc


Subject: Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis

Date: June 24, 2007 at 1:11 pm PST

Masatoshi Omoto · Tadaaki Yokota · Dan Cui Yoshinobu Hoshii · Hiroo Kawano · Toshikazu Gondo Tokuhiro Ishihara · Takashi Kanda

Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis

Abstract It is known that amyloid-enhancing factor (AEF) shortens the preamyloid phase in experimentally induced AA amyloidosis in mice. Because it is reported that AEF serves as both a nidus and a template for amyloid formation, AA amyloidosis may have transmissibility by a prionlike mechanism. It has been shown that amyloid fi brils also have AEF activity, and amyloid fi brils with AEF activity were named fi bril-amyloid enhancing factor (F-AEF). In this study, we investigated methods to inactivate the AEF activity. AEF was extracted from the thyroid gland obtained at autopsy of a patient with AA amyloidosis. Before injection into mice, AEF was treated with several methods for inactivation. Of all the tested treatments, 1 N NaOH, 0.1 N NaOH, and autoclaving consistently demonstrated complete inactivation of AEF. Heat treatment led to incomplete inactivation, but 0.01 N NaOH, 0.001 N NaOH, pepsin, trypsin, pronase, and proteinase K treatment had no effect on AEF activity. By analysis with transmission electron microscopy, the AEF preparation contains amyloid fi brils, and a change of ultrastructure was shown after 1 N NaOH, 0.1 N NaOH, and autoclaving treatment. Furthermore, immunoblotting of AEF with antihuman AA antibody revealed that the protein band was scarcely found after autoclaving, 1 N NaOH, and 0.1 N NaOH treatment. Our results suggest that, similar to Creutzfeldt–Jakob M. Omoto (*) · T. Kanda Department of Neurology and Clinical Neuroscience, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube City, Yamaguchi 755-8505, Japan Tel. +81-836-22-2719; Fax +81-836-22-2364 e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:omoto-path@umin.ac.jp T. Yokota Department of Pathology, Kokura Memorial Hospital, Yamaguchi, Japan D. Cui · Y. Hoshii · H. Kawano · T. Ishihara Department of Radiopathological and Science, Yamaguchi University School of Medicine, Fukuoka, Japan T. Gondo Department of Surgical Pathology, Yamaguchi University Hospital, Yamaguchi, Japan disease (CJD), amyloidosis may require chemical or autoclaving decontamination. Key words Amyloid-enhancing factor · Amyloidosis · Creutzfeldt–Jakob disease · Prion · Transmission electron

snip...

Discussion

Secondary amyloidosis occurs in individuals with longstanding infl ammatory diseases. Since the incidence of chronic infl ammatory diseases such as tuberculosis and leprosy has decreased in recent years, rheumatoid arthritis (RA) is now the most common disease involving secondary AA amyloidosis, especially in elderly patients with a long history of RA. Autopsy studies indicate that the incidence of secondary amyloidosis in RA patients may be between 20% and 25%.21 Generally, treating the underlying disease is the conventional approach in AA amyloidosis, because no specifi c treatment exists. It is not yet certain whether preventing amyloid proteins from aggregating will be therapeutically beneficial. An essential factor for the development of AA amyloidosis is a continual high plasma concentration of SAA. However, it is still unclear why only a subset of such individuals develops AA amyloidosis. Therefore, in addition to high concentrations of an amyloidogenic protein, other factors are thought to be necessary in the pathogenesis of AA amyloidosis. AEF is thought to be one of the essential factors for the development of amyloidosis, although the mechanism responsible for the formation of amyloid fi brils is still unclear. Many studies have identifi ed that AEF activity is a large macromolecular complex, and all tissue extracts studied to date appear to contain glycoprotein with an approximate size of 10–15 kD.4,22–24 Most strains of mice are susceptible to developing AA amyloid deposition following chronic administration of infl ammatory stimuli such as casein or azocasein.25 The prolonged preamyloid phase in experimentally induced AA amyloidosis can be dramatically shortened by intravenous or intraperitoneal administration of AEF with the infl am- matory stimuli.2–4 All mice that were exposed to AEF and injected with silver nitrate developed amyloidosis by day 7.16 Amyloid fi brils extracted from different types of amyloidosis from a wide variety of species display biologically similar AEF activity to that in experimental animals. In fact, Niewold et al.26 showed that intravenous and intraperitoneal injection of hamster AA amyloid fi brils, bovine AA amyloid fi brils, and human light chain-derived (A?) amyloid fi brils markedly accelerated hamster amyloidosis. The AEF activity found in the amyloid fi bril preparation was named F-AEF.6 Furthermore, intravenous injection of amyloid-like fi brils made from synthetic peptides of transthyretin27 or denatured silk28 accelerates murine AA amyloidosis. By double immunogold labeling and microautoradiographic methods, Johan et al. reported that intravenously administered, radiolabeled, heterologous, amyloid-like, synthetic fi brils reached the lung and spleen, accelerated amyloidosis, and were associated with topographical deposition of murine protein AA fi brils in the recipient mouse.29 Drastic structural changes of amyloid protein from the normal and soluble forms to the unique ß-sheet fi brils may be the most important event in amyloidosis. Recently, it was reported that AEF serves as both a nidus and a template for amyloid formation,8 and AA amyloidosis may show transmissibility as a prion-like mechanism.9 Johan et al. also suggested that amyloid-like synthetic fi brils had a nidus activity, 29 and amyloid-enhancing activity may occur through the mechanism of amyloid-like fi brils serving as seed for fi bril formation. Moreover, by using the method of negative staining with TEM, electron micrographs of amyloid fi brils were observed under some conditions. O’Nuallain et al. revealed that electron micrographs of islet amyloid polypeptide showed aggregates initially and then grew into fi bril formations after incubation.30 In contrast, Santhoshkumar et al. revealed that, using TEM, amyloid ß-peptide showed signifi cantly decreased fi bril formation and some amorphous aggregates after incubation with aA-crystallin in their in vitro study.31 They suggested that aA-crystallin had the ability to inhibit amyloid fi bril formation. Similarly, in our study, electron micrographs of F-AEF revealed some amorphous aggregates after autoclaving, 1 N NaOH, and 0.1 N NaOH treatment and short and transformed fi brils after heat treatment. Furthermore, immunoblotting of AEF with antihuman AA antibody revealed that a protein band was scarcely found after autoclaving, 1 N NaOH, and 0.1 N NaOH treatments and that weak protein bands were found after heat treatment. We suggested that these results indicated the activity of F-AEF disappeared after autoclaving, 1 N NaOH, and 0.1 N NaOH treatments and that the activity of F-AEF was decreased after heat treatment. Prion diseases are associated with the accumulation of a conformational isomer (PrPSc) of host-derived prion protein (PrPC), and PrPSc forms amyloid fi brils. The exogenous abnormal form of the prion protein is generally regarded as a seed that promotes the association of cellular proteins. Prions are very resistant to inactivation, and accidental transmission has occurred through the use of inadequate decontamination procedures.

In our experiments with mice, the activity of F-AEF was markedly decreased after autoclaving treatment under conditions of 132°C for 1 h and 1 N NaOH and 0.1 N NaOH treatment for 1 h. For CJD materials, the Committee on Health Care Issues of the American Neurological Association recommended treatment with 1 N NaOH as a standard sterilization procedure.18 Heat treatment led to substantial but incomplete inactivation in this study. The Committee on Health Care Issues of the American Neurological Association reported that boiling was an ineffective procedure for CJD tissues and contaminated materials.18 Tateishi et al. showed that heat treatment with SDS was effective.17 The acceleration of amyloid deposition may be a primary event in disease, CJD, bovine spongiform encephalopathy (BSE), familial amyloid polyneuropathy, and AA and human senile systemic amyloidosis.32 Walker et al. reported Aß amyloid extracted from an Alzheimer disease brain may have potential of prion protein.33

The property described for F-AEF is similar to that of prion reported in CJD. Chemical or autoclaving decontamination for CJD is necessary for most items associated with surgery or autopsy.34 We suggest that amyloidosis may need chemical or autoclaving decontamination similar to CJD.

Acknowledgments We thank Mr. Jitsuo Kashitani for excellent technical assistance. This work was supported by a grant from the Intractable Disease Division, the Ministry of Health and Welfare, a Research Committee for Epochal Diagnosis and Treatment of amyloidosis in Japan, and a Research Committee for amyloidosis.


http://www.springerlink.com/content/j6257362375470q8/fulltext.pdf


Unexpectedly high incidence of visceral AA-amyloidosis in slaughtered cattle in Japan Unexpectedly high incidence of visceral AA-amyloidosis in slaughtered cattle in Japan

Authors: Kana Tojo a; Takahiko Tokuda a; Yoshinobu Hoshii b; Xiaoying Fu c; Keiichi Higuchi c; Takane Matsui d; Fuyuki Kametani e; Dr Shu-Ichi Ikeda a Affiliations: a Third Department of Medicine, Shinshu University School of Medicine. Matsumoto. Japan b First Department of Pathology, Yamaguchi University School of Medicine. Ube. Japan c Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University, Graduate School of Medicine. Matsumoto. Japan d Department of Pathobiological Science, School of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine. Obihiro. Japan e Department of Molecular Biology, Tokyo Institute of Psychiatry. Tokyo. Japan

DOI: 10.1080/13506120500107097 Publication Frequency: 4 issues per year Published in: Amyloid, Volume 12, Issue 2 June 2005 , pages 103 - 108 Subjects: Biochemistry; Medicine; Number of References: 30 Formats available: HTML (English) : PDF (English) Previously published as: Amyloid: International Journal of Experimental & Clinical Investigation (1350-6129) until 2004 In order to give pricing details we need to know your country. Please register and/or sign in to identify your country. Sign In Online Sample

Abstract

Experimental mouse AA amyloidosis can be transmissible by dietary ingestion of amyloid fibrils and it is well known that AA amyloidosis occasionally develops in aged cattle. Bovine liver and intestine have conventionally been used in Oriental foods, and the incidence of visceral AA amyloidosis in slaughtered cattle was evaluated. Renal tissues from 302 aged cattle older than 4 years were obtained from a local abattoir. Amyloid deposition was microscopically examined and amyloid protein was immunochemically determined. Renal amyloid deposition was seen in 15 out of 302 cattle with no previous history of diseas, an incidence of 5.0%. Amyloid protein in these cattle was AA and they had pathological findings in their visceral organs on gross examination. The incidence of visceral AA amyloidosis in slaughtered cattle in this study was disturbingly high compared with those (0.4-2.7%) previously reported from Japan and other foreign countries. AA amyloidosis is a life-threatening complication in patients with chronic inflammatory diseases and these patients at risk should avoid ingesting food that may possibly contain AA amyloid fibrils. More detailed information on cattle amyloidosis is required to guarantee the safety of our food.

