More Evidence Mad Cow Same As CJD And Alzheimer's

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More Evidence Mad Cow Same As CJD And Alzheimer's 1-24-3 To: Terry S. Singletary Sr From Cindy B. Date: Friday, Jan 24 2003 Subj: CJD $ Alzheimer's Hi, I read your article on CJD on www.rense.com and was wondering when they are going to alert the population of this and start testing all these animals that are being consumed by humans. I have also read other articles that relate Alzheimer's, ALS, Parkinson's disease among others that have been linked to BSE/Mad Cow. Assuming all this is true (which I have no doubt it is), wouldn't everyone have to get tested to see if they have contracted any of these or their variants? I am really bothered by this whole thing and the lies that have been perpetuated by their many fronts in our government. Also, when they talk about "downers", does that refer to sick animals? And that even these sick animals are given as feed to the other animals? One last thing, I have information that an individual has "mad cow" who was in surgery here in our local hospital. The individual that told me says they are keeping it under tight wraps. Thanks for your work and the very informative article, Cindy Bouthillier Greeley, Colorado Date: Fri, 24 Jan 2003 From: Terry S. Singeltary Sr. Subject: Re: CJD $ Alzheimer's Hello Cindy, Thank you for your kind words. I have posted some data below on CJD and Alzheimer's that you may find interest in. Yes, there are about 200,000 downers annually in the USA. This involves cattle that go down for one reason or another and that includes prion/CNS disorder cattle of all sorts and yes, you are feeding dead doggy and kitty cat (and the chemicals used to euthanize old pets, dead downer cattle, 'roadkill' which includes scrapie infected sheep and CWD/mad deer infected deer and elk. It's just and endless cycle of greed. I would be interested to know more about the case of CJD and the hospital/surgical arena. This will be a major vector (of transmission) for prions. OH...and don't start looking for rapid TSE/prion testing in sufficient numbers to find TSEs/mad cow in US cattle anytime soon, because if you don't look...you don't find. Thus, you keep the 'gold card' of 'BSE/TSE FREE' status in US cattle. Of course, we know different... Kind regards, Terry Regarding Alzheimer's disease (note the substantial increase on a yearly basis) http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf snip... The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level... snip... http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf And NONE of this is relevant to BSE? There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present. http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf Human BSE snip... These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers. snip... http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf ===================================================== From: TSS (216-119-130-123.ipset10.wt.net) Subject: CJD or Alzheimer's, THE PA STUDY...full text Date: May 7, 2001 at 10:24 am PST Diagnosis of dementia: Clinicopathologic correlations Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life. NEUROLOGY 1989;39:76-79 Several recent papers and reports have addressed the problem of improving the clinician's ability to diagnose dementia. Notable among those reports are the diagnostic criteria for dementia of the American Psychiatric Association, known as DSM III,1 as well as the clinical and neuropathologic criteria for the diagnosis of Alzheimer's disease (AD).2,3 Other researchers have published guidelines for the differentiation of various types of dementia4 and for antemortem predictions about the neuropathologic findings of demented patients.5 Most studies on the accuracy of clinical diagnosis in patients with dementia, especially AD, have used clinicopathologic correlation,6-15 and have found a percentage of accuracy ranging from 43% to 87%. Two recent reports, however,16,17 have claimed an accuracy of 100%. These two reports are based on relatively small series and have consisted of very highly selected patient samples. In our own recent experience, several cases of dementia have yielded unexpected neuropathologic findings,18 and we hypothesized that, in larger series, there would be a significant number of discrepancies between clinical diagnoses and autopsy findings. The present paper reviews the neuropathologic diagnosis of 54 demented patients who were autopsied consecutively at the University of Pittsburgh over a 7-year period, and reports the ability of clinicians to predict autopsy findings. Material and methods. We independently reviewed the pathologic data and clinical records of 54 consecutive patients who had had an autopsy at the University of Pittsburgh (Presbyterian University Hospital [PUH] and the Pittsburgh (University Drive) Veterans Administration Medical Center [VAMC]), between 1980 and 1987. The 54 cases included all those where dementia was diagnosed clinically but for which an obvious etiology, such as neoplasm, trauma, major vascular lesions, or clinically evident infection had not been found. The brains, evaluated by the Division of Neuropathology of the University of Pittsburgh, were obtained from patients cared for in different settings at their time of death. On the basis of the amount of information available in each case, we divided the patients into three groups. Group 1 included 12 subjects who had been followed for a minimum of 1 year by the Alzheimer Disease Research Center (ADRC) of the University of Pittsburgh. ADRC evaluations include several visits and neurologic and neuropsychological testing as well as repeated laboratory tests, EEG, and CT.19,20 Group 2 included 28 patients who had been seen in the Neurology Service of PUH, of the VAMC, or in geriatric or psychiatric facilities of the University of Pittsburgh or at Western Psychiatric Institute and Clinic. All patients were personally evaluated by a neurologist and received a work-up to elucidate the etiology of their dementia. Group 3 included 14 patients seen in other institutions; in most cases, they had also been seen by a neurologist and had had laboratory studies that included CT of the head. In three of the 14 cases, however, the information could be gathered only from the clinical summary found in the autopsy records. Many of these subjects were referred for autopsy to the ADRC because of a public education campaign that encourages families to seek an autopsy for their relatives with dementia. Pathologic data. All brains were removed by a neuropathologist as the first procedure of the autopsy at postmortem intervals of between 4 and 12 hours. The unfixed brain was weighed and the