Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf
snip...
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf
Human BSE
snip...
These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.
snip...
http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf
=====================================================
From: TSS
Subject: CJD or Alzheimer's, THE PA STUDY...full text
Date: May 7, 2001 at 10:24 am PST
Diagnosis of dementia: Clinicopathologic correlations
Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD
Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.
NEUROLOGY 1989;39:76-79
Several recent papers and reports have addressed the problem of improving the clinician's ability to diagnose dementia. Notable among those reports are the diagnostic criteria for dementia of the American Psychiatric Association, known as DSM III,1 as well as the clinical and neuropathologic criteria for the diagnosis of Alzheimer's disease (AD).2,3 Other researchers have published guidelines for the differentiation of various types of dementia4 and for antemortem predictions about the neuropathologic findings of demented patients.5
Most studies on the accuracy of clinical diagnosis in patients with dementia, especially AD, have used clinicopathologic correlation,6-15 and have found a percentage of accuracy ranging from 43% to 87%. Two recent reports, however,16,17 have claimed an accuracy of 100%. These two reports are based on relatively small series and have consisted of very highly selected patient samples. In our own recent experience, several cases of dementia have yielded unexpected neuropathologic findings,18 and we hypothesized that, in larger series, there would be a significant number of discrepancies between clinical diagnoses and autopsy findings. The present paper reviews the neuropathologic diagnosis of 54 demented patients who were autopsied consecutively at the University of Pittsburgh over a 7-year period, and reports the ability of clinicians to predict autopsy findings.
Material and methods. We independently reviewed the pathologic data and clinical records of 54 consecutive patients who had had an autopsy at the University of Pittsburgh (Presbyterian University Hospital [PUH] and the Pittsburgh (University Drive) Veterans Administration Medical Center [VAMC]), between 1980 and 1987.
The 54 cases included all those where dementia was diagnosed clinically but for which an obvious etiology, such as neoplasm, trauma, major vascular lesions, or clinically evident infection had not been found. The brains, evaluated by the Division of Neuropathology of the University of Pittsburgh, were obtained from patients cared for in different settings at their time of death.
On the basis of the amount of information available in each case, we divided the patients into three groups. Group 1 included 12 subjects who had been followed for a minimum of 1 year by the Alzheimer Disease Research Center (ADRC) of the University of Pittsburgh. ADRC evaluations include several visits and neurologic and neuropsychological testing as well as repeated laboratory tests, EEG, and CT.19,20
Group 2 included 28 patients who had been seen in the Neurology Service of PUH, of the VAMC, or in geriatric or psychiatric facilities of the University of Pittsburgh or at Western Psychiatric Institute and Clinic. All patients were personally evaluated by a neurologist and received a work-up to elucidate the etiology of their dementia.
Group 3 included 14 patients seen in other institutions; in most cases, they had also been seen by a neurologist and had had laboratory studies that included CT of the head. In three of the 14 cases, however, the information could be gathered only from the clinical summary found in the autopsy records.
Many of these subjects were referred for autopsy to the ADRC because of a public education campaign that encourages families to seek an autopsy for their relatives with dementia.
Pathologic data. All brains were removed by a neuropathologist as the first procedure of the autopsy at postmortem intervals of between 4 and 12 hours. The unfixed brain was weighed and the brainstem and cerebellum were separated by intercollicular section. The cerebral hemispheres were sectioned at 1-cm intervals and placed on a glass surface cooled by ice to prevent adhesion of the tissue to the cutting surface. The brainstem and cerebellum were sectioned in the transverse plane at 6-mm intervals. Brain sections were fixed in 10% buffered formalin. Selected tissue blocks for light microscopy were obtained from sections corresponding as exactly as possible to a set of predetermined areas used for processing brains for the ADRC protocol; additional details of the neuropathologic protocol have been previously published.18,21 Following standard tissue processing and paraffin embedding, 8-um-thick sections stained with hematoxylin and eosin and with the Bielschowsky ammoniacal silver nitrate impregnation were evaluted. Additional stains were used when indicated by the survey stains, including the Bielschowsky silver technique as previously reported.21
Clinical data. The medical history, as well as the results of examinations and laboratory tests, were obtained from the medical records libraries of the institutions where the patient had been followed and had died. We supplemented these data, when appropriate, with a personal or telephone interview with the relatives.