Keywords: Cattle amyloidosis; transmissible amyloidosis; reactive amyloidosis; AA amyloidosis; chronic inflammation view references (30)


http://www.informaworld.com/smpp/content~content=a713998551~db=all~order=page


Subject: Amyloidogenic potential of foie gras Date: June 22, 2007 at 2:23 pm PST


http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0706&L=sanet-mg&P=9621


A case of sCJD with beta-amyloid deposits and alpha-synuclein inclusions

Abstract

Case Report

A sporadic case of Creutzfeldt–Jakob disease with beta-amyloid deposits and alpha-synuclein inclusions

Anne Vital,11Neuropathology Department, Victor Segalen – Bordeaux 2 University, Bordeaux,Anne Vital, MD, PhD, Laboratoire de Neuropathologie BP 42, Université Victor Segalen, Bordeaux 2, 146, rue Léo-Saignat, 33076 Bordeaux Cedex, France. Email: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:anne.vital@chu-bordeaux.fr Marie-Hélène Canron,11Neuropathology Department, Victor Segalen – Bordeaux 2 University, Bordeaux, Roger Gil,22Neurology Department, Poitiers University, Poitiers and Jean-Jacques Hauw33Neuropathology Department, Pitié-Salpêtrière Hospital, Paris, France and Claude Vital11Neuropathology Department, Victor Segalen – Bordeaux 2 University, Bordeaux, 1Neuropathology Department, Victor Segalen – Bordeaux 2 University, Bordeaux, 2Neurology Department, Poitiers University, Poitiers and 3Neuropathology Department, Pitié-Salpêtrière Hospital, Paris, France Anne Vital, MD, PhD, Laboratoire de Neuropathologie BP 42, Université Victor Segalen, Bordeaux 2, 146, rue Léo-Saignat, 33076 Bordeaux Cedex, France. Email: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:anne.vital@chu-bordeaux.fr

Abstract

Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha-synuclein inclusions in a sporadic, methionine/valine type 1, Creutzfeldt–Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha-synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson’s disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient’s age (79 years at autopsy) and the over 2-year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha-synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology-based surveillance systems.


http://www.blackwell-synergy.com/doi/abs/10.1111/j.1440-1789.2007.00755.x


P01.34

Pathological Interaction Between Protein Misfolding Disorders: Prions and Alzheimer's Disease

Morales, R; Estrada, L; Castilla, J; Soto, C University of Texas Medical Branch, Neurology, USA

Protein Misfolding Disorders (PMD) include several diverse diseases, such Alzheimer's, Parkinson's, Transmissible Spongiform Encephalopathies, Diabetes Type II and various systemic amyloidosis. The central event in these diseases is the accumulation of a misfolded, ß-sheet rich aggregated form of a naturally expressed protein. In vitro studies have shown that protein misfolding and aggregation follows a seedingnucleation mechanism similar to the process of crystallization. In this model, the limiting step is the formation of small oligomeric intermediates that act as seeds to catalyze the polymerization process. The seeding-nucleation model provides a rationale and plausible explanation for the infectious nature of prions. Infectivity lies on the capacity of preformed stable misfolded oligomeric proteins to act as a seed to catalyze the misfolding and aggregation process. The mechanism of misfolding and aggregation is similar in all PMD suggesting that misfolded aggregates have an inherent capability to be transmissible. Moreover, it has been shown that oligomeric seeds formed by one protein can accelerate the misfolding and aggregation of another protein, by a process termed cross-seeding. Our current study aims to assess the potential molecular cross-talk among PMD in vivo. For this purpose we inoculated with prions a transgenic mice model of Alzheimer's disease (tg2576) that develops typical amyloid plaques over time. 45, 303 and 365 days old transgenic and wild type mice were inoculated intraperitoneally with RML prions. We found significant diminution in prion incubation periods for tg2576 mice compared to age matched wild type controls. Moreover, a time dependent effect was observed, where the shorter incubation period was observed in animals containing larger number of amyloid plaques. Inoculation of tg2576-RML prions into wild type mice showed incubation periods similar to the original infectious material, suggesting that strains characteristics are maintained. In vitro data showed cross-seeding aggregation between PrPSc and Aß. Our findings suggest an interaction between Alzheimer's and prion pathologies, indicating that one protein misfolding process may be an important risk factor for the development of a second perhaps more prevalent disease.


http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


Subject: FELINE ALZHEIMER'S OR MAD CAT DISEASE I.E. FSE

Date: December 6, 2006 at 9:24 am PST

News & Events - 6 December 2006 Cats Can Succumb to Feline Alzheimer's Ageing cats can develop a feline form of Alzheimer's disease, a new study reveals.

Researchers at the Universities of Edinburgh, St Andrews, Bristol and California have identified a key protein which can build up in the nerve cells of a cat's brain and cause mental deterioration.

In humans with Alzheimer's disease, this protein creates ‘tangles’ inside the nerve cells which inhibit messages being processed by the brain. The team says that the presence of this protein in cats is proof that they too can develop this type of disease.

By carrying out post-mortem examination of cats which have succumbed naturally to the disease, scientists may now be able to uncover vital clues about how the condition develops. This may eventually help scientists to come up with possible treatments.

Researchers already thought cats were susceptible to dementia because previous studies had identified thick, gritty plaques on the outside of elderly cats' brain cells which are similar to those found in humans.

By pinpointing this second key marker, the Edinburgh-led team says we can be sure that cats can suffer from a feline form of Alzheimer's.

Dr Danielle Gunn-Moore, at the University of Edinburgh's Royal (Dick) School of Veterinary Studies, said:

“This newly discovered protein is crucial to our understanding of the ageing process in cats. We've known for a long time that cats develop dementia, but this study tells us that the cat's neural system is being compromised in a similar fashion to that we see in human Alzheimer's sufferers. The gritty plaques had only hinted that might be the case - now we know.

“The shorter life-span of a cat, compared to humans, allows researchers to more rapidly assess the effects of diet, high blood pressure, and prescribed drugs on the course of the disease. However, we also need to understand more about our geriatric cats for their own benefit, so we can slow down the degeneration the disease brings and keep them as happy cats for as long as possible.”

The findings of the study are published in a recent edition of the Journal of Feline Medicine.


http://www.ed.ac.uk/news/061206cats.html


Late onset cerebellar degeneration in a middle-aged cat

Arianna Negrin DVM1, , , Marco Bernardini DVM, Dipl ECVN2, Wolfgang Baumgärtner Dr Med Vet, PhD, Dipl ECVP3 and Massimo Castagnaro DVM, PhD, Dipl ECVP1

1Department of Public Health, Comparative Pathology and Veterinary Hygiene, Faculty of Veterinary Medicine, Università degli Studi di Padova, Viale dell'Università, 16, 35020 Legnaro, Padova, Italy 2Department of Veterinary Clinical Science, Faculty of Veterinary Medicine, Università degli Studi di Padova, Viale dell'Università, 16, 35020 Legnaro, Padova, Italy 3Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30599 Hannover, Germany

Accepted 24 April 2006. Available online 15 June 2006.

Cerebellar degeneration (abiotrophy) (CD) is a spontaneous and accelerated degeneration of one or several mature cerebellar neuronal cell populations and has been described in many domestic animals, especially in dogs, with numerous breed-related cases. In cats, CD is mentioned as a rare sporadic entity. Late onset CDs are exceptionally uncommon and only two cases are reported in young adults, both aged 18 months. This report describes clinical and pathological findings of a late onset feline CD in a 9-year-old male Persian cat. The cat was presented with a history of progressive ataxia lasting 2 years. Neurological examination revealed severe neurological deficits such as generalised and severe ataxia, hypermetria in all four limbs, and bilateral absence of menace response. The lesion was diffusely localised in cerebellum. On gross pathology, the cerebellum appeared of normal size and shape and kidneys were characterised by mild hyperaemia. Histologically, lesions were limited to the cerebellum and kidneys. In the cerebellum, all cerebellar folia of both hemispheres and the vermis were affected. Changes were characterised by severe and diffuse loss of Purkinje cells, loss of cellularity in the granular layer, mild astrogliosis associated with moderate hypertrophy of Bergmann's glia. Immunohistochemistry for feline parvovirus antigen revealed a negative result. Renal lesions consisted of chronic fibrosis associated with chronic interstitial nephritis. CD is a rare disease and occurs commonly in puppies or young animals, who are clinically normal at birth and usually develop neurological signs within a few weeks or months after birth. This report represents the first case of CD in a middle-aged cat.


http://www.sciencedirect.com/


It was thought likely that at least some, and probably all, of the cases in zoo animals were caused by the BSE agent. Strong support for this hypothesis came from the findings of Bruce and others (1994) ( Bruce, M.E., Chree, A., McConnell, I., Foster, J., Pearson, G. & Fraser, H. (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and species barrier. Philosophical Transactions of the Royal Society B 343, 405-411: J/PTRSL/343/405 ), who demonstrated that the pattern of variation in incubation period and lesion profile in six strains of mice inoculated with brain homogenates from an affected kudu and the nyala, was similar to that seen when this panel of mouse strains was inoculated with brain from cattle with BSE. The affected zoo bovids were all from herds that were exposed to feeds that were likely to have contained contaminated ruminant-derived protein and the zoo felids had been exposed, if only occasionally in some cases, to tissues from cattle unfit for human consumption.

snip...


http://www.bseinquiry.gov.uk/files/ws/s324.pdf


cases have been reported in domestic cats), are characterised by long asymptomatic incubation periods followed by progressive symptoms and signs of degeneration of the brain, leading eventually to death.


http://www.bsereview.org.uk/download/draft_2.pdf


PET FOODS MAD CATS AND MAD DOGS BSE/TSEs

worse still, there is serious risk the media could get to hear of such a meeting...

snip...