brainstem and cerebellum were separated by intercollicular section. The cerebral hemispheres were sectioned at 1-cm intervals and placed on a glass surface cooled by ice to prevent adhesion of the tissue to the cutting surface. The brainstem and cerebellum were sectioned in the transverse plane at 6-mm intervals. Brain sections were fixed in 10% buffered formalin. Selected tissue blocks for light microscopy were obtained from sections corresponding as exactly as possible to a set of predetermined areas used for processing brains for the ADRC protocol; additional details of the neuropathologic protocol have been previously published.18,21 Following standard tissue processing and paraffin embedding, 8-um-thick sections stained with hematoxylin and eosin and with the Bielschowsky ammoniacal silver nitrate impregnation were evaluted. Additional stains were used when indicated by the survey stains, including the Bielschowsky silver technique as previously reported.21 Clinical data. The medical history, as well as the results of examinations and laboratory tests, were obtained from the medical records libraries of the institutions where the patient had been followed and had died. We supplemented these data, when appropriate, with a personal or telephone interview with the relatives. One neurologist (O.L.L.) recorded the information to be evaluated on two forms. The first form included sex, age, handedness, age at onset, age at death, course and duration of the disease, education, family history, EEG, CT, NMR, medical history, and physical examination as well as examination of blood and CSF for factors that could affect memory and other cognitive functions. The form also listed the results of neuropsychological assessment, and the characteristics and course of psychiatric and neurologic symptoms. The form provided details on the presence, nature, and course of cognitive deficits and neurologic signs. The second form was a 26-item checklist derived from the NINCDS-ADRDA Work Group Criteria for probable Alzheimer's disease.2 The forms did not include the patient's identity, the institution where they had been evaluated, the clinical diagnosis, or the pathologic findings. Each form was reviewed independently by two other neurologists (F.B. and J.M.), who were asked to provide a clinical diagnosis. In cases of probable or possible AD, the two neurologists followed the diagnostic criteria of the NINCDS/ ADRDA work group.2 The results were tabulated on a summary sheet filled out after the two neurologists had provided their diagnosis on each case. The sheet included the diagnosis reached by the two neurologists and the diagnosis resulting from the autopsy. Table 1. Pathologic diagnosis in 54 patients with dementia N % Alzheimer's disease alone 34 62.9 Alzheimer's disease and 2 3.7 Parkinsons's disease Alzheimer's disease with 2 3.7 multi-infarct dementia Alzheimer's disease with amyotrophic lateral sclerosis 39 72.2 Total Alzheimers disease 39 72.2 Multi-infarct dementia 4 7.4 Multi-infarct dementa 1 1.8 with Parkinson's disease Parkinson's disease 2 3.7 Progressive subcortical gliosis 2 3.7 Creutzfeldt-Jakob disease 3 5.5 Progressive supranuclear palsy 1 1.8 Huntington's disease 1 1.8 Unclassified 1 1.8 Total other disease 15 27.7 Total all cases 54 Table 2. Clinical diagnosis Clinical diagnosis Clinician #1 --- #2 Probable AD 29 21 Probable AD and MID 3 0 Probable AD and thyroid disease 1 2 Probable AD and PD 3 1 Probable AD and ALS 1 0 Probable AD and 0 1 olivopontocerebellar degeneration Total probable AD 37 25 (68.5%) (46.2%) Possible AD 3 2 Possible AD and MID 2 2 Possible AD and alcoholism 0 1 Possible AD and depression 1 0 Possible and thyroid disease 0 3 Possible AD and traumatic 1 2 encephalopathy Possible AD and PD 3 6 Total Possible AD 10 16 (18.5%) (29.6%) Atypical AD 0 1 Atuypical AD and MID 0 1 MID 2 4 MID and PD 3 0 Dementia syndrome of depression 0 1 HD 1 1 Wernicke-Korsakoff syndrome 1 0 Dementia of unknown etiology 0 5 Total 54 54 Results. The subjects included 26 women and 28 men who ranged in age from 30 to 91 years (mean, 72.2; SD, 10.7). Autopsy findings. Table 1 shows that 39 (72.2%) of the 54 cases fulfilled histologic criteria for AD, with or without other histopathologic findings. The remaining 15 cases (27.7%) showed changes corresponding to other neurodegenerative disorders, cerebrovascular disease, or Creutzfeldt-Jakob disease (CJD). Seven cases met the histopathologic criteria for multi-infarct de-mentia (MID). Five cases (9.2%) showed changes associated with Parkinson's disease (PD). Twenty-two of the 39 AD patients (56%) were age 65 or greater at the time of the onset of the disease. Seven of the 15 patients in the group with other diseases (47%) were age 65 or older at the time of disease onset. Clinical diagnosis. There was a general adherence to the criteria specified by McKhann et al.2 However, the two clinicians in this study considered the diagnosis of probable AD when the probability of AD was strong even if a patient had another disease potentially associated with dementia that might or might not have made some contribution to the patient's clinical state (table 2). Accuracy of the clinical diagnosis (table 3). Group 1 (N = 12). There were six men and six women. Ten cases (83.3%) met the histologic criteria for AD. In nine cases (75.0%), the diagnosis of both clinicians agreed with the pathologic findings; in the other case (8.3%), one clinical diagnosis agreed with the histologic findings. The remaining two cases (16.6%) had histopathologic diagnoses of CJD and progressive supranuclear palsy (PSP), respectively. Both cases were incorrectly diagnosed by both clinicians. Group 2 (N = 28). There were 11 women and 17 men. Eighteen cases (64.2%) had the histopathologic features for AD with or without additional findings. Sixteen of these cases (57.1%) were correctly diagnosed by both clinicians, one case by one of them, and both incorrectly diagnosed one case. The remaining ten cases (35.7%) included two with CJD; two with subcortical gliosis (SG); two with PD, one of which was associated with MID; one case of Huntington's disease (HD); two cases with MID; and one unclassifed. Only one, the HD case (3.5%), was correctly diagnosed by both observers, and four cases (14.2%), two MID and two PD, one associated with MID, were correctly diagnosed by one clinician. Group 3 (N = 14). In this group there were nine women and five men. Eleven cases (78.5%) met the histopathologic criteria for AD with or without additional findings. Eight of these cases (57.1%) were correctly diagnosed by both clinicians, two cases by one of them, while both were incorrect in one case. Of the remaining three cases (21.4%), only one was correctly diagnosed (7.1%) by one