One neurologist (O.L.L.) recorded the information to be evaluated on two forms. The first form included sex, age, handedness, age at onset, age at death, course and duration of the disease, education, family history, EEG, CT, NMR, medical history, and physical examinationas well as examination of blood and CSF for factors that could affect memory and other cognitive functions. The form also listed the results of neuropsychological assessment, and the characteristics and course of psychiatric and neurologic symptoms. The form provided details on the presence, nature, and course of cognitive deficits and neurologic signs. The second form was a 26-item checklist derived from the NINCDS-ADRDA Work Group Criteria for probable Alzheimer's disease.2 The forms did not include the patient's identity, the institution where they had been evaluated, the clinical diagnosis, or the pathologic findings.
Each form was reviewed independently by two other neurologists (F.B. and J.M.), who were asked to provide a clinical diagnosis. In cases of probable or possible AD, the two neurologists followed the diagnostic criteria of the NINCDS/ ADRDA work group.2
The results were tabulated on a summary sheet filled out after the two neurologists had provided their diagnosis on each case. The sheet included the diagnosis reached by the two neurologists and the diagnosis resulting from the autopsy.
Table 1. Pathologic diagnosis in 54 patients with dementia
N %
Alzheimer's disease alone 34 62.9
Alzheimer's disease and 2 3.7 Parkinsons's disease
Alzheimer's disease with 2 3.7 multi-infarct dementia
Alzheimer's disease with amyotrophic lateral sclerosis 39 72.2
Total Alzheimers disease 39 72.2
Multi-infarct dementia 4 7.4
Multi-infarct dementa 1 1.8 with Parkinson's disease
Parkinson's disease 2 3.7
Progressive subcortical gliosis 2 3.7
Creutzfeldt-Jakob disease 3 5.5
Progressive supranuclear palsy 1 1.8
Huntington's disease 1 1.8
Unclassified 1 1.8
Total other disease 15 27.7
Total all cases 54
Table 2. Clinical diagnosis
Clinical diagnosis Clinician #1 --- #2
Probable AD 29 21
Probable AD and MID 3 0
Probable AD and thyroid disease 1 2
Probable AD and PD 3 1
Probable AD and ALS 1 0
Probable AD and 0 1 olivopontocerebellar degeneration
Total probable AD 37 25 (68.5%) (46.2%)
Possible AD 3 2
Possible AD and MID 2 2
Possible AD and alcoholism 0 1
Possible AD and depression 1 0
Possible and thyroid disease 0 3
Possible AD and traumatic 1 2 encephalopathy
Possible AD and PD 3 6
Total Possible AD 10 16 (18.5%) (29.6%)
Atypical AD 0 1
Atuypical AD and MID 0 1
MID 2 4
MID and PD 3 0
Dementia syndrome of depression 0 1
HD 1 1
Wernicke-Korsakoff syndrome 1 0
Dementia of unknown etiology 0 5
Total 54 54
Results. The subjects included 26 women and 28 men who ranged in age from 30 to 91 years (mean, 72.2; SD, 10.7).
Autopsy findings. Table 1 shows that 39 (72.2%) of the 54 cases fulfilled histologic criteria for AD, with or without other histopathologic findings. The remaining 15 cases (27.7%) showed changes corresponding to other neurodegenerative disorders, cerebrovascular disease, or Creutzfeldt-Jakob disease (CJD). Seven cases met the histopathologic criteria for multi-infarct de-mentia (MID). Five cases (9.2%) showed changes associated with Parkinson's disease (PD).
Twenty-two of the 39 AD patients (56%) were age 65 or greater at the time of the onset of the disease. Seven of the 15 patients in the group with other diseases (47%) were age 65 or older at the time of disease onset.