Crushed heads (which inevitably involve brain and spinal cord material) are used to a limited extent but will also form one of the constituent raw materials of meat and bone meal, which is used extensively in pet food manufacturer...


http://www.bseinquiry.gov.uk/files/yb/1989/03/17004001.pdf


2. The Parliamentary Secretary said that he was concerned about the possibility that countries in which BSE had not yet been detected could be exporting raw meat materials (in particular crushed heads) contaminated with the disease to the UK for use in petfood manufacture...

snip...

YOU explained that imported crushed heads were extensively used in the petfood industry...


http://www.bseinquiry.gov.uk/files/yb/1989/04/14001001.pdf


In particular I do not believe one can say that the levels of the scrapie agent in pet food are so low that domestic animals are not exposed...


http://www.bseinquiry.gov.uk/files/yb/1989/04/24003001.pdf


http://www.bseinquiry.gov.uk/files/yb/1989/04/25001001.pdf


some 100+ _documented_ TSE cats of all types later...tss

on occassions, materials obtained from slaughterhouses will be derived from sheep affected with scrapie or cattle that may be incubating BSE for use in petfood manufacture...


http://www.bseinquiry.gov.uk/files/yb/1989/05/03007001.pdf


Meldrum's notes on pet foods and materials used


http://www.bseinquiry.gov.uk/files/yb/1989/05/16001001.pdf


http://www.bseinquiry.gov.uk/files/yb/1989/05/16002001.pdf


IN CONFIDENCE CJD TO CATS...

http://www.bseinquiry.gov.uk/files/yb/1989/05/18002001.pdf


Confidential BSE and __________________


http://www.bseinquiry.gov.uk/files/yb/1989/05/22012001.pdf


1st case natural FSE


http://www.bseinquiry.gov.uk/files/yb/1990/05/09002001.pdf


FSE and pharmaceuticals


http://www.bseinquiry.gov.uk/files/yb/1990/05/10005001.pdf


confidential cats/dogs and unsatisfactory posture MAFFs failure to assure key research


http://www.bseinquiry.gov.uk/files/yb/1990/06/14006001.pdf


can't forget about the mad man and his mad cat ;

Deaths of CJD man and cat linked


http://news.bbc.co.uk/1/hi/health/184558.stm


In October 1998 the simultaneous occurrence of spongiform encephalopathy in a man and his pet cat was reported. The report from Italy noted that the cat did not display the same clinical features as FSE cases previously seen. Indeed, the presence of a new type of FSE was suggested. The man was diagnosed as having sporadic CJD, and neither case (man nor cat) appeared to be affected by a BSE-related condition.


http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html


Image] Research letters Volume 352, Number 9134 [Image] 3 October1998[Previous] [Next] [Image][Image]

Simultaneous occurrence of spongiform encephalopathy in a manand his cat in Italy

[Image] Gianluigi Zanusso, Ettore Nardelli, Anna Rosati, GianMaria Fabrizi, SergioFerrari, Antonella Carteri, Franco De Simone, Nicola Rizzuto, SalvatoreMonaco

Transmissible spongiform encephalopathies (TSE) encompass inherited,acquired, and sporadic mammalian neurological disorders, and arecharacterised by the conversion of the cellular prion protein (PrP) in aninsoluble and protease-resistant isoform (PrPres). In human TSE, four typesof PrPres have been identified according to size and glycoform ratios, whichmay represent different prion strains. Type-1 and type-2 PrPres areassociated with sporadic Creutzfeldt-Jakob disease (CJD), type 3 withiatrogenic CJD, and type 4 with variant CJD.1,2 There is evidence thatvariant CJD is caused by the bovine spongiform encephalopathy (BSE)-prionstrain.2-4 The BSE strain has been identified in three cats with felinespongiform encephalopathy (FSE), a prion disease which appeared in 1990 inthe UK.5 We report the simultaneous occurrence of sporadic CJD in a man anda new variety of FSE in his cat. A 60-year-old man, with no unusual dietary habits, was admitted in November,1993, because of dysarthria, cerebellar ataxic gait, visual agnosia, andmyoclonus. An electroencephalogram (EEG) showed diffuse theta-deltaactivity. A brain magnetic resonance imaging scan was unremarkable. 10 dayslater, he was speechless and able to follow only simple commands. RepeatEEGs showed periodic triphasic complexes. 2 weeks after admission, he wasmute, akinetic, and unable to swallow. He died in early January, 1994. His 7-year-old, neutered, female shorthaired cat presented in November,1993, with episodes of frenzy, twitching of its body, and hyperaesthesia.The cat was usually fed on canned food and slept on its owner's bed. Nobites from the cat were recalled. In the next few days, the cat becameataxic, with hindquarter locomotor dysfunction; the ataxia got worse andthere was diffuse myoclonus. The cat was killed in mid-January, 1994. No pathogenic mutations in the patient's PrP gene were found. The patientand the cat were methionine homozygous at codon 129. Histology of thepatient's brain showed neocortical and cerebellar neuronal loss,astrocytosis, and spongiosis (figure A). PrP immunoreactivity showed apunctate pattern and paralleled spongiform changes (figure B). The cat'sbrain showed mild and focal spongiosis in deeper cortical layers of all fourlobes (figure C), vacuolated cortical neurons (figure D), and mildastrogliosis. The cerebellar cortex and the dentate nucleus were gliosed.Immunoreactive PrP showed a punctate pattern in neocortex, allocortex, andcaudate nucleus (figure E). Western blot analysis of control and affectedhuman and cat brain homogenates showed 3 PrP bands of 27-35 kDa. Afterdigestion with proteinase K and deglycosylation, only samples from theaffected patient and cat showed type-1 PrPres, with PrP glycoform ratioscomparable to those observed in sporadic CJD1 (details available fromauthor). [Image] Microscopic sections of patient and cat brains A: Occipital cortex of the patient showing moderate spongiformdegeneration and neuronal loss (haematoxylin and eosin) and B: punctateperineuronal pattern of PrP immunoreactivity; peroxidaseimmunohistochemistry with monoclonal antibody 3F4. C: cat parietal cortexshowing mild spongiform degeneration (haematoxylin and eosin).D:vacuolated neurons (arrow, haematoxylin and eosin), E: peroxidaseimmunohistochemistry with antibody 3F4 shows punctate perineuronaldeposition of PrP in temporal cortex. This study shows a spatio-temporal association between human and felineprion diseases. The clinical features of the cat were different frompreviously reported cases of FSE which were characterised by gradual onsetof behavioural changes preceding locomotor dysfunction and ataxia.5Neuropathological changes were also at variance with the diffuse spongiosisand vacuolation of brainstem neurons, seen in FSE.5 The synaptic pattern ofPrP deposition, similar in the cat and in the patient, was atypical for aBSE-related condition. Evidence of a new type of FSE was further provided bythe detection of a type-1 PrPres, other than the BSE-associated type 4.2Taken together, our data suggest that the same agent strain of sporadic CJ was involved in the patient and in his cat. It is unknown whether these TSE occurred as the result of horizontaltransmission in either direction, infection from an unknown common source,or the chance occurrence of two sporadic forms. 1 Parchi P, Castellani R, Capellari S, et al. Molecular basis of phenotypicvariablity in sporadic Creutzfeldt-Jakob disease.

Ann Neurol 1996; 39:767-78 [PubMed]. 2 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis ofprion strain variation and the aetiology of 'new variant' CJD. Nature 1996;383: 685-90 [PubMed]. 3 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[PubMed]. 4 Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJDand BSE. Nature 1997; 389: 448-50 [PubMed]. 5 Pearson GR, Wyatt JM, Henderson JP, Gruffydd-Jones TJ. Feline spongiformencephalopathy: a review. Vet Annual 1993; 33: 1-10. Sezione di Neurologie Clinica, Dipartimento di Scienze Neurologiche e dellaVisione, Università di Verona, Policlinico Borgo Roma, 37134 Verona, Italy(S Monaco; e mail mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:rizzuto@Gorgorna.univr.it); and Istituto ZooprofilatticoSperimentale della Lombardia e dell' Emilia, Brescia =========================================TSS

indeed there have been 4 documented cases of TSE in Lions to date.

Lion 32 December 98 Born November 86

Lion 33 May 1999 (euthanased) Born November 81.

Lion 36 Euthanased August 2000 Born July 87. Deteriorating hind limb ataxia.