clinician. Both missed the two other cases of MID. There was no statistically significant difference in diagnostic agreement across patient groups in which the amount of clinical information was different (X2 = 1.19; p > 0.05). Table 3. Accuracy of the clinical diagnosis by two clinicians Both One Neither Correct Correct Correct Group 1 (N = 12) 9 1 2(16.6%) Group 2 (N = 28) 17 5 6(21.4%) Group 3 (N = 14) 8 3 3(21.4%) Table 4. Previously reported studies of clinicopathologic correlation in demented patients* Agreement % Number of cases AD Retrospective studies Todorov et al, 1975(7) 776 43 Perl et al, 1984(9) 26 81 Wade et al, 1987(12) 65 85 Alafuzoff et al, 1987(13) 55 63 Kokmen at al, 1987(14) 32 72 Joachim et al, 1987(15) 150 87 Prospective studies Sulkava et al, 1983(8) 27 82 Molsa et al, 1985(10) 58 71 Neary et al, 1986(11) 24 75 Martin et al, 1987(16) 11 100 Morris et al, 1987(17) 25 100 * Certain differences in methodology need clarification. Some authors7,8,10,11,12,13,16,17 tabulated patients with AD alone, and others9,14,15 included patients with AD plus other diseases, eg, Parkinson's disease and MID. We have combined AD alone and AD plus MID and other neurodegenerative diseases. Discussion. Our results indicate that in a population of patients with dementias of varied etiology, the diagnosis could be correctly inferred by at least one of two clinicians in approximately 80% of cases. For one observer, the sensitivity of clinical diagnosis for AD was 85% and the specificity was 13%, and for the other, it was 95% and 33% respectively. In the cases with a discrepancy between the clinical diagnosis and the neuropathologic findings, the great majority of patients had atypical clinical courses and findings. The three cases with autopsy findings of CJD had a much longer course than is usually seen with that condition and failed to show the usual EEG abnormalities. The patient with autopsy findings of PSP did not show the disorder in the extraocular movements usually associated with that condition. An atypical course was also present for two AD cases and two MID cases that did not have any feature suggestive of vascular disease. In one MID case, the CT did not show any focal lesions, while in the other it was not available. With regard to the two patients with SG, the pathologic diagnosis is so unusual and so infrequently recorded that clear clinical correlates are not evident.18 The third category of possible error is the patient listed as unclassified, for whom no specific neuropathologic diagnosis could be reached.22 The small number of neuropathologic diagnoses of Parkinson's disease reflects that, for the purpose of this series, the diagnosis of PD was made only when there were both a clear-cut clinical history and the neuropathologic findings characteristic of the disease, such as Lewy bodies, neuronal loss, globose neurofibrillary tangles, astrocytosis, and extraneuronal melanin pigment in substantia nigra and locus ceruleus. Are these results derived from a sample of 54 patients representative of disease patterns in the community? Generally, the diagnosis of patients reported from major medical centers tend to be biased since the more complicated cases are referred there. In this study, however, this bias may be less important. Due to the major public education campaign about dementia and AD sponsored by the ADRC, there is a widespread awareness in Pittsburgh and in the surrounding regions of Western Pennsylvania of the value of an autopsy for a definitive diagnosis. Therefore, the great majority of cases were referred to us because the family wanted to know the precise etiology of a case of dementia. The significant improvement in the clinical diagnosis of AD is a recent phenomenon. Due to the publicity and the advances in communication of scientific investigations, most physicians are more likely to consider AD as the main cause of dementia. The current risk of overdiagnosing AD reminds one of what occurred during the 1960s with the diagnosis of "atherosclerotic dementia."6 The high sensitivity and low specificity for AD shown in our study may reflect that possibility. Because of the varying criteria for "other dementias" in many publications, we chose to analyze the accuracy of clinical diagnosis in terms of the diagnosis of AD alone or AD plus other neuropathologic findings. Several retrospective studies have attempted to point out reliable clinical and pathologic features for diagnosing the dementias, especially AD. The study of Tomlinson et al6 is not included in table 4 because there was no attempt to validate the clinical diagnosis with pathologic findings. The reports surveyed vary considerably in size and methodology. Sample size, for example, ranges from 26 subjects9 to 776 subjects.7 Some studies base the diagnosis on limited clinical information,7'9'14'15 others use widely accepted diagnostic criteria such as those specified in DSM III,13 and one group uses a standardized clinical assessment of patients enrolled in a longitudinal study.12 The reported accuracy of the clinical diagnosis of AD ranges from 43%7 to 87%.15 Recent prospective studies that adhere to strict clinical criteria,10'11'17 those in DSM III8 or those proposed by McKhann et al,16 indicate improved accuracy of clinical diagnosis of the most common causes of dementia, especially AD. In sample sizes ranging from 11 subjects16 to 58 subjects,l0 the accuracy of clinical diagnosis is reported as ranging from 71%10 to 100%16'17' Only two series, both based on small samples, report a 100% accuracy. We consider it unlikely that such accuracy could be confirmed in large series because of some inevitable imprecision in clinical diagnoses and the variability of clinical pictures. Furthermore, although researchers generally agree on the application of uniform criteria in clinical diagnosis of dementia, opinions still differ about specific diagnostic criteria, as well as about the pathologic characterization of dementia. Except for those small series, the results summarized in table 4(7-15) is are remarkably consistent with ours. In table 3, although there was no statistical difference (p > 0.05) in diagnostic agreement across patient groups, there is a trend toward a lower percentage of diagnostic errors for the patients who had been followed most intensely (16% in group 1 compared with 21% in groups 2 and 3). The difference is not great, and it is, in fact, surprising to find out that in the patients about whom relatively little was known (group 3) the percentage of diagnostic error was the same as among patients seen by neurologists and for whom much more data were available (group 2). These paradoxical findings probably indicate that both clinicians learned to extract essential diagnostic criteria2 in spite of the variations in the amount of information available for consideration. It may well be that clinical, radiographic, and laboratory assessment of patients with dementia is burdened with information that is excessive and unessential for purely diagnostic purposes. Acknowledgments We thank Dr. A. Julio Martinez and Dr. Gutti Rao from the Division of Neuropathology for autopsy data. Mrs. Margaret Forbes, Ms. Annette Grechen, and Mrs. Paula Gent helped in the preparation of the manuscript. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Organic Dementia Disorders, 3rd ed. Washington DC, APA, 1983:101-161. 2. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Dis-ease. Neurology 1984;34:939-944. 3. Khachaturian Z. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105. 4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston: Butterworths, 1983. 5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7:486-488. 6. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11.205-242. 7. Todorov A, Go R, Constantinidis J, Elston R. Specificity of the clinical diagnosis of dementia. J Neurol Sci 1975;26:81-98. 8. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13. 9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua-tion of banked brain specimens submitted with clinical diagnosis of Alzheimer's disease. In: Wirtman R, Corkin S, Growdon J, eds. Alzheimer's disease: advances in basic research and therapies. Proceedings of the Fourth Meeting of International Study Group on the Treatment of Memory Disorders Associated with Aging. Zurich, January 1984. Cambridge, MA: CBSM, 1984:463. Molsa PK, Paljarvi L, Rinne JO, Rinne UK, Sako E. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 1985;48:1085-1090. 11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn-dromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986;49:163-174. 12. Wade J, Mirsen T, Hachinski V, Fismm~ M, Lau C, Merskey H. The clinical diagnosis of Alzheimer disease. Arch Neurol 1987;44:24-29. 13. Alafuzoff I, Igbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinicalpathological correlation and classification by multivariate data analysis. Acta Neuropathol (Berl) 1987,74:209-225. 14. Kokmen E, Offord K, Okazaki H. A clinical and autopsy study of dementia in Olmsted County, Minnesota, 1980-1981. Neurology 1987;37:426-430. 15. Joachim CL, Morris JH, Selkoe D. Clinically diagnosed Alzheimer's disease: autopsy neuropathological results in 150 cases. Ann Neurol 1988;24:50-56. 16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology 1987;37:1201-1204. 17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann Neurol 1987;22:122. 18. Moossy J, Martinaz J, Hanin I, Rao G, Yonas H, Boiler F. Thalamic and subcortical gliosis with dementia. Arch Neurol 1987;44:510-513. 19. Huff J, Becker J, Belle S, Nebes R, Holland A, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology 1987;37:1119-1124. 20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The neurological examination in patients with probable Alzheimer's disease. Arch Neurol 1987;44:929-932. 21. Moossy J, Zubenko G, Martinez AJ, Rao G. Bilateral symmetry of morphologic lesions in Alzheimer's disease. Arch Neurol 1988;45:251-254. 22. Heilig CW, Knopman DS, Mastri AR, Frey W II. Dementia without Alzheimer pathology. Neurology 1985;35:762-765. From the Departments of Neurology (Drs. Boller, Lopez, and Moossy), Psychiatry (Dr. Boller), Pittsburgh (University Drive) Veterans Administration Medical Center (Dr. Boller), Department of Pathology (Division of Neuropathology) (Dr. Moossy), and the Pittsburgh Alzheimer Disease Research Center (Drs. Boller, Lopez, and Moossy), University of Pittsburgh Medical School, Pittsburgh, PA. Supported in part by NIH Grants nos. AG05133 and AG03705, NIMH Grant no. MH30915, by funds from the Veterans Admin., and by the Pathology Education and Research Foundation (PERF) of the Department of Pathology, University of Pittsburgh. Presented in part at the fortieth annual meeting of the American Academy of Neurology, Cincinnati. OH, April 1988. Received April 7, 1988. Accepted for publication in final form July 20, 1988. Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261. January 1989 NEUROLOGY 39 79 TSS http://www.vegsource.com/talk/lyman/messages/9249.html From: TSS (216-119-130-151.ipset10.wt.net) Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: May 8, 2001 at 6:27 pm PST Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de ######### Bovine Spongiform Encephalopathy ######### Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd · To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic. (Arch Neurol. 1992;49:28-31) "Dementia" is a syndrome characterized by global deterioration of cognitive abilities and is the general term used to describe the symptom complex of intellectual deterioration in the adult. It is associated with multiple causes, although Alzheimer's disease (AD) alone accounts for approximately 60% of cases.1-3 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. Cerebral Biopsies in Dementia-- Hulette et al 31 Accepted for publication July 11, 1991. From the Department of Pathology, Division of Neuropathology (Drs Hulette and Crain), the Department of Medicine, Division of Neurology (Dr Earl), and the Department of Neurobiology (Dr. Crain), Duke University Medical Center, Durham, NC. Arch Neurol--Vol 49, January 1992 TSS/5/7/01 http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html http://www.vegsource.com/talk/lyman/messages/9254.html ============================== OTHER URLS OF INTEREST 1996). Stanley Prusinger, the scientist who coined the term prion, speculates Alzheimer's may in fact turn out to be a prion disease (Prusiner, 1984). In ... http://www.cyber-dyne.com/~tom/Alzheimer_cjd.html#similar http://216.239.39.100/search?q=cache:ujKcH823WucC:www.bse.org.uk/files/ws/s194.pdf+ PRION++ALZHEIMER%27S+BSE+INQUIRY&hl=en&start=4 http://www.bseinquiry.gov.uk/files/ws/s194.pdf http://www.cjd.ed.ac.uk/path.htm MULTIMODAL EVOKED POTENTIALS IN MOUSE MODELS OF NEURODEGENERATION Transmissible spongiform encephalopathies and Alzheimer's disease are neurodegenerative disorders in which neuropathologic changes are associated with accumulation of prion protein and deposition of amyloid ß-protein, respectively. Recently, transgenic mice that overexpress a mutant human ß-amyloid precursor protein and mice devoid of prion protein were generated. However, few electrophysiologic studies in intact freely moving... snip... full text; http://www.scripps.edu/research/sr2000/np11.html Causes of Alzheimer's and "Mad-Cow" Diseases Alzheimer's and "mad-cow" diseases are unique in that their infectious agents are not viruses or germs, but rather proteins. The brains of patients who