Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011
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.
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
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 dementia (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*
Number of cases AD
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
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.
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.
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 Disease. 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 evaluation 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 syndromes 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
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
######### 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 abnormalties, 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.
The clinical presentations, biopsy findings, and follow-up data, including postoperative complications, are summarized in Table 1 for all 14 patients. Their bipsy 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*
Duration of Symptoms, y
Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral synchronous discharges
Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal EEG
Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy ==========
Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic sharp waves
Dead at 61 y, autopsy showed CJD =========
Dementia, myclonus, ataxia, family history of early-onset dementia
Dead at 40 y, autopsy showed AD =========
Dementia, paranoia, agitation, rigidity
Diffuse Lewy body disease
Dead at 78 y, no autopsy =========
Dementia, dysarthria, abnormal eye movements, ataxia
Neuronal storage disorder, adultonset N-P type II
Stable at 39 y =========
Dementia, amnesia, depression, partial complex seizures
Dead at 58 y, no autopsy ==========
Dementia, dysarthria, upper-extremity atrophy and fasciculations
Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter gliosis =========
Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis
Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD =========
Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic sharp waves
Consistent with CJD
Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic resonance image showing small vessel disease
stable at 61 y =========
Dementia, aphasia, right-sided hemiparesis
Bedridden, severely demented at 54 y =========
Dementia, mild bifacial weakness, concrete thinking, altered speech
Stable at 41 y =========
Dementia, choreoathetosis, family history of senile dementia, computed tomographic scan showing normal caudate
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 =====
2 L temporal Open 1 cm3 + 0 =====
3 R temporal Open 1 cm3 + 0 =====
4 R frontal Open 1 cm3 0 100 + Amyloid angiopathy =====
5 R temporal Open 1 cm3 0 9 0 Lewy bodies =====
6 R temporal Open 1 cm3 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/anaplastic astrocytoma =====
8 R frontal Open 1 cm3 o + 0 =====
9 L parietal Open 1 cm3 0 +/- + 0 =====
10 R temporal Open 1 cm3 +/- 0 =====
11 L temporal Open 1 cm3 0 23 0 + 0 =====
12 L temporal Open 1 cm3 0 + 0 =====
13 r frontal Open 1 cm3 0 =====
14 L temporal/L frontal Open/open 1 cm3/ 1 cm3 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 Binswanger 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
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
Clinico-Pathological Correlation in Dementias
F. Teixeira, El Alonso, V. Romero, A. Ortiz, C. Martinez, E. Otero
Departments of Experimental Neuropathology and Genetics, and the Division of Psychology and Neurology, National Institute of Neurology Neurosurgery, Mexico City, Mexico
Sumitted: February 22, 1994 Accepted: February 9, 1995
The object of this study is to investigate whether or not there are clinical signs and symptoms in patients with dementia that, by themselves or jointly, can be associated with the pathological diagnosis of Alzheimer's disease. Twelve patients with dementia were studied, in whom the clinical diagnosis of Alzheimer's disease was made according to established criteria. A sample of leptomeninges, cortex and subcortical white matter was obtained from each patient and was processed for light and electron microscopy. In the cases in whom neuritic plaques and neurofibrilary tangles were present, pathological changes were quantified. The diagnosis of Alzheimer's disease was confirmed in 5 cases, wheras in 3 patients SPONGIFORM ENCEPHALOPATHY was present. In the remaining patients, the number of neuritic plaques was within normal limits for the age of the subjects. Comparison of the data in Alzheimer (n=5) and non-Alzheimer (n=7) groups showed an increased, statistically significant incidence of acalculia, abnormalities of judgement, impairment of abstraction and primitive reflexes in the former. Although good fitting models were obtained, none achieved perfect discrimination. The model that included alterations of judgement and acalculia gave the best fit...
The rates of accuracy of the clinical diagnosis of Alzheimer's disease in several clinico-patholigical studies range from 43% to 87% (Joachim et al 1988; Mosla et al 1985; Muller and Schwartz 1978; Nott and Fleminger 1975; Sulkava et al 1983; Todorov et al 1975; Wade et al 1987). It should be interesting, therefore, if selected clinical data could help to reach this diagnosis without the aid of a brain biopsy.
The results of this study show a very significant association of Alzheimer's disease with the following variables primitive reflexes, impairment of abstraction, changes in judgment and acalculie. In studying the joint effect of variables, it was seen that alterations of judgment and acal- culia produced the best fit.
The sample in this study may be considered small for the purpose of selecting a set of signs and symptoms that can characterize Alzheimer's disease clinically. However, it is not an easy task to obtain the permission to perform a brain biopsy which is of no benefit for the patient when the relative is informed of the risks involved.