Lion 37 Euthanased November 2001 Male, 14 years. Deteriorating hind limb ataxia since September 2001. (Litter mate to Ref. 36.)


http://www.defra.gov.uk/animalh/bse/index.html


go to the url above, on the bar at the top, click on _statistics_, then in middle of next page, click on _other TSEs_.

or go here;


http://www.defra.gov.uk/animalh/bse/bse-statistics/level-3-tsestat.html


and


http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html


http://www.bseinquiry.gov.uk/files/yb/1992/11/13001001.pdf


also;

Reports on the clinical symptoms presented by these cats give a relatively homogeneous picture: Affected cats show a lack of coordination with an ataxia mainly of the hind limbs, they often fall and miss their target when jumping. Fear and increased aggressiveness against the owner and also other animals is often seen. They do not longer tolerate to be touched (stroked) and start hiding. These behavioural chances might be the result of a hypersensibility to touch and noise, but also to increased fear. Excessive salivation is another more frequently seen symptom. Cats with FSE in general show severe behavioural disturbances, restlessness and depression, and a lack of coat cleaning. Symptoms in large cats in general are comparable to those in domestic cats. A report on FSE (in german) has been presented in 2001 in the Swiss FVO Magazin. A paper on the first FSE case in a domestic cat in Switzerland is currently in press in the Journal Schweizer Archiv für Tierheilkunde (SAT).


http://www.neurocenter-bern.ch/tse_e.shtml


Subject: DEER SPONGIFORM ENCEPHALOPATHY SURVEY & HOUND STUDY

Date: Thu, 17 Oct 2002 17:04:51 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: BSE-L

Greetings BSE-L,

is there any other CWD surveys/testing in the UK on their deer? what sort of testing has been done to date on UK/EU deer? any input would be helpful... thank you

DEER SPONGIFORM ENCEPHALOPATHY SURVEY


http://www.bseinquiry.gov.uk/files/yb/1991/11/20004001.pdf


http://www.bseinquiry.gov.uk/files/yb/1992/11/04002001.pdf


hope they did not go by the wayside as the hound study;


http://www.bseinquiry.gov.uk/files/yb/1991/10/18001001.pdf


http://www.bseinquiry.gov.uk/files/yb/1993/12/06001001.pdf


37. Putative TSE in hounds - work started 1990 -(see para 41)

Robert Higgins, a Veterinary Investigation Officer at Thirsk, had been working on a hound survey in 1990. Gerald Wells and I myself received histological sections from this survey along with the accompanying letter (YB90/11.28/1.1) dated November 1990. This letter details spongiform changes found in brains from hunt hounds failing to keep up with the rest of the pack, along with the results of SAF extractions from fresh brain material from these same animals. SAFs were not found in brains unless spongiform changes were also present. The spongiform changes were not pathognomonic (ie. conclusive proof) for prion disease, as they were atypical, being largely present in white matter rather than grey matter in the brain and spinal cord. However, Tony Scott, then head of electron microscopy work on TSEs, had no doubt that these SAFs were genuine and that these hounds therefore must have had a scrapie-like disease. I reviewed all the sections myself (original notes appended) and although the pathology was not typical, I could not exclude the possibility that this was a scrapie-like disorder, as white matter vacuolation is seen in TSEs and Wallerian degeneration was also present in the white matter of the hounds, another feature of scrapie.

38. I reviewed the literature on hound neuropathology, and discovered that micrographs and descriptive neuropathology from papers on 'hound ataxia' mirrored those in material from Robert Higgins' hound survey. Dr Tony Palmer (Cambridge) had done much of this work, and I obtained original sections from hound ataxia cases from him. This enabled me provisionally to conclude that Robert Higgins had in all probability detected hound ataxia, but also that hound ataxia itself was possibly a TSE. Gerald Wells confirmed in 'blind' examination of single restricted microscopic fields that there was no distinction between the white matter vacuolation present in BSE and scrapie cases, and that occurring in hound ataxia and the hound survey cases.

39. Hound ataxia had reportedly been occurring since the 1930's, and a known risk factor for its development was the feeding to hounds of downer cows, and particularly bovine offal. Circumstantial evidence suggests that bovine offal may also be causal in FSE, and TME in mink. Despite the inconclusive nature of the neuropathology, it was clearly evident that this putative canine spongiform encephalopathy merited further investigation.

40. The inconclusive results in hounds were never confirmed, nor was the link with hound ataxia pursued. I telephoned Robert Higgins six years after he first sent the slides to CVL. I was informed that despite his submitting a yearly report to the CVO including the suggestion that the hound work be continued, no further work had been done since 1991. This was surprising, to say the very least.

41. The hound work could have provided valuable evidence that a scrapie-like agent may have been present in cattle offal long before the BSE epidemic was recognised. The MAFF hound survey remains unpublished.

Histopathological support to various other published MAFF experiments

42. These included neuropathological examination of material from experiments studying the attempted transmission of BSE to chickens and pigs (CVL 1991) and to mice (RVC 1994).


http://www.bseinquiry.gov.uk/witness/htm/stat067.htm


nothing to offer scientifically;


http://www.bseinquiry.gov.uk/files/yb/1991/10/17001001.pdf


maddogs and Englishman


http://www.bseinquiry.gov.uk/files/yb/1990/11/28001001.pdf


kind regards, terry

###########bse-l ############

Subject: Re: DEER SPONGIFORM ENCEPHALOPATHY SURVEY & HOUND STUDY Date: Fri, 18 Oct 2002 23:12:22 +0100 From: Steve Dealler Reply-To: Bovine Spongiform Encephalopathy Organization: Netscape Online member To: BSE-L@ References:

Dear Terry,

An excellent piece of review as this literature is desparately difficult to get back from Government sites.

What happened with the deer was that an association between deer meat eating and sporadic CJD was found in about 1993. The evidence was not great but did not disappear after several years of asking CJD cases what they had eaten. I think that the work into deer disease largely stopped because it was not helpful to the UK industry...and no specific cases were reported. Well, if you dont look adequately like they are in USA currenly then you wont find any!

Steve Dealler ===============

Incubation periods for BSE are proportional to the life expectancy of the animal affected. The disease's incubation period is 18% of a cow's life expectancy and would be expected to about double when crossing to another species [-] that is, to 36% of 70 years in humans.

Steve Dealler, consultant in medical microbiology. Burnley General Hospital, Burnley BB10 2PQ mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000102/!x-usc:mailto:deal@airtime.co.uk

TSS


########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############


Docket Management Docket: 02N-0273 - Substances Prohibited From Use in Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed Comment Number: EC -10 Accepted - Volume 2 [PART 1]


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html


Docket Management Docket: 02N-0273 - Substances Prohibited From Use in Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed Comment Number: EC -11 Accepted - Volume 2 [PART 2]


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html


August 22, 2003 5:11 PM


Mad cat disease

A second case of feline spongiform encephalopathy (FSE), a disease affecting the brain tissue of cats, has been recorded in Switzerland. The veterinary authorities said the likely cause of the infection, which is similar to mad cow disease, was contaminated pet food. A first case of FSE was reported two years ago. Experts say the disease poses no health risk for people.

swissinfo


http://www.swissinfo.org/sen/Swissinfo.html?siteSect=113&sid=41558971


: Ann N Y Acad Sci. 1982;396:131-43. Links Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC. Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=6758661&query_hl=3&itool=pubmed_DocSum1:


Neurology. 1990 Feb;40(2):226-8. Coexistence of Creutzfeldt-Jakob disease and Alzheimer's disease in the same patient.Brown P, Jannotta F, Gibbs CJ Jr, Baron H, Guiroy DC, Gajdusek DC. Laboratory of CNS Studies, NINDS, National Institutes of Health, Bethesda, MD 20892.

We report the case of a 73-year-old patient in whom a diagnosis of Creutzfeldt-Jakob disease, suggested by the clinical course, was verified by the neuropathologic finding of widespread spongiform change and astrogliosis, the presence of proteinase-resistant protein in brain extracts, and the experimental transmission of spongiform encephalopathy to primates inoculated with brain tissue. However, neuropathologic examination also revealed a profusion of senile and neuritic plaques and neurofibrillary tangles that reacted with antibody to the amyloid beta-protein characteristic of Alzheimer's disease, but not with antibody to the scrapie amyloid protein characteristic of Creutzfeldt-Jakob disease.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2405293&query_hl=9&itool=pubmed_DocSum1:


Prog Clin Biol Res. 1989;317:549-57. Links Neuroaxonal dystrophy: an ultrastructural link between subacute spongiform virus encephalopathies and Alzheimer's disease.Liberski PP, Yanagihara R, Gibbs CJ Jr, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892.====================