suffered from Alzheimer's or cows that died of "mad-cow" disease show deposits of abnormal tissue called amyloid plaques. The primary component of these plaques is a protein called prion protein or PrP. Chemical and biochemical analysis showed that there was no difference in composition or primary structure between the normal, cellular form of PrP (PrPC, shown at right) and the disease form of PrP (PrPSc). Further analysis showed that PrPC can change into PrPSc when two of the a helices (shown in green) change into ß sheets. This ß sheet can then induce a similar change in another molecule of PrPC and hydrogen bond to it. The PrPSc 's then polymerize and come out of solution, forming the plaques found in Alzheimer's patients and mad cows. How the plaques cause the symptoms of the diseases is still not clear, but the prion protein holds the unique distinction of causing a disease solely through a small alteration in secondary structure. full text; http://genchem.chem.wisc.edu/netorial/modules/biomolecules/protein2/prot210.htm importantly, recent findings indicating that the cellular accumulation of incorrectly folded proteins is the molecular basis of many diseases, including Alzheimer's Disease, Prion Diseases and Huntington Disease, underscore the importance of understanding the mechanisms of folding in vivo. Alzheimer's and prion disease appear to be caused by the generation of a "pathological" conformation in the newly translated protein that would otherwise fold to a normal conformation that does not produce the disease. In some model systems, molecular chaperones appear to play a role in this conformational change. Thus, developing approaches to study protein folding under physiological conditions is essential to understand how folding defects can lead to disease. full text; http://www.stanford.edu/group/frydman/interests.htm Implications for Alzheimer's disease Harris also has recently expanded his research to include Alzheimer's disease, which shares several features with prion diseases despite being non-infectious. Leonard Berg, M.D., professor of neurology and former director of the Alzheimer's Disease Research Center at the medical school, and other colleagues say Harris readily applies his extensive knowledge of cell biology to this area as well. http://record.wustl.edu/archive/1998/02-12-98/3678.html RESEARCH LETTERS Early-Onset Familial Alzheimer Disease With Coexisting [beta] -Amyloid and Prion Pathology To the Editor: Familial Alzheimer disease (AD) with early onset has been linked to 3 different genes with an autosomal dominant mode of inheritance: [beta] -amyloid, protein precursor, and the presenilins 1 and 2, representing not more than 50% of all cases of early-onset AD cases.1 Thus, the genetic defect remains unexplained in at least half of the families with histories of early onset of AD. We have recently described such a Swiss family whose members presented with a standard clinical and neuropathologic profile of AD.2 In particular, severe neurofibrillary tangle degeneration was present in the hippocampus and in several cortical areas, together with a large amount of [beta] -amyloid deposits and senile plaques (SPs). However, known mutations have not been found, either in the [beta] -amyloid precursor protein or in the presenilin 1 and 2 genes.2 We now report that the brains of 5 deceased members of this family, from 2 generations, present a coexisting [beta] -amyloid and prion protein (PrP) pathology. Methods <http://jama.ama-assn.org/images/dot_lgray_999999.gif> Five available cases with clinical AD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. The age at onset of disease ranged from 43 to 64 years (mean, 55.8 years) and age at death ranged from 55 to 81 years (mean, 67.4 years). In addition, 4 of the 5 cases had epileptic features. Serial frozen sections (50 µm thick) through the temporal and frontal cortex of the 5 formalin-treated brains were pretreated with formic acid. They were then processed using monoclonal antibodies against amyloid- [beta] 40 peptide (1:100; [Sigma] ) and against PrP106-126 (1:200; produced by one of us).3 The latter antibody specifically marks the pathological isoform of the PrP and does not cross-react with [beta] -amyloid deposits. In addition, double immunostaining using successive anti- [beta] -amyloid and anti-PrP106-126 antibodies was performed. Results <http://jama.ama-assn.org/images/dot_lgray_999999.gif> In all 5 cases, the cerebral cortex revealed spongiform changes, mainly in superficial layers, and some degree of gliosis. Neurofibrillary tangle and neuritic plaques revealed by Gallyas were numerous in all cortical regions including the primary visual area. In addition, frequent [beta] -amyloid-positive SPs were observed, together with SP stained by the monoclonal antibody against PrP106-126. Successive sections alternately stained with the 2 antibodies showed that both [beta] -amyloid and PrP106-126 positive SP are deposited in all layers of the frontal and temporal cortex. A population of SP, marked on 2 serial sections with both antibodies, was positive for both [beta] -amyloid and PrP106-126. Double-stained sections with [beta] -amyloid and PrP106-126 antibodies further demonstrate that 3 populations of plaques exist: only [beta] -amyloid, only PrP106-126 positive, or positive for both antibodies (Figure 1) and a majority of SPs (>50%) are immunopositive for both [beta] -amyloid and PrP106-126 antibodies. Comparatively, the relative proportion of SPs marked for each antibody alone is smaller. In particular, SPs marked for PrP106-126 represent approximately 5% to 10% of the whole population. Comment <http://jama.ama-assn.org/images/dot_lgray_999999.gif> Coexistence of Creutzfeldt-Jakob disease (CJD) and AD in some patients has been described but appears mainly related to age in patients proven to have CJD.4 However, since the individuals in the Swiss family died over a long interval and were all similarly affected, it is unlikely that CJD is purely coincidental. On the other hand, familial Gerstmann-Straüssler-Scheinker disease can present a variant with concomitant neurofibrillary tangle and prion-positive plaques, but not [beta] -amyloid-positive plaques. Within this variant, 2 mutations in the gene for the PrP have been identified in 2 different families, and the clinical profile with cerebellar ataxia and extrapyramidal signs5 differs from our findings.2 Base pair deletion in the prion gene segregating as an uncommon polymorphism has been described in a family with a history of late-onset AD, but there is no neuropathological confirmation and the genetic association is uncertain.6 Thus, the data presented herein support the existence of a possible new subtype of familial early-onset AD with a concomitant [beta] -amyloid and prion brain pathology, together with a massive neurofibrillary tangle degeneration. Although all known mutations have been excluded in the coding regions of the AD genes, numerous candidate chromosome sites, either in the AD genes outside the coding regions or in other genes including PrP, must be considered. G. Leuba, PhD, PD K. Saini, PhD University Psychogeriatrics Hospital Lausanne-Prilly, Switzerland A. Savioz, PhD Y. Charnay, PhD University of Geneva School of Medicine Geneva, Switzerland 1. Cruts M, Van Broekhoven C. Molecular genetics of Alzheimer's diease. Ann Med. 1998;6:560-565. 