The definite diagnosis of Alzheimer's disease depends on the microscopical examination of brain tissue, either by autopsy or biopsy. In the USA, the Alzheimer Disease Research Center of the University of Pittsburgh has launched a public campaign to encourage relatives of demented pa- tients to request a postmortem examination of the brain (Boiler et al 1989). However, in Mexico, a similar campaign has enjoyed little success so far for several reasons. The patient who suffers from Alzheimer's disease usually dies at home. The relatives, who are already exhausted by the de- mands of caretaking, obtain a death certificate from the family physician, and proceed quickly to the funeral rites. The few families who do request an autopsy are almost invariably denied admission to the hospital where the patient had been admitted because cadavers without a death certifi- cate must be sent to the police department for autopsy. Many Patients die in small towns or villages where there are no pathologist, let alone neuropathologists. Therefore, brain biopsy remains the only possibility for confirming the clinical diagnosis. It is true that there is no benefit derived by the Patient from this procedure and that he or she faces surgical and anesthetic risks. In contrast, brain biopsy allows: 1. the development of new diagnostic procedures that might, in the future, replace it; 2. adequate genetic counseling in cases with an autosomal dominant pattern of inheritance, so that family members can take part in studies at the molecular biology level; and 3. the performance of therapeutic trials and of epidemiological surveys in Mexico.
Familiar aggregation has been demonstrated in 40% of cases of Alzheimer's disease. In 15% of these cases, the pattern of inheritance was autosomal dominant (Heston el 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 al the medial temporal isocortex, where it has a high, statistically significant asso- ciation with the presence of large numbers of neurofibrillary tangles and argyrophllic plaques (Smith et al 1987) This study considered the possibility that cases 5 to 7, diagnosed as Jakob-Creutzfeldt disease, could be, in fact, Alzheimer cases with this peculiar vacuolar change. A good method for separating the two entities would be the use of antibodies against prion (Pr-P) proteins (Tateishi et a] 1988), which were, unfortunately, not available to the authors. However, none of these cases showed positivity for A4 protein. neither had one single argyrophilic plaque or tangle. Moreover, the biopsies were taken from the frontal regions, which are reported to be free of involvement in instances of Alzheimer's disease with vaeuolar changes (Smith et al 1987).
Although the diagnosis of probable Alzheimer's disease was made in all of the patients in this study, according to the criteria established by McKhann et al (1984), this diagnosis was confirmed in only 47.1% of them, This low rate might be the result of several factors. The National Institute of Neurology and Neurosurgery in Mexico City is an institution that concentrates especially on difficult or unusual cases that are referred from all over the country. Therefore, it received a biased sample that included as many as 3 cases of spongi- form encephalopathy. In addition, it is important to remember that a small. 1 cubic centimeter sample of cortex and white matter may not be representative of the extent of the damage in other areas of the brain, and so, correlates poorly with the clinical picture. This illustration is particularly true of cases 1 to 4. which did not fit into any of the pathological entities that manifest clinically as dementia. To understand more clearly the relation between damage and clinical impairment, further prospective studies using autopsy material are needed...
Subject: Re: Hello Dr. Manuelidis
Date: Fri, 22 Dec 2000 17:47:09 -0500
From: laura manuelidis
Organization: Yale Medical School
To: "Terry S. Singeltary Sr."
References: <email@example.com> <firstname.lastname@example.org> <email@example.com> <firstname.lastname@example.org> <email@example.com> <firstname.lastname@example.org> <email@example.com>
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...
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??????
IN STRICT CONFIDENCE
Dr McGovern From: Dr A Wight
Date: 5 January 1993
Copies: Dr Metters
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.
What are the implications for public health?
3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
also, see the increase of Alzheimer's from 1981 to 1986
BSE Standing Committee - Dr C Gibbs 12/13 March 1990
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level. Alterations in the PrP gene may increase the probability of altered PrP being formed from the normal host protein. A discussion followed in which it was stated that the increased incidence of PrP related disease is due to an increased awareness of these diseases and not due to BSE. Professor Gajdusek also discussed the nucleation of amyloid as a model for these diseases. ...
From: TSS (216-119-138-131.ipset18.wt.net)
Subject: BSE Standing Committee--Dr. C. Gibbs
Date: August 10, 2000 at 12:17 pm PST
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
sporadic cases of encephalopathies in ungulates attributable to scrapie-like agent via ruminant derived MBM
now were getting somewheres, now to just convince them of that, with man and the sporadic CJD...
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
WEYBRIDGE Central Veterinary Laboratory New Haw, Weybridge, Surrey KT15 3NB Tel: (0932) 341111 Telex: 262318 VetWey G Fax: (0932) 347046
Page 3 amended - The human spongiform eneephalogathies and BSE R Ridley & H Baker - line 8 - dementias.
J Pink (Mrs) 8.5.90
Ministry of Agriculture, Fisheries and Food
BSE Standing Committee - Dr C Gibbs 12/13 March 1990
A Record of the Meeting
Firstly, a welcome was given by Dr W A Watson. An introduction to BSE was given by Mr R Bradley and Dr K J MacOwan. Mr Bradley acknowledged the great contribution made to the field of scrapie by Dr W Hadlow. Mr Bradley also discussed the media interest in BSE, some of which is adverse. Dr MacOwan discussed the funding of BSE research.