Unconventional Viruses and the Origin and Disappearance of Kuru

333334 Physiology or Medicine 1976Table 12.

Creutzfeldt-Jakob disease in cats Incubation period(months)Duration(months)Primary passage Human brain Serial passage Cat brain (passage 1)Cat brain (passage 2)This geographic and temporal clustering does not apply, however, to a majority of cases and is unexplained by the 10% of the cases that are familial.Matthews has recently made a similar observation in two clusters in England(50). There are two reports of conjugal disease in which husband and wife diedof CJD within a few years of each other (30, 50).The prevalence of CJD has varied markedly in time and place throughout the United States and Europe, but we have noted a trend toward making the diagnosis more frequently in many neurological clinics in recent years, sinceattention has been drawn to the syndrome by its transmission to primates(3, 33). For many large population centers of the United States, Europe,Australia, and Asia, we have found a prevalence approaching one per millionwith an annual incidence and a mortality of about the same magnitude, asthe average duration of the disease is 8 to 12 months. Matthews (50) found anannual incidence of 1.3 per million in one of his clusters, which was over 10times the overall annual incidence for the past decade for England andWales (0.09 per million). Kahana et al. (40) reported the annual incidence ofCJD ranging from 0.4 to 1.9 per million in various ethnic groups in Israel. Theynoted, however, a 30-fold higher incidence of CJD in Jews of Libyan originabove the incidence in Jews of European origin. From recent discussions withour Scandinavian colleagues it is apparent that an annual incidence of at leastone per million applies to Sweden and Finland in recent years.Probable man-to-man transmission of CJD has been reported in a recipientof a cornea1 graft, which was taken from a donor who was diagnosed retrospectivelyto have had pathologically confirmed CJD ( 12). The disease occurred18 months after the transplant, an incubation period just the average forchimpanzees inoculated with human CJD brain tissue (32, 62). From suspensionof brain of the cornea1 graft recipient we succeeded in transmitting CJDto a chimpanzee although the brain had been at room temperature in 10%formol-saline for seven months (26a). More recently we learned that two of ourconfirmed cases of TVD were professional blood donors until shortly beforethe onset of their symptoms. To date, there have been no transmissions of CJDfrom blood of either human patients or animals affected with the experimentallytransmitted disease. However, we have only transfused two chimpanzees eachwith more than 300 ml of human whole blood from a different CJD patientUnconventional Viruses and the origin and Disappearance of KuruFigure 20. Six serial passages of CJD in chimpanzees, starting with brain tissue from abiopsy of a patient (R. R.) with CJD in the United Kingdom (U. K.). Also shown is transmissionof the disease directly from man to the capuchin monkey and marmoset, and fromchimpanzee brain to three species of New World monkeys (squirrel, capuchin, spidermonkeys), and to six Old World species (rhesus, stumptailed, cynomolgus, African green,pigtailed, and sooty mangabey). Incubation periods in the New World monkeys rangedfrom 19 to 47 months, and in the Old World monkeys from 43 to 60 months. The pigtailedmacaque and the sooty mangabey showed positive CJD pathology when sacrificed without336 Physiology or Medicine 1976within the past several months. Finally, the recognition of TVD in a neurosurgeon(27), and more recently in two physicians, has raised the question ofpossible occupational infection, particularly in those exposed to infected humanbrain tissue during surgery, or at postmortem examination (61, 63).The unexpectedly high incidence of previous craniotomy in CJD patientsnoted first by Nevin et al. (51) and more recently by Matthews (50) and byourselves (62), raises the possibility of brain surgery either affording a mode ofentry for the agent or of precipitating the disease in patients already carryinga latent infection. The former unwelcome possibility now eems to be areality with the probable transmission of CJD to two young patients withepilepsy from the use of implanted silver electrodes sterilized with 70%ethanol and formaldehyde vapor after contamination from their use on apatient who had CJD. The patients had undergone such electrode implantationfor stereotactic electroencephalographic localization of the epileptic focusat the time of correctional neurosurgery (3a).Two patients with transmissible virus dementias were not diagnosed clinicallyor neuropathologically as having CJD, but rather as having Alzheimer’sdisease (62). In both cases the disease was familial: in one (Fig. 21) therewere six close family members with the disease in two generations; in the otherboth the patient’s father and sister had died of presenile dementia. Thediseases as transmitted to primates were clinically and pathologically typicalsubacute spongiform virus encephalopathies, and did not have pathologicalfeatures of Alzheimer’s disease in man. More than 30 additional specimens ofbrain tissue from non-familial Alzheimer’s disease have been inoculated intoTVD-susceptible primates without producing disease. Therefore, although weclinical disease. A third passage to the chimpanzee was accomplished using frozen andthawed explanted tissue culture of brain cells that had been growing in vitro for 36 days.Using 10-3, 10-4, and 10-4 dilutions of brain, respectively, the 4th, 5th, and 6th chimpanzeepassages were accomplished. This indicates that the chimpanzee brain contains >50,000infectious doses per gram, and that such infectivity is maintained in brain cells cultivatedin vitro at 37” C for at least one month. The lower left shows transmission of CJD from asecond human patient (J. T.) to a cat with a 30 month incubation and serial passage in thecat with 19 to 24 month incubation.Unconventional Viruses and the Origin and Disappearance of Kum 337Figure 21a. Y family. Brain tissue obtained from patient A. Y. at biopsy induced subacutespongiform encephalopathy in a squirrel monkey 24 months after intracerebral inoculation.The patient, a 48-year old woman who died after a 68 month course of progressive dementia,quite similar in clinical aspects to the progressive dementia from which her fatherand brother had died at 54 and 56 years of age, respectively, was diagnosed clinically andneuropathologically as suffering from Alzheimer’s disease. Her sister is at present incapacitatedby a similar progressive dementia of 4 years’ duration. Although the transmitteddisease in the squirrel monkey was characterized by severe status spongiosis, none was seenin the patient. although amyloid plaques and neurofibrillary tangles were frequent.21b. H family. Brain tissue obtained from patient B. H. at surgical biopsy induced subacutespongiform encephalopathy in a squirrel monkey and a capuchin monkey 29 1/2 monthsand 43 months, respectively, after intracerebral inoculations. The patient, a 57 year oldwoman, has had slowly progressive dementia and deterioration for the past 7 years. Neuropathologicalfindings revealed abundant neurofibrillary tangles and senile plaques and noevidence of status spongiosis. The patient’s father, A. S., had died at age 64 following severalyears of progressive dementia, behavioral change and memory loss. B. H. is presently aliveand institutionalized.338 Physiology or Medicine 1976cannot claim to have transmitted the classical sporadic Alzheimer’s disease toprimates, we are confronted with the anomaly that the familial form ofAlzheimer’s disease has, in these two instances, transmitted as though it wereCJD.The above findings have added impetus to our already extensive studies ofHuntington’s chorea, Alzheimer’s and Pick’s diseases, parkinsonism-dementia,senile dementia, and even “dementia praecox", the organic brain diseaseassociated with late uncontrolled schizophrenia. ......


http://nobelprize.org/nobel_prizes/medicine/laureates/1976/gajdusek-lecture.pdf


GAH WELLS (very important statement here...TSS)

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

snip...


http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf


76 pages on hound study;


http://www.bseinquiry.gov.uk/files/sc/seac16/tab04.pdf



The spongiform changes were not pathognomonic (ie. conclusive proof) for prion disease, as they were atypical, being largely present in white matter rather than grey matter in the brain and spinal cord. However, Tony Scott, then head of electron microscopy work on TSEs, had no doubt that these SAFs were genuine and that these hounds therefore must have had a scrapie-like disease. I reviewed all the sections myself (original notes appended) and although the pathology was not typical, I could not exclude the possibility that this was a scrapie-like disorder, as white matter vacuolation is seen in TSEs and Wallerian degeneration was also present in the white matter of the hounds, another feature of scrapie. 38.I reviewed the literature on hound neuropathology, and discovered that micrographs and descriptive neuropathology from papers on 'hound ataxia' mirrored those in material from Robert Higgins' hound survey. Dr Tony Palmer (Cambridge) had done much of this work, and I obtained original sections from hound ataxia cases from him. This enabled me provisionally to conclude that Robert Higgins had in all probability detected hound ataxia, but also that hound ataxia itself was possibly a TSE. Gerald Wells confirmed in 'blind' examination of single restricted microscopic fields that there was no distinction between the white matter vacuolation present in BSE and scrapie cases, and that occurring in hound ataxia and the hound survey cases. 39.Hound ataxia had reportedly been occurring since the 1930's, and a known risk factor for its development was the feeding to hounds of downer cows, and particularly bovine offal. Circumstantial evidence suggests that bovine offal may also be causal in FSE, and TME in mink. Despite the inconclusive nature of the neuropathology, it was clearly evident that this putative canine spongiform encephalopathy merited further investigation. 40.The inconclusive results in hounds were never confirmed, nor was the link with hound ataxia pursued. I telephoned Robert Higgins six years after he first sent the slides to CVL. I was informed that despite his submitting a yearly report to the CVO including the suggestion that the hound work be continued, no further work had been done since 1991. This was surprising, to say the very least. 41.The hound work could have provided valuable evidence that a scrapie-like agent may have been present in cattle offal long before the BSE epidemic was recognised. The MAFF hound survey remains unpublished. Histopathological support to various other published MAFF experiments 42.These included neuropathological examination of material from experiments studying the attempted transmission of BSE to chickens and pigs (CVL 1991) and to mice (RVC 1994).


http://www.bseinquiry.gov.uk/witness/htm/stat067.htm


It was thought likely that at least some, and probably all, of the cases in zoo animals were caused by the BSE agent. Strong support for this hypothesis came from the findings of Bruce and others (1994) ( Bruce, M.E., Chree, A., McConnell, I., Foster, J., Pearson, G. & Fraser, H. (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and species barrier. Philosophical Transactions of the Royal Society B 343, 405-411: J/PTRSL/343/405 ), who demonstrated that the pattern of variation in incubation period and lesion profile in six strains of mice inoculated with brain homogenates from an affected kudu and the nyala, was similar to that seen when this panel of mouse strains was inoculated with brain from cattle with BSE. The affected zoo bovids were all from herds that were exposed to feeds that were likely to have contained contaminated ruminant-derived protein and the zoo felids had been exposed, if only occasionally in some cases, to tissues from cattle unfit for human consumption.

snip...


http://www.bseinquiry.gov.uk/files/ws/s324.pdf


2005

DEFRADepartment for Environment,Food & Rural Affairs

Area 307, London, SW1P 4PQTelephone: 0207 904 6000Direct line: 0207 904 6287E-mail: h.mcdonagh.defra.gsi.gov.uk

GTN:FAX:

Mr T S SingeltaryP.O. Box 42BacliffTexasUSA 77518

21 November 2001

Dear Mr Singeltary TSE IN HOUNDS

Thank you for e-mail regarding the hounds survey. I am sorry for the long delay in responding.

As you note, the hound survey remains unpublished. However the Spongiform Encephalopathy Advisory Committee (SEAC), the UK Government's independent Advisory Committee on all aspects related to BSE-like disease, gave the hound study detailed consideration at their meeting in January 1994. As a summary of this meeting published in the BSE inquiry noted, the Committee were clearly concerned about the work that had been carried out, concluding that there had clearly been problems with it, particularly the control on the histology, and that it was more or less inconclusive. However was agreed that there should be a re-evaluation of the pathological material in the study.

Later, at their meeting in June 95, The Committee re-evaluated the hound study to see if any useful results could be gained from it. The Chairman concluded that there were varying opinions within the Committee on further work. It did not suggest any further transmission studies and thought that the lack of clinical data was a major weakness.