Clinical diagnosis. There was a general adherence to the criteria specified by McKhann et al.2 However, the two clinicians in this study considered the diagnosis of probable AD when the probability of AD was strong even if a patient had another disease potentially associated with dementia that might or might not have made some contribution to the patient's clinical state (table 2).
Accuracy of the clinical diagnosis (table 3). Group 1 (N = 12). There were six men and six women. Ten cases (83.3%) met the histologic criteria for AD. In nine cases (75.0%), the diagnosis of both clinicians agreed with the pathologic findings; in the other case (8.3%), one clinical diagnosis agreed with the histologic findings. The remaining two cases (16.6%) had histopathologic diagnoses of CJD and progressive supranuclear palsy (PSP), respectively. Both cases were incorrectly diagnosed by both clinicians.
Group 2 (N = 28). There were 11 women and 17 men. Eighteen cases (64.2%) had the histopathologic features for AD with or without additional findings. Sixteen of these cases (57.1%) were correctly diagnosed by both clinicians, one case by one of them, and both incorrectly diagnosed one case. The remaining ten cases (35.7%) included two with CJD; two with subcortical gliosis (SG); two with PD, one of which was associated with MID; one case of Huntington's disease (HD); two cases with MID; and one unclassifed. Only one, the HD case (3.5%), was correctly diagnosed by both observers, and four cases (14.2%), two MID and two PD, one associated with MID, were correctly diagnosed by one clinician.
Group 3 (N = 14). In this group there were nine women and five men. Eleven cases (78.5%) met the histopathologic criteria for AD with or without additional findings. Eight of these cases (57.1%) were correctly diagnosed by both clinicians, two cases by one of them, while both were incorrect in one case. Of the remaining three cases (21.4%), only one was correctly diagnosed (7.1%) by one clinician. Both missed the two other cases of MID.
There was no statistically significant difference in diagnostic agreement across patient groups in which the amount of clinical information was different (X2 = 1.19; p > 0.05).
Table 3. Accuracy of the clinical diagnosis by two clinicians
Both One Neither Correct Correct Correct
Group 1 (N = 12) 9 1 2(16.6%)
Group 2 (N = 28) 17 5 6(21.4%)
Group 3 (N = 14) 8 3 3(21.4%)
Table 4. Previously reported studies of clinicopathologic correlation in demented patients*
Agreement %
Number of cases AD
Retrospective studies
Todorov et al, 1975(7) 776 43
Perl et al, 1984(9) 26 81
Wade et al, 1987(12) 65 85
Alafuzoff et al, 1987(13) 55 63
Kokmen at al, 1987(14) 32 72
Joachim et al, 1987(15) 150 87
Prospective studies
Sulkava et al, 1983(8) 27 82
Molsa et al, 1985(10) 58 71
Neary et al, 1986(11) 24 75
Martin et al, 1987(16) 11 100
Morris et al, 1987(17) 25 100
* Certain differences in methodology need clarification. Some authors7,8,10,11,12,13,16,17 tabulated patients with AD alone, and others9,14,15 included patients with AD plus other diseases, eg, Parkinson's disease and MID. We have combined AD alone and AD plus MID and other neurodegenerative diseases.
Discussion. Our results indicate that in a population of patients with dementias of varied etiology, the diagnosis could be correctly inferred by at least one of two clinicians in approximately 80% of cases. For one observer, the sensitivity of clinical diagnosis for AD was 85% and the specificity was 13%, and for the other, it was 95% and 33% respectively.