Epidemiolosy/Offspring - Mr J W Wilesmith A stepwise increase in the incidence of BSE may have been caused by the recycling of BSE-affected cattle back into the cattle food chain. If this is so, a further increase may be anticipated. Since 100 per cent compensation has been announced there has been an increase in the reporting of BSE suspect cases. There is a much higher incidence of the disease in South-east England and avery low incidence in Scotland. Studies in progress at present are:
1. Descriptive analysis already published. 2. Simulation modelling to assess the likely incidence of the disease in future. 3. Case control study to assess if meat and bone meal is the source of the epidemic and to investigate the geographical risk. 4. Offspring study to assess whether BSE can be transmitted maternally. A summary of current thinking on the cause of the epidemic was given, ie. that BSE is a new disease caused by exposure of cattle to a scrapie-like agent in meat and bone meal commencing in 1981/82. A discussion followed on the husbandry of British cattle, the lack of any change in pathology or clinical signs during the outbreak and the possibility of stating BSE risks for certain British products for export.
Control and Exports - Dr D Matthews
A history of legislation and publications connected with BSE was given. BSE was first confirmed in November 1986 and made notifiable on June 21, 1988. Ruminant-derived protein was banned from ruminant feed from July 18, 1988. A slaughter and compensation policy started on August 8, 1988 with payment limited to 50 percent of market value up to a ceiling which was adjusted monthly and certain bovine offals were banned from being used for human consumption in November 1989. In February 1990 100 per cent compensation was awarded. During this time period scientific papers were published on the transmission of BSE to mice and cattle, and two advisory committees published their reports, namely the Southwood Report and the Tyrrell Report. Some countries have imposed a total embargo on the exports of livestock from Britain and some other countries require additional certification.
A discussion followed on the rendering process and the point was made that offals covered by the ban can go into animal feeds for non-ruminants.
Transmission and CVL molecular studies - Mr N Dawson
Four cases of natural BSE from widely separated herds in England were used for transmission studies. Recipients were either Holstein/Friesian or Jersey cattle and they were challenged intravenously and by injection into the rostral brainstem. All challenged animals have become affected with BSE and there is a very constant period between challenge and diagnosis of between 520 to 610 days. The clinical signs were identical to the natural disease, with the possible exception that Jerseys may have more forelimb ataxia. Two animals developed clinical signs rapidly after sustaining fractures. In 22 BSE-affected brains, scrapie associated fibril detection was successful in almost 100 per cent of cases in certain brain areas such as the basal nuclei, mid brain and medulla. A discussion followed of waste disposal which is incinerated, and oral transmission experiments which have been initiated looking at transmission via placenta to calves orally, but no experiments have been initiated as yet to assess whether brain can trailsmit BSE orally.
Pathology - Mr G A H Wells
In BSE neuropil vacuolation is a more prominent feature of the pathology as compared to scrapie where neuronal vacuolation is more prominent. Neuronal vacuolation and astraytic reaction also occur in BSE. A full account of the distribution of lesions was given. The spinal tract nucleus of the trigeminal nerve and the nucleus of the solitary tract are invariably involved and using these areas 99.6 per cent diagnostic accuracy is obtained for routine diagnosis of BSE. There is good correlation of vacuolarion to scrapie-asscoiated fibril score in brain stem areas, but this is poorer in cortical areas. Amyloid plaques are only a rare feature of BSE pathology, but PrP immunostaining shows definite differences from control animals. Spongiform encephalopathies also occur in exotic ruminants. A discussion ensued in which it was stated that the neuropathology is not always well correlated in severity to the clinical signs, but that the neutropathology in experimental cases was similar to that seen in field cases.
Mouse, Sheep, Goat Studies - Dr H Fraser
The mouse can be used as a typing system for strains of the agent. Strain typing may or may not indicate the origin of infection. The same three strains have been isolated from many different scrapie sources, namely ME7, 87A and 87V. In the attempt to type the BSE agent the same four BSE cases as previously discussed were used. Two surprising things came out of these results. Firstly, the rapidity with which mice went down with the disease which in some cases was considerably shorter than scrapie. Secondly, there were differences between strains of mice which had the same genotype at the S7/P7 locus which controls scrapie incubation period. This implied that there might be another gene controlling incubation period for BSE in mice. It is important that mice with the genotype S7/P7 are challenged with the BSE agent because from sheep scrapie this cross gives a longer incubation peried than in S7 and P7 homozygotes. Upon sub-passage from S7 homozygous mice unusually short incubation periods were seen. An account of the pathology of BSE in mice was given such as neuropil vacuolation, amyloid, PrP immunostaining and asymmetrical pathology. A discussion followed in
which the bioassay was explained and Dr Fraser suggested that the particularly short incubation periods were due to the selection of a rapidly replicating mutant. The species barrier and the differences between intraperitoneal and intracerebral challenge were also discussed.