2. Savioz A, Leuba G, Forsell C, et al. No detected mutations in the genes for the amyloid precursor protein and presenilins 1 and 2 in a Swiss early-onset Alzheimer's disease family with a dominant mode of inheritance. Dement Geriatr Cogn Disord. 1999;10:431-436. MEDLINE 3. Boris N, Mestre-Frances N, Charnay Y, Tagliavini F. Spontaneous spongiform encephalopathy in a young adult rhesus monkey. Lancet. 1996;348:55. MEDLINE 4. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol (Berl). 1998;96:116-122. MEDLINE 5. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Straüssler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. 1994;8:41-48. MEDLINE 6. Perry RT, Go RCP, Harrell LE, Acton RT. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer's disease family. Am J Med Genet. 1995;60:12-18. MEDLINE Funding/Support: This study was supported by grants 3100-045960.95 and 3100-043573.95 from the Swiss National Science Foundation. http://jama.ama-assn.org/issues/v283n13/ffull/jlt0405-5.html Slide show ... Many neurodegenerative disorders -- such as prion diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease, frontotemporal dementia -- are ... www.nature.com/nrm/journal/v1/n3/slideshow/nrm1200_217a_F1.html Occasional PrP plaques are seen in cases of Alzheimer's Disease snip... full text; http://www.bseinquiry.gov.uk/files/ws/s310.pdf 2 3 Once isolated, the agent must be capable of reproducing the disease in experimental animals. 4 The agent must be recovered from the experimental disease produced. 3. In the case of transmissible spongiform encephalopathies (TSEs), these postulates are not fulfilled in the following ways: 4. Unfulfillments of Postulate 1. 4.1 Transgenic mice with a codon 102 mutation involving a leucine substitution spontaneously develop spongiform encephalopathy with no detectable mutant prion protein (PrPsc). (Ref. Hsiao K.K. et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science (1990) 250: 1587-1590.) (J/S/250/1587) 4.2 Spongiform encephalopathy in zitter rats does not involved PrP. (ref. Gomi H. et al. Prion protein (PrP) is not involved in the pathogenesis of spongiform encephalopathy in zitter rats. Neurosci. Lett (1994) 166: 171-174.) (J/NSC/166/171) 4.3 Many viruses and retroviruses can produced spongiform encephalopathies without PrPsc involvement. (Ref. Wiley C.A. Gardner M. The pathogenesis of murine retroviral infection of the central nervous system. Brain Path (1993) 3: 123-128.) (J/BRP/3/123) 4.4 Experiments involving the transmission of the 'BSE agent' in mice produced symptoms of TSE, but in 55% no PrPsc could be detected. (Ref. Lasmesaz. C. et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science (1997) 275: 402- 405.) (J/S/275/402) 5. Unfulfillment of Postulate 2 5.1 Occasional PrP plaques are seen in cases of Alzheimer's Disease, where they coexist with the more usual beta amyloid plaques. (Ref. Baker H. F. Ridley R.M. Duchen L.W. Crow T.J. Bruton C.J. Induction of beta full text; http://www.bse.org.uk/files/ws/s310.pdf Wednesday, 23 August, 2000, 23:54 GMT 00:54 UK Alzheimer's and CJD 'similar' [Brain] Rogue proteins are thought to cause degenerative brain disorders Scientists have discovered striking similarities between Alzheimer's disease and the human form of mad cow disease, vCJD. They believe the breakthrough could lead to drugs to treat both conditions. Both are marked by a gradual and ultimately fatal deterioration of the brain and both are associated with rogue proteins. Now Professor Chi Ming Yang, of Nankai University in Tianjin, China, has discovered that these proteins have very similar structures. This could mean that the molecular mechanism underlying Alzheimer's disease and vCJD is the same. Professor Yang used a computer model to map the prion protein associated with vCJD and the amyloid precursor protein associated with early stage Alzheimer's. He found that the two proteins had a similar pattern of component parts known as amino acids. Each are made up of a reductive amino acid followed by three non-reductive amino acids. Reductive amino acids are more prone to damage by free radicals - charged oxygen particles that can disrupt the DNA of the body's cells. Normally, the body can clear itself of free radicals. But with age, this system may fail. When enough free radicals accumulate to damage a protein molecule it can malfunction. Scientists believe this mechanism may lead to Alzheimer's, the most common cause of dementia, affecting an estimated 12 million people worldwide. The disease is characterised by include messy "tangles" of nerve fibres and "plaques" rich in the amyloid proteins. CJD is the human version of bovine spongiform encephalitis (BSE or mad cow disease). It occurs naturally in about one in a million people but a new version, vCJD, has been linked with eating BSE-infected meat. BSE and vCJD are believed to be caused by prion proteins that do not fold normally. http://news.bbc.co.uk/hi/english/health/newsid_892000/892819.stm Stanley Prusiner, M.D. Stanley Prusiner, M.D., a neurobiologist at the University of California at San Francisco, was awarded the 1997 Nobel Prize in Medicine for his groundbreaking discovery and definition of a new class of disease-causing agents called prions (pronounced pree-ons). The Nobel Prize, is the most prestigious award given for research in medicine. Dr. Prusiner's award is the culmination of 25 years of sometimes controversial research on the prion, a natural human protein that, under certain conditions, can interact with other prion proteins, ultimately forming harmful deposits in the brain. The American Health Assistance Foundation (AHAF) has awarded more than $1.2 million in research grants through its Alzheimer's Disease Research program to Dr. Prusiner to develop his prion theory as a model for Alzheimer's disease. According to AHAF President Eugene Michaels, "Dr. Prusiner has proven that the most promising discoveries are often the result of innovative scientific inquiry. We are honored to have played a part in Dr. Prusiner's groundbreaking research." Prions have been implicated in dementia-causing diseases such as mad