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From: TSS ()
In Reply to: Re: Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease posted by TSS on March 27, 2008 at 10:45 am:
Original Paper Association between Deposition of Beta-Amyloid and Pathological Prion Laura Debatina, Johannes Strefferb, Markus Geissenc, Jakob Matschkec, aInstitute of Neuropathology, and Neurodegenerative Dis (DOI: 10.1159/000121389) Key Words Sporadic Creutzfeldt-Jakob disease ---------------------------------------------------------------------------- Abstract Background: Alzheimer's disease (AD) and prion diseases such as sporadic Copyright © 2008 S. Karger AG, Basel Author Contacts Markus Glatzel http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000121389 Since this article does not have an abstract, we have provided the first 150 In their Research Letter, Dr Gibbons and colleagues1 reported that the Terry S. Singeltary, Sr 1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob 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 The pathogenesis of these diseases was compared to Alzheimer's disease at a snip... http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf There is also the matter whether the spectrum of ''prion disease'' is wider http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf snip... These are not relevant to any possible human hazard from BSE nor to the much snip... http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES References: < manuelidis ="=" href="http://neurotalk.psychcentral.com/thread13175.html">http://neurotalk.psychcentral.com/thread13175.html 1-24-3 To: Terry S. Singletary Sr 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 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 (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... 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 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 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 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. 1. Chui HC. Dementia: a review emphasizing clinicopathologic correlation and brain-behavior relationships. Arch NeuroI. 1989;46;806-814. 2. Jellinger K, Danielczyk W, Fischer P, Gabriel E. Clinicopathological analysis of dementia disorder's in the elderly, J Neurol Sci. 1990:95:239-258. 3. Katzman R. Alzheimer's disease. N Engl J Med. 1986;314:964-973. 4. Katzman R, Lasker B, Bernstein N. Advances in the diagnosis of dementia: accuracy of diagnosis and consequences of misdiagnosis of disorders causing dementia. In: Terry RD ed. Aging and the Brain. New York, NY: Raven Press; 1988: 17-62. 5. Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol. 1985;42;1097-1105. 6. Koranyi E. The cortical dementias. Can J Psychiatry 1988;33;838-845. 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. 9. Sim M, Bale RN. Familial pre-senile dementia: the relevance of a histological diagnosis of Pick's disease. Br J Psychiatry. 1973;122;671-673. 10. Tomlinson BE, Corsellis JAN. Aging and the dementias, In Adams JH, Cosellis JAN, Duchen LW, eds. Greensfield's Neuropathology. New York, NY: John Wiley & Sons Inc; 1984:951-1025 11. F;endheim PE. The hunmn spongitbrm ence-phahq,athies. Ncl~rol Clim 19¥,1:2:281-29¥. 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. F. TeixeiraI, E. Alonso2, V. Romerol, A. Ortiz', C. Martinez3, E. Otero4 Submitted: February 22, 1994 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 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. 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 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 REFERENCES American Psychiatric Association. 1987. Diagnostic and 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. 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 Download Report: 2007 Alzheimer’s Disease Facts and Figures (28 pages) Quote Sheet (2 pages) http://www.alz.org/national/documents/PR_FFquotesheet.pdf http://www.alz.org/news_and_events_rates_rise.asp Sun Feb 19, 2006 11:14 71.248.144.164 Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting 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. http://jnnp.bmjjournals.com/ IN STRICT CONFIDENCE Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray 2. Briefly, the meeting agreed that: i) Dr Ridley et als findings of experimental induction of p amyloid ii) there were no immediate implications for the public health, and no iii) additional research was desirable, both epidemiological and at the 93/01.05/4.1tss BSE101/1 0136 5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992 121/YdeStss 92/11.4/1.2 http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf (note the substantial increase on a yearly basistss) http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf There is also the matter whether the spectrum of ''prion disease'' is wider snip... These are not relevant to any possible human hazard from BSE nor to the much snip... http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0612&L=sanet-mg&T=0&P=8525 From: "Terry S. Singeltary Sr." <[log in to unmask]> i have written about this many times and spoke with colm on several > between vCJD and alzeheimer's in that alzheimers may be misdiagnosed AND personally i think there is a potential that Alzheimers may be low IN CONFIDENCE TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES H F BAKER, R M RIDLEY, L W DUCHEN, T J CROW, C J BRUTON 1) a 56 year old patient with severe Alzheimer's disease - B - amyloid 2) a 62 year old patient with Gerstmann-Straussler disease, a spongiform These monkeys were killed more than 6 years after inoculation and their It should be stressed, however, that we are not claiming to have transmitted 1) the animals were behaving normally when killed and 2) no neurofibrillary tangles were seen. We have argued previously that transmission of spongiform encephalopathy, Furthermore, BEFORE DISCLOSURE, IT IS IMPORTANT THAT INTERESTED PARTIES BE Previous attempts to transmit Alzheimer's disease to rodents and large At this point we would like to stress again the lack of evidence relating The interpretation we have made that B-amyloidosis as a self-peretuating 1) serial passage of B-amyloidosis in order to strengthen the evidence of 2) transmission from other cases of Alzheimer's disease in order to 3) transmission to primates which are allowed to run their full course, ie 4) comparison of transmission from cases which contain only CAA and those 5) establishment of the time course of the development of B-amyloidosis. The 6) transmission using larger quantities of purified preparations of 7) transmission using animals of different initial ages to investigate the 8) manipulation of transmission time by treatments which may speed up plaque The proposal is to inoculate about 