The human spongiform encephalopathies and BSE - R Ridley and H Baker
From a family with the autosomal dominant Gerstmann-Straussler Syndrome (GSS), transmission to non-human primates was successful with tissue homogenates from two members but failed with material from two other members of the same family. (Dr Gibbs later indicated in discussion he had realised 100 per cent transmission success with GSS brain). Because this disease is not always transmissible or spongiform, PrP diseases has been adopted as an appellation. Alterations in the PrP gene have now been seen in a wide variety of atypical dementias. Three hypotheses to explain the familial, genetic and sporadic nature of these diseases were explained, together with problems which each theory encountered. The various alterations in the PrP gene seen in some of these diseases was explained. An account of the age of onset and length of the course of disease for the human spongiform encephalopathies was given. The opinion was expressed that most human cases of spongiform encephalopathy are not caught, but are familial neuro-degenerative diseases transmissible in certain circumstances. The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level. Alterations in the PrP gene may increase the probability of altered PrP being formed from the normal host protein. A discussion followed in which it was stated that the increased incidence of PrP related diseases is due to an increased awareness of these diseases and not due to BSE. Professor Gajdusek also discussed the nucleation of amyloid by fibril amyloid enhancing factor.
Molecular chemistry and genetics - Dr J Hope
PrP is a normal host protein and in BSE and scrapie an abnormality in this protein causes its accumulation and relative protease resistance. Messenger RNA for the PrP protein in ruminants is twice the size of that in rodents and man. Differences in PrP genes are linked to differences in the incidence and incubation of these diseases. In sheep the sip-gene affects the incubation period for scrapie and this can be detected by classical genetics and by restriction fragment length polymorphism analysis of DNA in the region of the PrP gene. Altered PrP can be detected in the spleen of a mouse terminally affected with scrapie but PrP is only relatively protease resistant. A discussion followed about proteinase K treatment of PrP. the site of action of Sip, and the possibility of asymptomatic carriers of scrapie.
Inactivation studies - Dr D Taylor
Various groups are concerned about the inactivation of the BSE and scrapie agents. This group includes farmers, vets, the food stuff manufacturers, the renderers, medicinal product manufacturers and the general public. In the 1930s scrapie was transmitted to sheep given a formalin-inactivated louping ill virus vaccine. In 1977 a paper was published demonstratLng that Creutzfeldt-Jakob disease had been transmitted via brain electrodes. Botb these occurrences were due to failure of inactivation of the agent. Hypochlorite needs a very long time and a very high concentration to
inactivate the agent. The use of sodium hydroxide needs further clarification and peracetic acid or phenolic disinfectant are not very effective methods of inactivation. Autoclaving is effective if used correctly and at a high enough temperature for a sufficient length of time, but dry heat will not totally inactivate the agent at 160°C for 24 hours. Some strains of the agent are more thermostable than others such as the 22A strain. As regards BSE it would appear that we are dealing with a single strain only. A discussion followed on inactivation. It was stated that formic acid is effective if only used for 15 minutes and this treatment does not adversely affect pathological examination, whereas a temperature of 270°C does not totally inactivate formlin fixed material. Various other techniques were discussed and it was stated that some previous transmission experiments may have been adversely affected by contaminated instruments. In discussion Dr Gibbs pointed out that work in his and Dr Gajdusek's laboratories showed that 1N NaOH (vol/vol) was an effective decontaminating agent, completely inactivating high titreing 263K scrapie strain, CJD and kuru agents. Also sodium hypochlorite Dr Gibbs mentioned was an effective chemical if utilised at full Strength.
Please see the report on Bovine Spongiform Encephalopathy - Report of a Work Study Group distributed at the Weybridge Meeting and in press in the Journal of the American Veterinary Association (June 1990 issue).
Embryo Transfer - Miss K Brown
Embryo transfer is the safest way of moving the full genetic complement of an animal without running the risk of disease. The embryo must be in a pre-implant stage, with a zona pellucida which is intact and free from cracks and debris. Embryos are washed 10 times with 100 fold dilution taking place each time. This procedure removes a number of organisms. The objective of the experiment is to determine whether BSE derived embryos can infect the recipient or her progeny. Donors are BSE affected field cases and recipients are imported New Zealand heifers. The donors will be super-ovulated, embryos collected non-surgically and implanted into recipients who will be kept for 7 years. Implanted embryos may be ++ using BSE affected bull semen or +- using New Zealand bull semen or pre 1980 semen. Transmission studies will also be undertaken. Unfertilised and fertilised embryos, flushing media and washing media will all be separately inoculated intracerebully into mice to assess transmissibility. Many precautions will have to be taken throughout the course of the experiment to ensure that the experimental animals are not exposed to BSE from other sources such as contact with people, other animals or equipment, or through food or biological products. It is possible that difficulties may be encountered with super-ovulating BSE affected animals, for example, they may stop cycling. One thousand embryos will be needed in all and 550 heifers are being imported as recipients from New Zealand. A discussion followed in which it was explained that whilst W Foote in America used surgical collection of embryos in his work with sheep scrapie, this was not necessary in cattle. It was also explained that whilst it was feasible that in the early stages of the disease, a viraemia eight infect the
uterine tract to a greater degree, it was irrelevant because it was not possible to detect animals which would go on to develop BSE.