Overall, it is clear that SEAC had major concerns about the survey as conducted. As a result it is likely that the authors felt that it would not stand up to peer review and hence it was never published. As noted above, and in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether additional work should be performed to examine dogs for evidence of TSE infection. Although the Committee had mixed views about the merits of conducting further work, the Chairman noted that when the Southwood Committee made their recommendation to complete an assessment of possible spongiform disease in dogs, no TSEs had been identified in other species and hence dogs were perceived as a high risk population and worthy of study. However subsequent to the original recommendation, made in 1990, a number of other species had been identified with TSE ( e.g. cats) so a study in hounds was less critical.

For more details see-


http://www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf


As this study remains unpublished, my understanding is that the ownership of the data essentially remains with the original researchers. Thus unfortunately, I am unable to help with your request to supply information on the hound survey directly. My only suggestion is that you contact one of the researchers originally involved in the project, such as Gerald Wells. He can be contacted at the following address.

Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT 15 3NB, UK

You may also wish to be aware that since November 1994 all suspected cases of spongiform encephalopathy in animals and poultry were made notifiable. Hence since that date there has been a requirement for vets to report any suspect SE in dogs for further investigation. To date there has never been positive identification of a TSE in a dog.

I hope this is helpful

Yours sincerely 4

HUGH MCDONAGHBSE CORRESPONDENCE SECTION

============================================

This an excellent review by Terry Singeltary: see message on 1.3.5 concerning pet food manufacture and rulings. http://www.priondata.org/data/A_deerdog.html

NOW, ASK yourself how many dogs and cats are ever examined and autopsied for a TSE in the USA SAME AS HUMANS, OR EVEN LESS, VERY VERY FEW............

Cerebral Biopsies in Dementia-- Hulette et al 31

Accepted for publication July 11, 1991. From the Department of Pathology, Division of Neuropathology (Drs Hulette and Crain), the Department of Medicine, Division of Neurology (Dr Earl), and the Department of Neurobiology (Dr. Crain), Duke University Medical Center, Durham, NC.

Arch Neurol--Vol 49, January 1992

TSS/5/7/01

http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html

==============================

OTHER URLS OF INTEREST

1996). Stanley Prusinger, the scientist who coined the term prion, speculates Alzheimer's may in fact turn out to be a prion disease (Prusiner, 1984). In ...


http://www.cyber-dyne.com/~tom/Alzheimer_cjd.html#similar


http://www.bseinquiry.gov.uk/files/ws/s194.pdf


http://www.cjd.ed.ac.uk/path.htm


MULTIMODAL EVOKED POTENTIALS IN MOUSE MODELS OF NEURODEGENERATION

Transmissible spongiform encephalopathies and Alzheimer's disease are neurodegenerative disorders in which neuropathologic changes are associated with accumulation of prion protein and deposition of amyloid ß-protein, respectively. Recently, transgenic mice that overexpress a mutant human ß-amyloid precursor protein and mice devoid of prion protein were generated. However, few electrophysiologic studies in intact freely moving...

snip...

full text;


http://www.scripps.edu/research/sr2000/np11.html


Causes of Alzheimer's and "Mad-Cow" Diseases

Alzheimer's and "mad-cow" diseases are unique in that their infectious agents are not viruses or germs, but rather proteins. The brains of patients who suffered from Alzheimer's or cows that died of "mad-cow" disease show deposits of abnormal tissue called amyloid plaques. The primary component of these plaques is a protein called prion protein or PrP. Chemical and biochemical analysis showed that there was no difference in composition or primary structure between the normal, cellular form of PrP (PrPC, shown at right) and the disease form of PrP (PrPSc). Further analysis showed that PrPC can change into PrPSc when two of the a helices (shown in green) change into ß sheets. This ß sheet can then induce a similar change in another molecule of PrPC and hydrogen bond to it. The PrPSc 's then polymerize and come out of solution, forming the plaques found in Alzheimer's patients and mad cows. How the plaques cause the symptoms of the diseases is still not clear, but the prion protein holds the unique distinction of causing a disease solely through a small alteration in secondary structure.

full text;


http://genchem.chem.wisc.edu/netorial/modules/biomolecules/protein2/prot210.htm


importantly, recent findings indicating that the cellular accumulation of incorrectly folded proteins is the molecular basis of many diseases, including Alzheimer's Disease, Prion Diseases and Huntington Disease, underscore the importance of understanding the mechanisms of folding in vivo. Alzheimer's and prion disease appear to be caused by the generation of a "pathological" conformation in the newly translated protein that would otherwise fold to a normal conformation that does not produce the disease. In some model systems, molecular chaperones appear to play a role in this conformational change. Thus, developing approaches to study protein folding under physiological conditions is essential to understand how folding defects can lead to disease.

full text;


http://www.stanford.edu/group/frydman/interests.htm


Implications for Alzheimer's disease

Harris also has recently expanded his research to include Alzheimer's disease, which shares several features with prion diseases despite being non-infectious. Leonard Berg, M.D., professor of neurology and former director of the Alzheimer's Disease Research Center at the medical school, and other colleagues say Harris readily applies his extensive knowledge of cell biology to this area as well.


http://record.wustl.edu/archive/1998/02-12-98/3678.html


RESEARCH LETTERS

Early-Onset Familial Alzheimer Disease With Coexisting [beta] -Amyloid and Prion Pathology

To the Editor: Familial Alzheimer disease (AD) with early onset has been linked to 3 different genes with an autosomal dominant mode of inheritance: [beta] -amyloid, protein precursor, and the presenilins 1 and 2, representing not more than 50% of all cases of early-onset AD cases.1 Thus, the genetic defect remains unexplained in at least half of the families with histories of early onset of AD. We have recently described such a Swiss family whose members presented with a standard clinical and neuropathologic profile of AD.2 In particular, severe neurofibrillary tangle degeneration was present in the hippocampus and in several cortical areas, together with a large amount of [beta] -amyloid deposits and senile plaques (SPs). However, known mutations have not been found, either in the [beta] -amyloid precursor protein or in the presenilin 1 and 2 genes.2 We now report that the brains of 5 deceased members of this family, from 2 generations, present a coexisting [beta] -amyloid and prion protein (PrP) pathology.


Methods http://jama.ama-assn.org/images/dot_lgray_999999.gif


Five available cases with clinical AD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. The age at onset of disease ranged from 43 to 64 years (mean, 55.8 years) and age at death ranged from 55 to 81 years (mean, 67.4 years). In addition, 4 of the 5 cases had epileptic features. Serial frozen sections (50 µm thick) through the temporal and frontal cortex of the 5 formalin-treated brains were pretreated with formic acid. They were then processed using monoclonal antibodies against amyloid- [beta] 40 peptide (1:100; [Sigma] ) and against PrP106-126 (1:200; produced by one of us).3 The latter antibody specifically marks the pathological isoform of the PrP and does not cross-react with [beta] -amyloid deposits. In addition, double immunostaining using successive anti- [beta] -amyloid and anti-PrP106-126 antibodies was performed.

Results http://jama.ama-assn.org/images/dot_lgray_999999.gif


In all 5 cases, the cerebral cortex revealed spongiform changes, mainly in superficial layers, and some degree of gliosis. Neurofibrillary tangle and neuritic plaques revealed by Gallyas were numerous in all cortical regions including the primary visual area. In addition, frequent [beta] -amyloid-positive SPs were observed, together with SP stained by the monoclonal antibody against PrP106-126. Successive sections alternately stained with the 2 antibodies showed that both [beta] -amyloid and PrP106-126 positive SP are deposited in all layers of the frontal and temporal cortex. A population of SP, marked on 2 serial sections with both antibodies, was positive for both [beta] -amyloid and PrP106-126. Double-stained sections with [beta] -amyloid and PrP106-126 antibodies further demonstrate that 3 populations of plaques exist: only [beta] -amyloid, only PrP106-126 positive, or positive for both antibodies (Figure 1) and a majority of SPs (>50%) are immunopositive for both [beta] -amyloid and PrP106-126 antibodies. Comparatively, the relative proportion of SPs marked for each antibody alone is smaller. In particular, SPs marked for PrP106-126 represent approximately 5% to 10% of the whole population.

Comment http://jama.ama-assn.org/images/dot_lgray_999999.gif


Coexistence of Creutzfeldt-Jakob disease (CJD) and AD in some patients has been described but appears mainly related to age in patients proven to have CJD.4 However, since the individuals in the Swiss family died over a long interval and were all similarly affected, it is unlikely that CJD is purely coincidental. On the other hand, familial Gerstmann-Straüssler-Scheinker disease can present a variant with concomitant neurofibrillary tangle and prion-positive plaques, but not [beta] -amyloid-positive plaques. Within this variant, 2 mutations in the gene for the PrP have been identified in 2 different families, and the clinical profile with cerebellar ataxia and extrapyramidal signs5 differs from our findings.2 Base pair deletion in the prion gene segregating as an uncommon polymorphism has been described in a family with a history of late-onset AD, but there is no neuropathological confirmation and the genetic association is uncertain.6

Thus, the data presented herein support the existence of a possible new subtype of familial early-onset AD with a concomitant [beta] -amyloid and prion brain pathology, together with a massive neurofibrillary tangle degeneration. Although all known mutations have been excluded in the coding regions of the AD genes, numerous candidate chromosome sites, either in the AD genes outside the coding regions or in other genes including PrP, must be considered.