cow disease and scrapie in animals, and Creutzfeldt-Jakob Disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS) in humans. Unlike infectious agents such as bacteria, viruses and parasites, whose ability to grow and reproduce is governed by genetic material made up of RNA and DNA, prions appear to be made up entirely of proteins with no accompanying DNA or RNA. Prions are present in normal cells, and the gene that codes for the production of the prion protein is part of a normal human chromosome. Since 1985, the American Health Assistance Foundation has supported studies of the structures and properties of prions, and investigations that led to the purification and identification of the prion protein in the brains of scrapie-infected sheep. AHAF also awarded a grant to Dr. Prusiner to study CJD and GSS, using molecular biology methods to introduce genes from mutated prion proteins into mice to create an animal model for these diseases. His current AHAF grant is focused on the development of a new system to determine when in the life of a mouse the prion protein leads to disease. He is also studying a method to prevent prion disease by blocking prions from converting normal proteins into more prions. There are similarities between the loss of brain function in prion diseases and in Alzheimer's disease, and an understanding of how prion diseases begin and develop will add to our understanding of what happens to the brain in Alzheimer's disease. Dr. Prusiner's research may one day lead to a treatment and a cure for Alzheimer's. http://www.ahaf.org/alzdis/about/prusiner.htm Date: Posted 8/24/2000 "Strikingly Similar" Protein May Be In Alzheimer's And Mad Cow Disease Washington D.C., August 23 -- A "striking similarity" between proteins involved in the early stages of Alzheimer's disease and mad cow disease was described here today at the 220th national meeting of the American Chemical Society, the world's largest scientific society. The theory, if verified by other researchers, could help focus efforts to develop preventive drugs, according to the study's lead researcher, Chi Ming Yang, Ph.D., a professor of chemistry at Nankai University in Tianjin, China. Prion diseases -- which include, among others, neurodegenerative diseases such as mad cow disease and its human counterpart, Creutzfeldt-Jakob disease -- are caused by a malfunctioning prion protein. In Alzheimer's disease, another neurodegenerative disease, the amyloid precursor protein has been implicated. Using computer modeling, Yang discovered a similar pattern of amino acids in the prion protein and the amyloid precursor protein: a reductive amino acid followed by three non-reductive amino acids. "This suggests a common molecular mechanism underlying the initiation stages of sporadic Alzheimer's disease and both sporadic and genetic prion diseases," says Yang. Reductive amino acids are more prone to damage by oxygen-containing free radicals (molecules with a highly reactive unpaired electron) than other amino acids, explained Yang. Normally, the body can clear itself of free radicals. But with age, this system may fail. When enough free radicals accumulate to damage a protein molecule, it can malfunction, he says. Proteins typically fold into specific three-dimensional structures that determine their functions. A malfunctioning protein may remain partially unfolded, which can place different amino acids in close proximity, Yang explained. In the case of Alzheimer's and prion diseases, the reductive amino acids in close proximity can lead to the formation of protein plaques, according to Yang. Although Alzheimer's and prion diseases seem to start in similar ways, they progress differently. This may explain why Alzheimer's disease advances at a much slower pace than Creutzfeldt-Jakob disease, says Yang. The paper on this research, PHYS 460, will be presented at 7 p.m., Wednesday, Aug. 23, in the Washington Convention Center, Exhibit Hall D. Chi Ming Yang, Ph.D., is a chemistry professor at Nankai University, Tianjin, China. A nonprofit organization with a membership of 161,000 chemists and chemical engineers, the American Chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio. http://www.sciencedaily.com/releases/2000/08/000824081151.htm http://www.sciencedaily.com/releases/2000/08/000824081151.htm ======================================================= Some references that may be interesting on the topic... References. Aguzzi, A. and Weismann, C. Prion Research: the Next Frontiers. Nature, Vol.389 pp.796-79 ,1997. Alper , T.; Cramp, W.; Haig , D. and Clarke, M. Does the agent of scrapie replicate without nucleic acid?, Nature, Vol.214, pp.764-766.1967 Aldudo, J.; Bullido, M.J; De Miguel, C.; Valdivieso, F.; and Vazquez, J. Presenilin-1 genotype[2/2] is associated with late onset Alzheimer's disease in Spanish patients. Alzheimer's Res. Vol.3, pp.141-143.1997 Avila , J. and Colaco, A.L. The role of sulphated glycosaminoglycans in Alzheimer's disease.: a hypothesis. Alzheimer's Res., Vol.3,pp.77-81.1997 Avila, J. Modification of proteins related with the onset of Alzheimer's disease: Tau phosphorilation, glycosylation and oxydation in Alzheimer's disease. Current Drugs , Vol.2,pp.141-143.1997 Baldwin , M.; James , T.; Cohen, F.; and Pruisiner , S. The three-dimensional structure of prion protein : implications for Prion disease. Biochemical Society Transactions , Vol.26, pp.481-486.1998 Baldwin, M.; Pan ,K.; Nguyen , J.; Huang, Z. Groth, D.; Serban, A. et al. Spectroscopic Characterization of conformational differences between PrPc and PrPsc-An Alpha-helix to Beta-sheet transition. Philosophical Transactions of the Royal Society of London, series B-Biological Sciences,Vol.343, number 1306, pp-435-441.1992 Ball, M. Features of Creutzfeldt-Jakobs disease in brains of patients with familial dementia of Alzheimer's type. Canadian Journal of Neurological Sc.Vol.7 , pp.51-57.1980 Banissi-Sabourdi, C.; Planques, B.; David, J.P.; Jeannin, C.; Potel , M; Bizien, M.; Di Menza, C.; Brugère -Picoux, J.; Brugère, H.; Chatelain , J. Electroanalytical characterization of Alzheimer's disease and ovine spongiform encephalopathy by repeated cyclic voltametry at a capillary graphite paste electrode .Bioelectrochemistry and Bioenergetics. Vol. 28, pp.127-147.1992 Bernouli, C.; Siegfried, J.; Baumgartner,g. et al. Danger of accidental person to person transmission of Creutzfeldt-Jakobs disease by surgery . The Lancet.Vol.1,pp.478-479.1997 Borner, C.; Oliver, r.; Martinou, I.; Mattman ,C.; Tschopp, J.; and Martinou ,J.C. Dissection of functional domains in bcl-2 alpha by site directed mutagenesis . Biochemical Cellular Biology.Vol.72, pp463-469.1994 Brandner, s.; Isenmann, S; Raeber, A.; Fischer ,M.; Sailer, A.; Koyba et