Prof C J Gibbs and Colleagues (via Prof Gibbs) Dr C L Bolis Dr H Diringer Dr W A Watson Dr R H Kimberlin Speakers Observers Dr K J MacOwan Mr B Marchant Dr M Robinson
cc: CVO Dr T W A Little Dr B J Shreeve Prof J Bourne Dr C Bostock I. Mc Gill (written in...TSS)
PATHOLOGY OF BOVINE SPONGIFORM ENCEPHALOPATHY
Gerald A H wells Head of neuropathology Central Veterinary Laboratory Weybridge, UK
The component light microscopic histopathological features of Bovine Spongiform Eucephalopathy (BSE), in common vith other subacute spongiform encephalopathies due to unconventional viral agents, are neuroparenchymal vacuolarion, neuronal degeneration and astrocytosis. Rarely, amyloid plaques occur. Vacuolar changes comprise grey matter nueuropil vacuolation (spongiosis or spongiform change) and vacuoles in neuronal perikarya. Spongiosis is the most prominent aspect of the vacuolation. The neuropil vacuoles are seldom so numerous as to appear confluent and status spongiosis, described in Creutzfeldt-Jakoh Disease as an end stage appearance accompanied by severe gliosis, is not seen in BSE, even in cases vith a prolonged clinical course.
The distribution of vacuolar changes in BSE presents a relentless uniformity with certain neuronal groups constantly affected. From the examination of single sections of medulla from a large series of histopathologically confirmed cases it was found that in 99.6% of the cases the diagnosis can be achieved by the presence of spongiosis in the solitary tract nucleus and the spinal tract nucleus of the trigeminal nerve. Similarly in the pons, for example, the vestibular nuclei and reticular formation are invariably affected as too are the central grey matter, substantia nigra, superior colliculus and some tectal nuclei in the midbrain.
Subjective assessments of vacuolation density in HE sections, examining constantly involved nuclei throughout the brain stem, have provided a reproducible scoring system of severity. Using this method the vacuolation in 14 neuronal groups from each of the regions - medulla, pons and midbrain -increased in severity with increasing clinical duration.
Probably less than 5 per cent of BSE cases have demonstrable amyloid plaques and in these it is focally distributed or extremely localised.
Abnormal fibrils, extracted from affected cattle brains, closely resemble scrapie associated fibrils (SAF) regarded as specific ultrastructural markers of uncouventional virus or "prion" diseases. Fibril prevalence was assessed in 22 affected cows brains and compared with severity of vacuolation according to neuroanatomic location. Fibril prevalence approximated to vacuolar severity throughout the brain stem.
Anti-mouse SAF-protein antibodies raised in rabbits label plaques and particles within the neuropil of some grey matter areas in which spongiform change is also present. This staining appears disease specific. A granular immunostaintng can also be achieved in the perikarya of some neurons in affected brains but can feature also, at a much reduced frequency, in the braime of clinically normal cattle. This demonstrates the problem inherent in polyclonal PrP antibodies which recognise both the host protein and the modified form.
The sporadic cases of encephalopathies observed recently in several different species of exotic ungulates in zoological collections in the UK do not differ essentially from BSE in domestic cattle and it is considered that such case are attributable also to exposure to a scrapie-like agent via ruminant derived meat amd bone meal in commercial rations.
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
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.
These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
IN STRICT CONFIDENCE
From: Dr. A Wight
Date: 5 January 1993
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
*** Thursday, December 23, 2010
Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011
David W. Colby1,* and Stanley B. Prusiner1,2
Wednesday, January 19, 2011
EFSA BIOHAZ Scientific Opinion on the revision of the quantitative risk assessment (QRA) of the BSE risk posed by processed animal proteins (PAPs)
EFSA Journal 2011;9(1):1947
Monday, January 17, 2011
MAD COW Update on Feed Enforcement Activities to Limit the Spread of BSE January 13, 2011
Friday, January 7, 2011
MEAT AND BONE MEAL AND MINERAL FEED ADDITIVES MAY INCREASE THE RISK OF ORAL PRION DISEASE TRANSMISSION
Journal of Toxicology and Environmental Health, Part A, 74:161-166, 2011 Copyright © Taylor & Francis Group, LLC ISSN: 1528-7394 print / 1087-2620 online DOI: 10.1080/15287394.2011.529066
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011
UPDATED DATA ON 2ND CWD STRAIN
Wednesday, September 08, 2010
CWD PRION CONGRESS SEPTEMBER 8-11 2010
Tuesday, January 18, 2011
Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease
Tuesday, December 14, 2010
Infection control of CJD, vCJD and other human prion diseases in healthcare and community settings part 4, Annex A1, Annex J, UPDATE DECEMBER 2010
BRITISH MEDICAL JOURNAL
BMJ 1999;319:1312 (Published 13 November 1999)
Re: vCJD in the USA * BSE in U.S. 15 November 1999
Terry S Singeltary
It's their move, it's CHECK, but once CHECKMATE has been called, how many thousands or millions, will be at risk or infected or even dead. You can't play around with these TSE's. I cannot stress that enough. They are only looking at body bags, and the fact the count is so low. But, then you have to look at the fact it is not a reportable disease in most states, mis-diagnosis, no autopsies performed. The fact that their one-in-a- million theory is a crude survey done about 5 years ago, that's a joke, under the above circumstances. A bad joke indeed........