G. Leuba, PhD, PD K. Saini, PhD University Psychogeriatrics Hospital Lausanne-Prilly, Switzerland

A. Savioz, PhD Y. Charnay, PhD University of Geneva School of Medicine Geneva, Switzerland

1. Cruts M, Van Broekhoven C. Molecular genetics of Alzheimer's diease. Ann Med. 1998;6:560-565.

2. Savioz A, Leuba G, Forsell C, et al. No detected mutations in the genes for the amyloid precursor protein and presenilins 1 and 2 in a Swiss early-onset Alzheimer's disease family with a dominant mode of inheritance. Dement Geriatr Cogn Disord. 1999;10:431-436. MEDLINE

3. Boris N, Mestre-Frances N, Charnay Y, Tagliavini F. Spontaneous spongiform encephalopathy in a young adult rhesus monkey. Lancet. 1996;348:55. MEDLINE

4. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol (Berl). 1998;96:116-122. MEDLINE

5. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Straüssler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. 1994;8:41-48. MEDLINE

6. Perry RT, Go RCP, Harrell LE, Acton RT. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer's disease family. Am J Med Genet. 1995;60:12-18. MEDLINE

Funding/Support: This study was supported by grants 3100-045960.95 and 3100-043573.95 from the Swiss National Science Foundation.


http://jama.ama-assn.org/issues/v283n13/ffull/jlt0405-5.html


Slide show

... Many neurodegenerative disorders -- such as prion diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease, frontotemporal dementia -- are ...


www.nature.com/nrm/journal/v1/n3/slideshow/nrm1200_217a_F1.html


Occasional PrP plaques are seen in cases of Alzheimer's Disease

snip...

full text;


http://www.bseinquiry.gov.uk/files/ws/s310.pdf


2 3 Once isolated, the agent must be capable of reproducing the disease in experimental animals. 4 The agent must be recovered from the experimental disease produced. 3. In the case of transmissible spongiform encephalopathies (TSEs), these postulates are not fulfilled in the following ways: 4. Unfulfillments of Postulate 1. 4.1 Transgenic mice with a codon 102 mutation involving a leucine substitution spontaneously develop spongiform encephalopathy with no detectable mutant prion protein (PrPsc). (Ref. Hsiao K.K. et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science (1990) 250: 1587-1590.) (J/S/250/1587) 4.2 Spongiform encephalopathy in zitter rats does not involved PrP. (ref. Gomi H. et al. Prion protein (PrP) is not involved in the pathogenesis of spongiform encephalopathy in zitter rats. Neurosci. Lett (1994) 166: 171-174.) (J/NSC/166/171) 4.3 Many viruses and retroviruses can produced spongiform encephalopathies without PrPsc involvement. (Ref. Wiley C.A. Gardner M. The pathogenesis of murine retroviral infection of the central nervous system. Brain Path (1993) 3: 123-128.) (J/BRP/3/123) 4.4 Experiments involving the transmission of the 'BSE agent' in mice produced symptoms of TSE, but in 55% no PrPsc could be detected. (Ref. Lasmesaz. C. et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science (1997) 275: 402- 405.) (J/S/275/402) 5. Unfulfillment of Postulate 2 5.1 Occasional PrP plaques are seen in cases of Alzheimer's Disease, where they coexist with the more usual beta amyloid plaques. (Ref. Baker H. F. Ridley R.M. Duchen L.W. Crow T.J. Bruton C.J. Induction of beta

full text;


http://www.bse.org.uk/files/ws/s310.pdf


Wednesday, 23 August, 2000, 23:54 GMT 00:54 UK Alzheimer's and CJD 'similar' [Brain] Rogue proteins are thought to cause degenerative brain disorders Scientists have discovered striking similarities between Alzheimer's disease and the human form of mad cow disease, vCJD.

They believe the breakthrough could lead to drugs to treat both conditions.

Both are marked by a gradual and ultimately fatal deterioration of the brain and both are associated with rogue proteins.

Now Professor Chi Ming Yang, of Nankai University in Tianjin, China, has discovered that these proteins have very similar structures.

This could mean that the molecular mechanism underlying Alzheimer's disease and vCJD is the same.

Professor Yang used a computer model to map the prion protein associated with vCJD and the amyloid precursor protein associated with early stage Alzheimer's.

He found that the two proteins had a similar pattern of component parts known as amino acids.

Each are made up of a reductive amino acid followed by three non-reductive amino acids.

Reductive amino acids are more prone to damage by free radicals - charged oxygen particles that can disrupt the DNA of the body's cells.

Normally, the body can clear itself of free radicals. But with age, this system may fail.

When enough free radicals accumulate to damage a protein molecule it can malfunction.

Scientists believe this mechanism may lead to Alzheimer's, the most common cause of dementia, affecting an estimated 12 million people worldwide.

The disease is characterised by include messy "tangles" of nerve fibres and "plaques" rich in the amyloid proteins.

CJD is the human version of bovine spongiform encephalitis (BSE or mad cow disease).

It occurs naturally in about one in a million people but a new version, vCJD, has been linked with eating BSE-infected meat.

BSE and vCJD are believed to be caused by prion proteins that do not fold normally.


http://news.bbc.co.uk/hi/english/health/newsid_892000/892819.stm


Stanley Prusiner, M.D.

Stanley Prusiner, M.D., a neurobiologist at the University of California at San Francisco, was awarded the 1997 Nobel Prize in Medicine for his groundbreaking discovery and definition of a new class of disease-causing agents called prions (pronounced pree-ons). The Nobel Prize, is the most prestigious award given for research in medicine.

Dr. Prusiner's award is the culmination of 25 years of sometimes controversial research on the prion, a natural human protein that, under certain conditions, can interact with other prion proteins, ultimately forming harmful deposits in the brain. The American Health Assistance Foundation (AHAF) has awarded more than $1.2 million in research grants through its Alzheimer's Disease Research program to Dr. Prusiner to develop his prion theory as a model for Alzheimer's disease. According to AHAF President Eugene Michaels, "Dr. Prusiner has proven that the most promising discoveries are often the result of innovative scientific inquiry. We are honored to have played a part in Dr. Prusiner's groundbreaking research."

Prions have been implicated in dementia-causing diseases such as mad cow disease and scrapie in animals, and Creutzfeldt-Jakob Disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS) in humans. Unlike infectious agents such as bacteria, viruses and parasites, whose ability to grow and reproduce is governed by genetic material made up of RNA and DNA, prions appear to be made up entirely of proteins with no accompanying DNA or RNA. Prions are present in normal cells, and the gene that codes for the production of the prion protein is part of a normal human chromosome.

Since 1985, the American Health Assistance Foundation has supported studies of the structures and properties of prions, and investigations that led to the purification and identification of the prion protein in the brains of scrapie-infected sheep. AHAF also awarded a grant to Dr. Prusiner to study CJD and GSS, using molecular biology methods to introduce genes from mutated prion proteins into mice to create an animal model for these diseases. His current AHAF grant is focused on the development of a new system to determine when in the life of a mouse the prion protein leads to disease. He is also studying a method to prevent prion disease by blocking prions from converting normal proteins into more prions.

There are similarities between the loss of brain function in prion diseases and in Alzheimer's disease, and an understanding of how prion diseases begin and develop will add to our understanding of what happens to the brain in Alzheimer's disease. Dr. Prusiner's research may one day lead to a treatment and a cure for Alzheimer's.


http://www.ahaf.org/alzdis/about/prusiner.htm


Date: Posted 8/24/2000

"Strikingly Similar" Protein May Be In Alzheimer's And Mad Cow Disease Washington D.C., August 23 -- A "striking similarity" between proteins involved in the early stages of Alzheimer's disease and mad cow disease was described here today at the 220th national meeting of the American Chemical Society, the world's largest scientific society. The theory, if verified by other researchers, could help focus efforts to develop preventive drugs, according to the study's lead researcher, Chi Ming Yang, Ph.D., a professor of chemistry at Nankai University in Tianjin, China.

Prion diseases -- which include, among others, neurodegenerative diseases such as mad cow disease and its human counterpart, Creutzfeldt-Jakob disease -- are caused by a malfunctioning prion protein. In Alzheimer's disease, another neurodegenerative disease, the amyloid precursor protein has been implicated.

Using computer modeling, Yang discovered a similar pattern of amino acids in the prion protein and the amyloid precursor protein: a reductive amino acid followed by three non-reductive amino acids.

"This suggests a common molecular mechanism underlying the initiation stages of sporadic Alzheimer's disease and both sporadic and genetic prion diseases," says Yang.

Reductive amino acids are more prone to damage by oxygen-containing free radicals (molecules with a highly reactive unpaired electron) than other amino acids, explained Yang. Normally, the body can clear itself of free radicals. But with age, this system may fail. When enough free radicals accumulate to damage a protein molecule, it can malfunction, he says.

Proteins typically fold into specific three-dimensional structures that determine their functions. A malfunctioning protein may remain partially unfolded, which can place different amino acids in close proximity, Yang explained. In the case of Alzheimer's and prion diseases, the reductive amino acids in close proximity can lead to the formation of protein plaques, according to Yang.

Although Alzheimer's and prion diseases seem to start in similar ways, they progress differently. This may explain why Alzheimer's disease advances at a much slower pace than Creutzfeldt-Jakob disease, says Yang.

The paper on this research, PHYS 460, will be presented at 7 p.m., Wednesday, Aug. 23, in the Washington Convention Center, Exhibit Hall D.

Chi Ming Yang, Ph.D., is a chemistry professor at Nankai University, Tianjin, China.

A nonprofit organization with a membership of 161,000 chemists and chemical engineers, the American Chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.


http://www.sciencedaily.com/releases/2000/08/000824081151.htm


http://www.sciencedaily.com/releases/2000/08/000824081151.htm


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Some references that may be interesting on the topic...