al. normal host prion protein necessary for scrapie-induced neurotoxicity.Nature.Vol.379, pp.339-343.1996 Braham, J . Ceutzfeldt-Jakob Disease: treatment by Amantidine. Brit. Med . J. Vol. 4, pp.213-213.1971 Brown, P.; Cathala, F.; and Gjdusek, D.C. Creutzfeldt-Jakob disease in France III. Epidemiological study of 170 patients dying during the decade 1968-1977. Ann. Of Neur.vol.6, pp.438-446.1979 Brugère, H.; Banissi, C.; Brugère-Picoux, J.; Chatelain, J. et Buvet, R. Recherche d'un temoin biochimique urinaire de l'infection du mouton par la tremblante. Bull. Acad. Vet. de France.Vol.64, pp.139-145.1991 Brugère, H.; Banissi, C.; Brugère-Picoux ,J .;Chatelain, J.; Tournaire, M.C et Buvet, R. Electrochemical analysis of urine in Alzheimer's patients and ruminants with spongiform encephalopaties ( scrapie and BSE) .III Int. Symp. on Transmissible subacute spogiform encephalopaties: Prion diseases, Paris, Val de Grace, 18-20 March.1996 Bruce, M.; Will, r.; Ironside, J.; McConnell, I.; Dummond , D,; and Suttie, A. Transmission to mice indicates that "new variant" CJD is caused by BSE agent. Nature. Vol.389, pp.498-501.1997 Byeler, H.; Aguzzi, A.; Sailer, A.; Greiner, r.; Autenreid, P.; Aguet, M.. and Weissman, C. Mice devoid of PrP are resistant to scrapie. Cell.vol.73, pp.1339-1347.1993 Carpenter, C.; Fishl, M.; Hammer, S.M; et al . Anti-retroviral therapy for HIV infection in 1996: Recommendations of an international panel. JAMA. Vol. 276,pp.146-154.1996 Cathala, F.; Brown, P.; Rahison, S et al. Maladie de Creutzfeldt-Jakob en France. Revue Neurologique (Paris).Vol.7,pp56-62.1982 Caughey, W.; Raymond, L .; Horiuchi, M.; and Caughey, B. Inhibition of protease-resistant prion protein formation by porphyrins and phtalocyanines.PNAS.Vol.95.Iss.21,pp.12117-12122.Oct.17th,1998. Cohen, F.; Pan, K.; Huang, Z; Baldwin, M.; Fletterick, R. and Pruisiner, S. Structural clues to prion replication.Science.Vol.264, pp.530-531. 1994 Collinge, J.; and Hawke, S. B lymphocytes in prion neuroinvasion: central or peripheral players?. Nature Medicine .Vol.4,pp.1369-1370.1998. Collinge, J. and Palmer, M. Prion Diseases. Oxford University Press.1997 Collinge, J.; Whittington ,M.; Siddle, K. et al. Prion protein is necessary of synaptic formation. Nature. Vol.370, pp.277-295.1994 Cook, B.H.; Ward, B.; and Austin, J. Studies in ageing in the brain IV. Familial Alzheimer's disease : elation to transmissible dementia, aneuploidy and microtubular defects. Neur.Vol.29, pp.1402-1412.1979 De Armond, S.; Sanchez, h.; Yehiely, Q et al. Selective Neuronal targeting in prion disease.Neuron.Vol.19, pp.1337-1348.1997 De Wolfe, F.; Lukashnov, V. Danner, S et al .Clearance of HIV-1 following treatment with two, three, four or five anti-HIV drugs. Program and abstracts of the 5th conference on retroviruses and opportunistic infections.Feb.1-5th. Chicago, Ill.1998.Abs.384 Garrett, L. The Coming Plague. Penguin USA. 1995 Gibbs, T.; Baldwin, M.; Lloyd, D. et al. Predicted alpha-helical regions of the prion protein when synthesized as peptides from amyloid. PNAS.Vol.89,pp.10940-10944.1992 Goudsmith, J.; Morrow, C.; Asher, D. et al. Evidence for and against the transmissibility of Alzheimer's disease.Neurology.Vol.30pp.945-950.1980 Herishanu, Y. Antiviral drugs in Creutzfeldt-Jakob disease. J. of Am. Soc. of Geriatrics.Vol.21,pp.229-273.1973 Ikeda, K.; Kawada, N.; Wang ,Y. et al .Expression of cellular prion protein in activated hepatic stellate cells. Am. J. of Path.Vol.6,N.6, pp.1695-1700.1999 Jellinger, K.; and Seitelberger, F. Spongy degeneration in the central nervous system in infancy. Curr. Top. in Path.Vol.53, pp.90-160.1970 Kimberlin, R. and Walker , C. Anti-viral compound effective against experimental scrapie. The Lancet.Vol.2, pp.591-592.1979 Knusel, B. and Hefti ,Development of cholinergic pedunculopontine neurons in vitro: comparison with cholinergic septal cells and response to nerve growth factor, ciliary neurothrophic factor and retinoic acid. J. of Neurosc. Res. Vol.21,pp.365-375.1988 Manuelidis, E.; Manuelidis, L.; Pincus , J. et al. Transmission from man to hamster of Creutzfeldt-Jakob disease with clinical recovery. The Lancet. Vol.2.pp.40-42.1978 Munoz-Montano, J.; Moreno, F.; Avila, J. et al. Lithium inhibits Alzheimer's disease-like tau protein phosphoryllation in neurons .FEBS Lett.Vol.411,pp.183-188.1997 Perez, M.; Wandosell, F.; Colaco, C. and Avila, J. Sulphated glycosaminoglycans prevent neurotoxicity of human prion protein fragment . Pruisiner,S.Prions.PNAS.1998 Sadler, I.; Smith, D.; Sherman, M. et al .sulphated compounds attenuate Beta-amyloid toxicity by inhibiting its association with cells .Neuroreport.Vol.7,pp.49-53.1995 Sadler, I.; Hawtin, S.; Tailor, V. et al . Glucosaminoglycans and sulphated polyanions attenuate neurotoxic effects of beta-amyloid. Biochem. Soc. Trans. Vol.23,p.1065.1995 Sukhalayan,C.; Khalequz, Z.; Hoon, R.; Conforto, A.; and Rajiv, R. Sequence-Selective DNA binding drugs Mitramyacin A and Chromomyacin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons.Ann.Neurol.Vol.49,pp.345-354.2001 Diagnosis and Reporting of Creutzfeldt-Jakob Disease T. S. Singeltary, Sr; D. E. Kraemer; R. V. Gibbons, R. C. Holman, E. D. Belay, L. B. Schonberger http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html IN STICT CONFIDENCE TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf Subject: Re: Hello Dr. Manuelidis Date: Fri, 22 Dec 2000 17:47:09 -0500 From: laura manuelidis <laura.manuelidis@yale.edu> Reply-To: laura.manuelidis@yale.edu Organization: Yale Medical School To: "Terry S. Singeltary Sr." <flounder@wt.net> References: <39B5561A.87B84A28@wt.net> <39B64574.A4835745@yale.edu> <39B680D8.3872535B@wt.net> <39B66EF1.4CE25685@yale.edu> <39BBB812.425109F@wt.net> <39BE84CB.D7C0C16B@yale.edu> <3A3BA197.7F60D376@wt.net> Dear Terry, One of our papers (in Alzheimer's Disease Related Disord. 3:100-109, 1989) in text cites 6 of 46 (13%) of clinical AD as CJD. There may be a later paper from another lab showing the same higher than expected incidence but I can't put my hands on it right now. We also have a lot of papers from 1985 on stating that there are likely many silent (non-clinical) CJD infections, i.e. much greater than the "tip of the iceberg" of long standing end-stage cases with clinical symptoms. Hope this helps. best wishes for the new year laura manuelidis "Terry S. Singeltary Sr." wrote: > > Hello again Dr. Manuelidis, > > could you please help me locate the 2 studies that were > done on CJD where it showed that up to 13% of the people > diagnosed as having Alzheimer's actually had CJD. > trying to find reference... > > thank you, > Terry S. Singeltary Sr. 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
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