BRITISH MEDICAL JOURNAL
BMJ 2000;320:8 doi:10.1136/bmj.320.7226.8/b (Published 1 January 2000)
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well...
2 January 2000
Terry S Singeltary
In reading your short article about 'Scientist warn of CJD epidemic' news in brief Jan. 1, 2000. I find the findings in the PNAS old news, made famous again. Why is the U.S. still sitting on their butts, ignoring the facts? We have the beginning of a CJD epidemic in the U.S., and the U.S. Gov. is doing everything in it's power to conceal it.
The exact same recipe for B.S.E. existed in the U.S. for years and years. In reading over the Qualitative Analysis of BSE Risk Factors-1, this is a 25 page report by the USDA:APHIS:VS. It could have been done in one page. The first page, fourth paragraph says it all;
"Similarities exist in the two countries usage of continuous rendering technology and the lack of usage of solvents, however, large differences still remain with other risk factors which greatly reduce the potential risk at the national level."
Then, the next 24 pages tries to down-play the high risks of B.S.E. in the U.S., with nothing more than the cattle to sheep ratio count, and the geographical locations of herds and flocks. That's all the evidence they can come up with, in the next 24 pages.
Something else I find odd, page 16;
"In the United Kingdom there is much concern for a specific continuous rendering technology which uses lower temperatures and accounts for 25 percent of total output. This technology was _originally_ designed and imported from the United States. However, the specific application in the production process is _believed_ to be different in the two countries."
A few more factors to consider, page 15;
snip...see full text ;
Vol. 285 No. 6, February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
JOURNAL OF NEUROLOGY
doi: 10.1212/01.WNL.0000036913.87823.D6 Neurology January 28, 2003 vol. 60 no. 2 176-181
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Email Terry S. Singeltary:
[log in to unmask]
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al  have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003
doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI
Tracking spongiform encephalopathies in North America
"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." 49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of documents on transmissible spongiform encephalopathies (TSE) and realised that if Britons could get variant CJD from bovine spongiform encephalopathy (BSE), Americans might get a similar disorder from chronic wasting disease (CWD)-the relative of mad cow disease seen among deer and elk in the USA. Although his feverish.
PLoS ONE 5(1): e8521. doi:10.1371/journal.pone.0008521
Human Prion Diseases in the United States
Robert C. Holman1*, Ermias D. Belay1, Krista Y. Christensen1, Ryan A. Maddox1, Arialdi M. Minino2, Arianne M. Folkema1, Dana L. Haberling1, Teresa A. Hammett1, Kenneth D. Kochanek2, James J. Sejvar1, Lawrence B. Schonberger1
1 Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-borne and Enteric Diseases, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services (USDHHS), Atlanta, Georgia, United States of America, 2 Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services (USDHHS), Hyattsville, Maryland, United States of America
re-Human Prion Diseases in the United States
Posted by flounder on 01 Jan 2010 at 18:11 GMT
I kindly disagree with your synopsis for the following reasons ;
THE PATHOLOGICAL PROTEIN
BY Philip Yam
Yam Philip Yam News Editor Scientific American www.sciam.com
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
Are prion diseases more prevalent than we thought?
Researchers and government officials badly underestimated the threat that mad cow disease posed when it first appeared in Britain. They didn't think bovine spongiform encephalopathy was a zoonosis-an animal disease that can sicken people. The 1996 news that BSE could infect humans with a new form of Creutzfeldt-Jakob disease stunned the world. It also got some biomedical researchers wondering whether sporadic CJD may really be a manifestation of a zoonotic sickness. Might it be caused by the ingestion of prions, as variant CJD is?