25 marmosets in the first instance and to A preliminary report of our findings will be presented by Professor L W http://www.bseinquiry.gov.uk/ 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 *** 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: n.m.hooper@leeds.ac.uk www.pnas.org/cgi/doi/10.1073/pnas.0609621104 Date: June 24, 2007 at 1:11 pm PST Masatoshi Omoto · Tadaaki Yokota · Dan Cui Inactivation of amyloid-enhancing factor (AEF): study on experimental Abstract It is known that amyloid-enhancing factor (AEF) Secondary amyloidosis occurs in individuals with longstanding In our experiments with mice, the activity of F-AEF was The property described for F-AEF is similar to that Acknowledgments We thank Mr. Jitsuo Kash!tani for excellent technical Authors: Kana Tojo a; Takahiko Tokuda a; Yoshinobu Hoshii b; Xiaoying Fu DOI: 10.1080/13506120500107097 Abstract Experimental mouse AA amyloidosis can be transmissible by dietary ingestion Keywords: Cattle amyloidosis; transmissible amyloidosis; reactive http://www.informaworld.com/smpp/content~content=a713998551~db=all~order=page 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: 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 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. Pathological Interaction Between Protein Misfolding Disorders: Prions and Morales, R; Estrada, L; Castilla, J; Soto, C Protein Misfolding Disorders (PMD) include several diverse diseases, such Alzheimer's, Date: December 6, 2006 at 9:24 am PST News & Events - 6 December 2006 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 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. snip... http://www.bseinquiry.gov.uk/files/ws/s324.pdf http://www.bsereview.org.uk/download/draft_2.pdf worse still, there is serious risk the media could get snip... Crushed heads (which inevitably involve brain and spinal cord material) http://www.bseinquiry.gov.uk/files/yb/1989/03/17004001.pdf snip... YOU explained that imported crushed heads were extensively used in the http://www.bseinquiry.gov.uk/files/yb/1989/04/14001001.pdf http://www.bseinquiry.gov.uk/files/yb/1989/04/24003001.pdf on occassions, materials obtained from slaughterhouses http://www.bseinquiry.gov.uk/files/yb/1989/05/03007001.pdf http://www.bseinquiry.gov.uk/files/yb/1989/05/16001001.pdf http://www.bseinquiry.gov.uk/files/yb/1989/05/16002001.pdf http://www.bseinquiry.gov.uk/files/yb/1989/05/18002001.pdf http://www.bseinquiry.gov.uk/files/yb/1989/05/22012001.pdf http://www.bseinquiry.gov.uk/files/yb/1990/05/09002001.pdf http://www.bseinquiry.gov.uk/files/yb/1990/05/10005001.pdf http://www.bseinquiry.gov.uk/files/yb/1990/06/14006001.pdf Deaths of CJD man and cat linked http://news.bbc.co.uk/1/hi/health/184558.stm http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html 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 CJD 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 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 Lion 37 Euthanased November 2001 Male, 14 years. Deteriorating hind http://www.defra.gov.uk/animalh/bse/index.html 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 Reports on the clinical symptoms presented by these cats give a http://www.neurocenter-bern.ch/tse_e.shtml Date: Thu, 17 Oct 2002 17:04:51 -0700 Greetings BSE-L, is there any other CWD surveys/testing in the UK on their deer? DEER SPONGIFORM ENCEPHALOPATHY SURVEY http://www.bseinquiry.gov.uk/files/yb/1991/11/20004001.pdf http://www.bseinquiry.gov.uk/files/yb/1991/10/18001001.pdf Robert Higgins, a Veterinary Investigation Officer at Thirsk, 38. I reviewed the literature on hound neuropathology, and 39. Hound ataxia had reportedly been occurring since the 1930's, 40. The inconclusive results in hounds were never confirmed, 41. The hound work could have provided valuable evidence Histopathological support to various other published 42. These included neuropathological examination of material http://www.bseinquiry.gov.uk/witness/htm/stat067.htm http://www.bseinquiry.gov.uk/files/yb/1991/10/17001001.pdf http://www.bseinquiry.gov.uk/files/yb/1990/11/28001001.pdf ###########bse-l ############ Subject: Re: DEER SPONGIFORM ENCEPHALOPATHY SURVEY & HOUND STUDY Dear Terry, An excellent piece of review as this literature is desparately difficult What happened with the deer was that an association between deer meat Steve Dealler Incubation periods for BSE are proportional to the life expectancy of Steve Dealler, consultant in medical microbiology. TSS ########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############ Docket Management Docket: 02N-0273 - Substances Prohibited From Use in http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html Docket Management Docket: 02N-0273 - Substances Prohibited From Use in http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html Mad cat disease A second case of feline spongiform encephalopathy (FSE), a disease swissinfo http://www.swissinfo.org/sen/Swissinfo.html?siteSect=113&sid=41558971 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=6758661&query_hl=3&itool=pubmed_DocSum1: 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: 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 seems 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 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. 76 pages on hound study; 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 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 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............ 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 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 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 full text; http://www.stanford.edu/group/frydman/interests.htm 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 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. 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. A. Savioz, PhD Y. Charnay, PhD University of Geneva School of Medicine Geneva, Switzerland 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 http://jama.ama-assn.org/issues/v283n13/ffull/jlt0405-5.html ... 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 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., 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 "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 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. 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Schonberger http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html 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 Proof Mad Cow Is The Same As Alzheimer's And CJD By Terry Singletary, Sr http://www.rense.com/general46/proofa.html http://neurotalk.psychcentral.com/thread13175.html
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