References. Aguzzi, A. and Weismann, C. Prion Research: the Next Frontiers. Nature, Vol.389 pp.796-79 ,1997. Alper , T.; Cramp, W.; Haig , D. and Clarke, M. Does the agent of scrapie replicate without nucleic acid?, Nature, Vol.214, pp.764-766.1967 Aldudo, J.; Bullido, M.J; De Miguel, C.; Valdivieso, F.; and Vazquez, J. Presenilin-1 genotype[2/2] is associated with late onset Alzheimer's disease in Spanish patients. Alzheimer's Res. Vol.3, pp.141-143.1997 Avila , J. and Colaco, A.L. The role of sulphated glycosaminoglycans in Alzheimer's disease.: a hypothesis. Alzheimer's Res., Vol.3,pp.77-81.1997 Avila, J. Modification of proteins related with the onset of Alzheimer's disease: Tau phosphorilation, glycosylation and oxydation in Alzheimer's disease. Current Drugs , Vol.2,pp.141-143.1997 Baldwin , M.; James , T.; Cohen, F.; and Pruisiner , S. The three-dimensional structure of prion protein : implications for Prion disease. Biochemical Society Transactions , Vol.26, pp.481-486.1998 Baldwin, M.; Pan ,K.; Nguyen , J.; Huang, Z. Groth, D.; Serban, A. et al. Spectroscopic Characterization of conformational differences between PrPc and PrPsc-An Alpha-helix to Beta-sheet transition. Philosophical Transactions of the Royal Society of London, series B-Biological Sciences,Vol.343, number 1306, pp-435-441.1992 Ball, M. Features of Creutzfeldt-Jakobs disease in brains of patients with familial dementia of Alzheimer's type. Canadian Journal of Neurological Sc.Vol.7 , pp.51-57.1980 Banissi-Sabourdi, C.; Planques, B.; David, J.P.; Jeannin, C.; Potel , M; Bizien, M.; Di Menza, C.; Brugère -Picoux, J.; Brugère, H.; Chatelain , J. Electroanalytical characterization of Alzheimer's disease and ovine spongiform encephalopathy by repeated cyclic voltametry at a capillary graphite paste electrode .Bioelectrochemistry and Bioenergetics. Vol. 28, pp.127-147.1992 Bernouli, C.; Siegfried, J.; Baumgartner,g. et al. Danger of accidental person to person transmission of Creutzfeldt-Jakobs disease by surgery . The Lancet.Vol.1,pp.478-479.1997 Borner, C.; Oliver, r.; Martinou, I.; Mattman ,C.; Tschopp, J.; and Martinou ,J.C. Dissection of functional domains in bcl-2 alpha by site directed mutagenesis . Biochemical Cellular Biology.Vol.72, pp463-469.1994 Brandner, s.; Isenmann, S; Raeber, A.; Fischer ,M.; Sailer, A.; Koyba et al. normal host prion protein necessary for scrapie-induced neurotoxicity.Nature.Vol.379, pp.339-343.1996 Braham, J . Ceutzfeldt-Jakob Disease: treatment by Amantidine. Brit. Med . J. Vol. 4, pp.213-213.1971 Brown, P.; Cathala, F.; and Gjdusek, D.C. Creutzfeldt-Jakob disease in France III. Epidemiological study of 170 patients dying during the decade 1968-1977. Ann. Of Neur.vol.6, pp.438-446.1979 Brugère, H.; Banissi, C.; Brugère-Picoux, J.; Chatelain, J. et Buvet, R. Recherche d'un temoin biochimique urinaire de l'infection du mouton par la tremblante. Bull. Acad. Vet. de France.Vol.64, pp.139-145.1991 Brugère, H.; Banissi, C.; Brugère-Picoux ,J .;Chatelain, J.; Tournaire, M.C et Buvet, R. Electrochemical analysis of urine in Alzheimer's patients and ruminants with spongiform encephalopaties ( scrapie and BSE) .III Int. Symp. on Transmissible subacute spogiform encephalopaties: Prion diseases, Paris, Val de Grace, 18-20 March.1996 Bruce, M.; Will, r.; Ironside, J.; McConnell, I.; Dummond , D,; and Suttie, A. Transmission to mice indicates that "new variant" CJD is caused by BSE agent. Nature. Vol.389, pp.498-501.1997 Byeler, H.; Aguzzi, A.; Sailer, A.; Greiner, r.; Autenreid, P.; Aguet, M.. and Weissman, C. Mice devoid of PrP are resistant to scrapie. Cell.vol.73, pp.1339-1347.1993 Carpenter, C.; Fishl, M.; Hammer, S.M; et al . Anti-retroviral therapy for HIV infection in 1996: Recommendations of an international panel. JAMA. Vol. 276,pp.146-154.1996 Cathala, F.; Brown, P.; Rahison, S et al. Maladie de Creutzfeldt-Jakob en France. Revue Neurologique (Paris).Vol.7,pp56-62.1982 Caughey, W.; Raymond, L .; Horiuchi, M.; and Caughey, B. Inhibition of protease-resistant prion protein formation by porphyrins and phtalocyanines.PNAS.Vol. 5.Iss.21,pp.12117-12122.Oct.17th,1998. Cohen, F.; Pan, K.; Huang, Z; Baldwin, M.; Fletterick, R. and Pruisiner, S. Structural clues to prion replication.Science.Vol.264, pp.530-531. 1994 Collinge, J.; and Hawke, S. B lymphocytes in prion neuroinvasion: central or peripheral players?. Nature Medicine .Vol.4,pp.1369-1370.1998. Collinge, J. and Palmer, M. Prion Diseases. Oxford University Press.1997 Collinge, J.; Whittington ,M.; Siddle, K. et al. Prion protein is necessary of synaptic formation. Nature. Vol.370, pp.277-295.1994 Cook, B.H.; Ward, B.; and Austin, J. Studies in ageing in the brain IV. Familial Alzheimer's disease : elation to transmissible dementia, aneuploidy and microtubular defects. Neur.Vol.29, pp.1402-1412.1979 De Armond, S.; Sanchez, h.; Yehiely, Q et al. Selective Neuronal targeting in prion disease.Neuron.Vol.19, pp.1337-1348.1997 De Wolfe, F.; Lukashnov, V. Danner, S et al .Clearance of HIV-1 following treatment with two, three, four or five anti-HIV drugs. Program and abstracts of the 5th conference on retroviruses and opportunistic infections.Feb.1-5th. Chicago, Ill.1998.Abs.384 Garrett, L. The Coming Plague. Penguin USA. 1995 Gibbs, T.; Baldwin, M.; Lloyd, D. et al. Predicted alpha-helical regions of the prion protein when synthesized as peptides from amyloid. PNAS.Vol.89,pp.10940-10944.1992 Goudsmith, J.; Morrow, C.; Asher, D. et al. Evidence for and against the transmissibility of Alzheimer's disease.Neurology.Vol.30pp.945-950.1980 Herishanu, Y. Antiviral drugs in Creutzfeldt-Jakob disease. J. of Am. Soc. of Geriatrics.Vol.21,pp.229-273.1973 Ikeda, K.; Kawada, N.; Wang ,Y. et al .Expression of cellular prion protein in activated hepatic stellate cells. Am. J. of Path.Vol.6,N.6, pp.1695-1700.1999 Jellinger, K.; and Seitelberger, F. Spongy degeneration in the central nervous system in infancy. Curr. Top. in Path.Vol.53, pp.90-160.1970 Kimberlin, R. and Walker , C. Anti-viral compound effective against experimental scrapie. The Lancet.Vol.2, pp.591-592.1979 Knusel, B. and Hefti ,Development of cholinergic pedunculopontine neurons in vitro: comparison with cholinergic septal cells and response to nerve growth factor, ciliary neurothrophic factor and retinoic acid. J. of Neurosc. Res. Vol.21,pp.365-375.1988 Manuelidis, E.; Manuelidis, L.; Pincus , J. et al. Transmission from man to hamster of Creutzfeldt-Jakob disease with clinical recovery. The Lancet. Vol.2.pp.40-42.1978 Munoz-Montano, J.; Moreno, F.; Avila, J. et al. Lithium inhibits Alzheimer's disease-like tau protein phosphoryllation in neurons .FEBS Lett.Vol.411,pp.183-188.1997 Perez, M.; Wandosell, F.; Colaco, C. and Avila, J. Sulphated glycosaminoglycans prevent neurotoxicity of human prion protein fragment . Pruisiner,S.Prions.PNAS.1998 Sadler, I.; Smith, D.; Sherman, M. et al .sulphated compounds attenuate Beta-amyloid toxicity by inhibiting its association with cells .Neuroreport.Vol.7,pp.49-53.1995 Sadler, I.; Hawtin, S.; Tailor, V. et al . Glucosaminoglycans and sulphated polyanions attenuate neurotoxic effects of beta-amyloid. Biochem. Soc. Trans. Vol.23,p.1065.1995 Sukhalayan,C.; Khalequz, Z.; Hoon, R.; Conforto, A.; and Rajiv, R. Sequence-Selective DNA binding drugs Mitramyacin A and Chromomyacin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons.Ann.Neurol.Vol.49,pp.345-354.2001

Diagnosis and Reporting of Creutzfeldt-Jakob Disease T. S. Singeltary, Sr; D. E. Kraemer; R. V. Gibbons, R. C. Holman, E. D. Belay, L. B. Schonberger


http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html


IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES


http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf


4.5 MILLION DEMENTED ALZHEIMER'S PATIENTS, HOW MANY ARE CJD/TSEs ???

HOW CAN ONE-IN-A-MILLION BE ACCURATE WHEN CJD IS NOT REPORTABLE,

AND WHEN THE ELDERLY DO NOT GET AUTOPSIED??????

TSS

http://www.rense.com/general34/cjmd.htm


Proof Mad Cow Is The Same As Alzheimer's And CJD How Many Of Them Are Really Mad Cow/vCJD/TSEs ??? How Can Government Claims Of Just 'One In A Million' Be Accurate When CJD Is Not A Reportable Disease? And When The Elderly Do Not Get Routinely Autopsied??

By Terry Singletary, Sr 12-27-03

Note - This extensive, powerful assemblage of science was first posted on 1-24-3. The following data is even more important today. -ed

snip...

http://www.rense.com/general46/proofa.html


Alzheimer's and Transmissible Spongiform Encephalopathies

http://neurotalk.psychcentral.com/thread13175.html


TSS