Revisiting Sporadic CJD
It's not hard to get Terry Singeltary going. "I have my conspiracy theories," admitted the 49-year-old Texan.1 Singeltary is probably the nation's most relentless consumer advocate when it comes to issues in prion diseases. He has helped families learn about the sickness and coordinated efforts with support groups such as CJD Voice and the CJD Foundation. He has also connected with others who are critical of the American way of handling the threat of prion diseases. Such critics include Consumers Union's Michael Hansen, journalist John Stauber, and Thomas Pringle, who used to run the voluminous www.madcow. org Web site. These three lend their expertise to newspaper and magazine stories about prion diseases, and they usually argue that prions represent more of a threat than people realize, and that the government has responded poorly to the dangers because it is more concerned about protecting the beef industry than people's health.
Singeltary has similar inclinations. ...
DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen) USA: Loch in der Mauer Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehördensind lax.Link auf diesen Artikel im Archiv:
"Löcher wie in einem Schweizer Käse" hat auch Terry Singeltary im Regelwerk der FDA ausgemacht. Der Texaner kam auf einem tragischen Umweg zu dem Thema: Nachdem seine Mutter 1997 binnen weniger Wochen an der Creutzfeldt-Jakob-Krankheit gestorben war, versuchte er, die Ursachen der Infektion aufzuspüren. Er klagte auf die Herausgabe von Regierungsdokumenten und arbeitete sich durch Fachliteratur; heute ist er überzeugt, dass seine Mutter durch die stetige Einnahme von angeblich kräftigenden Mitteln erkrankte, in denen - völlig legal - Anteile aus Rinderprodukten enthalten sind.
Von der Fachwelt wurde Singeltary lange als versponnener Außenseiter belächelt. Doch mittlerweile sorgen sich auch Experten, dass ausgerechnet diese verschreibungsfreien Wundercocktails zur Stärkung von Intelligenz, Immunsystem oder Libido von den Importbeschränkungen ausgenommen sind. Dabei enthalten die Pillen und Ampullen, die in Supermärkten verkauft werden, exotische Mixturen aus Rinderaugen; dazu Extrakte von Hypophyse oder Kälberföten, Prostata, Lymphknoten und gefriergetrocknetem Schweinemagen. In die USA hereingelassen werden auch Blut, Fett, Gelatine und Samen. Diese Stoffe tauchen noch immer in US-Produkten auf, inklusive Medizin und Kosmetika. Selbst in Impfstoffen waren möglicherweise gefährliche Rinderprodukte enthalten. Zwar fordert die FDA schon seit acht Jahren die US-Pharmaindustrie auf, keine Stoffe aus Ländern zu benutzen, in denen die Gefahr einer BSE-Infizierung besteht. Aber erst kürzlich verpflichteten sich fünf Unternehmen, darunter Branchenführer wie GlaxoSmithKline, Aventis und American Home Products, ihre Seren nur noch aus unverdächtigem Material herzustellen.
"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
28 Mar 2001
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine issue 2284. Subscribe and get 4 free issues. FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris. Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb.
Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health. But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD. They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three. Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.
As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain. As expected, they all affected the brain in a different way from BSE and vCJD. But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology.
"The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys. "You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie." In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar.
But there are more than 20 strains of scrapie, and six of sCJD. "You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys. Bruce is cautious about the mouse results, but agrees they require further investigation. Other trials of scrapie and sCJD in mice, she says, are in progress.
People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways. Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD.
But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD. "If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere. Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain. Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.
Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE. And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011
I disagree with there assumption that classic scrapie will not transmit to man. which classic scrapie strain are they speaking of ? considering that natural scrapie will transmit to primate by their non-forced oral consumption, i would not continue to rule this out, until science proves it. on the contrary science shows that humans are susceptible to natural scrapie strains.
also, the nor-98 atypical scrapie, and the fact the USDA and the OIE worked side by side to expose the whole world to this TSE agent via the fact they decided to exempt it from scrapie regulations and decided to make it legal to import and export nor-98 atypical scrapie. kinda put the cart before the horse.
it's really disgusting to me and sad that these same governing bodies continue to flounder on stringent TSE regulations, all for trade and the almighty dollar $$$ by working so hard to prove that these different TSE will not transmit to man, they missed the science that in fact most all could. ...
snip... please see full text ;
Monday, January 17, 2011
Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
update October 2009
Bacliff, TX, USA
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
12 years independent research of available data
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.
*** Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.
Rural and Regional Affairs and Transport References Committee The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010
2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49
2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
Tuesday, March 16, 2010
COMMONWEALTH OF AUSTRALIA Hansard Import restrictions on beef FRIDAY, 5 FEBRUARY 2010 AUSTRALIA
COMMONWEALTH OF AUSTRALIA
Proof Committee Hansard
RRA&T 2 Senate Friday, 5 February 2010
RURAL AND REGIONAL AFFAIRS AND TRANSPORT
BELLINGER, Mr Brad, Chairman, Australian Beef Association
CARTER, Mr John Edward, Director, Australian Beef Association
CHAIR—Welcome. Would you like to make an opening statement?
Mr Bellinger—Thank you. The ABA stands by its submission, which we made on 14 December last year, that the decision made by the government to allow the importation of beef from BSE affected countries is politically based, not science based. During this hearing we will bring forward compelling new evidence to back up this statement. When I returned to my property after the December hearing I received a note from an American citizen. I will read a small excerpt from the mail he sent me in order to reinforce the dangers of allowing the importation of beef from BSE affected countries. I have done a number of press releases on this topic, and this fellow has obviously picked my details up from the internet. His name is Terry Singeltary and he is from Bacliff, Texas. He states, and rightfully so:
You should be worried. Please let me explain. I’ve kept up with the mad cow saga for 12 years today, on December 14th 1997, some four months post voluntary and partial mad cow feed ban in the USA, I lost my mother to the Heidenhain variant Creutzfeldt-Jakob disease (CJD). I know this is just another phenotype of the infamous sporadic CJDs. Here in the USA, when USA sheep scrapie was transmitted to USA bovine, the agent was not UK BSE—it was a different strain. So why then would human TSE from USA cattle look like UK CJD from UK BSE? It would not. So this accentuates that the science is inconclusive still on this devastating disease. He goes on to state:
The OIE— the International Organisation of Epizootics, the arm of the WTO— is a failed global agent that in my opinion is bought off via bogus regulations for global trade and industry reps. I have done this all these years for nothing but the truth. I am a consumer, I eat meat, but I do not have to sit idly by and see the ignorance and greed of it all while countless numbers of humans and animals are being exposed to the TSE agents. All the USA is interested in is trade, nothing else matters.
Even Dr Stanley Prusiner, who incidentally won the Nobel Health Prize in 1997 for his work on the prion—he invented the word ‘prion’, or it came from him—states:
snip...see full text 110 pages ;
for those interested, please see much more here ;
Tuesday, July 13, 2010
(SEE BEEF PRODUCTS EXPORTED TO AUSTRALIA FROM USA...TSS)
AUSTRALIAN QUESTIONNAIRE TO ASSESS BSE RISK (OIE) Terrestrial Animal Health Code, 2009 and USA export risk factor for BSE to Australia
Saturday, August 14, 2010
USA NON-SPECIES CODING SYSTEM (BEEF IMPORT EXPORT BSE RISK THERE FROM)
US denies it's illegally sending beef to Australia ?
Saturday, June 19, 2010
U.S. DENIED UPGRADED BSE STATUS FROM OIE
Sunday, August 15, 2010
ATYPICAL BSE NOW LINKED TO CAUSING SPORADIC CJD OVERSEAS Commonwealth of Australia
Tuesday, January 5, 2010
JOINT STATEMENT FROM USTR, USDA ON TAIWAN'S ACTIONS TO UNJUSTIFIABLY RESTRICT U.S. BEEF IMPORTS IN VIOLATION OF OUR BILATERAL AGREEMENT Release No. 0002.10 Contact: USTR, Nefeterius McPherson (202) 395-3230 USDA, Caleb Weaver (202) 720-4623
Friday, April 02, 2010 U.S.
beef trade talks to continue but curbs to remain: Japan
Even McDonald’s, an international business symbolic of American culture, advertises that it uses only “pure Australian beef” in South Korea. Burger King announced that it only uses beef from Australia and New Zealand. Why? Even famous brands like McDonald’s cannot survive if they are perceived as using unsafe ingredients. They know that Koreans still do not trust the safety of American beef and must distance their brands from American beef.
Therefore the U.S. should aim to export only the best quality beef to Korea and regain the Korean people’s trust. Regaining Koreans’ confidence in U.S. beef will be a long-term gain for many American industries seeking to access the 12th largest economy in the world.
How will we know that U.S. beef has regained trust in South Korea? When McDonald’s in South Korea announces it uses “pure American beef.”
Kwon Seung-woo, a professor at Korea University Business School
hmmmm, let's see just what the BIG MAC himself had to say ;
Wednesday, November 10, 2010
McDonald's and USA BSE aka mad cow disease McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW
Wednesday, March 31, 2010
Atypical BSE in Cattle
let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.
This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$
ALABAMA MAD COW g-h-BSEalabama
In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
Saturday, June 12, 2010
PUBLICATION REQUEST AND FOIA REQUEST Project Number: 3625-32000-086-05 Study of Atypical Bse
Wednesday, July 28, 2010
re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010
Wednesday, December 29, 2010
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY PRION END OF YEAR REPORT DECEMBER 29, 2010
PLEASE REMEMBER ;
The Akron, Ohio-based CJD Foundation said the Center for Disease Control revised that number in October of 2004 to about one in 9,000 CJD cases per year in the population group age 55 and older.
HAVE YOU GOT YOUR CJD QUESTIONNAIRE ASKING REAL QUESTIONS PERTAINING TO ROUTE AND SOURCE OF THE TSE AGENT THAT KILLED YOUR LOVED ONE ???
if not, why not...
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518