In the cases with a discrepancy between the clinical diagnosis and the neuropathologic findings, the great majority of patients had atypical clinical courses and findings. The three cases with autopsy findings of CJD had a much longer course than is usually seen with that condition and failed to show the usual EEG abnormalities. The patient with autopsy findings of PSP did not show the disorder in the extraocular movements usually associated with that condition. An atypical course was also present for two AD cases and two MID cases that did not have any feature suggestive of vascular disease. In one MID case, the CT did not show any focal lesions, while in the other it was not available. With regard to the two patients with SG, the pathologic diagnosis is so unusual and so infrequently recorded that clear clinical correlates are not evident.18 The third category of possible error is the patient listed as unclassified, for whom no specific neuropathologic diagnosis could be reached.22
The small number of neuropathologic diagnoses of Parkinson's disease reflects that, for the purpose of this series, the diagnosis of PD was made only when there were both a clear-cut clinical history and the neuropathologic findings characteristic of the disease, such as Lewy bodies, neuronal loss, globose neurofibrillary tangles, astrocytosis, and extraneuronal melanin pigment in substantia nigra and locus ceruleus.
Are these results derived from a sample of 54 patients representative of disease patterns in the community? Generally, the diagnosis of patients reported from major medical centers tend to be biased since the more complicated cases are referred there. In this study, however, this bias may be less important. Due to the major public education campaign about dementia and AD sponsored by the ADRC, there is a widespread awareness in Pittsburgh and in the surrounding regions of Western Pennsylvania of the value of an autopsy for a definitive diagnosis. Therefore, the great majority of cases were referred to us because the family wanted to know the precise etiology of a case of dementia.
The significant improvement in the clinical diagnosis of AD is a recent phenomenon. Due to the publicity and the advances in communication of scientific investigations, most physicians are more likely to consider AD as the main cause of dementia. The current risk of overdiagnosing AD reminds one of what occurred during the 1960s with the diagnosis of "atherosclerotic dementia."6 The high sensitivity and low specificity for AD shown in our study may reflect that possibility.
Because of the varying criteria for "other dementias" in many publications, we chose to analyze the accuracy of clinical diagnosis in terms of the diagnosis of AD alone or AD plus other neuropathologic findings. Several retrospective studies have attempted to point out reliable clinical and pathologic features for diagnosing the dementias, especially AD. The study of Tomlinson et al6 is not included in table 4 because there was no attempt to validate the clinical diagnosis with pathologic findings. The reports surveyed vary considerably in size and methodology. Sample size, for example, ranges from 26 subjects9 to 776 subjects.7 Some studies base the diagnosis on limited clinical information,7'9'14'15 others use widely accepted diagnostic criteria such as those specified in DSM III,13 and one group uses a standardized clinical assessment of patients enrolled in a longitudinal study.12 The reported accuracy of the clinical diagnosis of AD ranges from 43%7 to 87%.15
Recent prospective studies that adhere to strict clinical criteria,10'11'17 those in DSM III8 or those proposed by McKhann et al,16 indicate improved accuracy of clinical diagnosis of the most common causes of dementia, especially AD. In sample sizes ranging from 11 subjects16 to 58 subjects,l0 the accuracy of clinical diagnosis is reported as ranging from 71%10 to 100%16'17' Only two series, both based on small samples, report a 100% accuracy. We consider it unlikely that such accuracy could be confirmed in large series because of some inevitable imprecision in clinical diagnoses and the variability of clinical pictures. Furthermore, although researchers generally agree on the application of uniform criteria in clinical diagnosis of dementia, opinions still differ about specific diagnostic criteria, as well as about the pathologic characterization of dementia. Except for those small series, the results summarized in table 4(7-15) is are remarkably consistent with ours.
In table 3, although there was no statistical difference (p > 0.05) in diagnostic agreement across patient groups, there is a trend toward a lower percentage of diagnostic errors for the patients who had been followed most intensely (16% in group 1 compared with 21% in groups 2 and 3). The difference is not great, and it is, in fact, surprising to find out that in the patients about whom relatively little was known (group 3) the percentage of diagnostic error was the same as among patients seen by neurologists and for whom much more data were available (group 2). These paradoxical findings probably indicate that both clinicians learned to extract essential diagnostic criteria2 in spite of the variations in the amount of information available for consideration. It may well be that clinical, radiographic, and laboratory assessment of patients with dementia is burdened with information that is excessive and unessential for purely diagnostic purposes.
Acknowledgments
We thank Dr. A. Julio Martinez and Dr. Gutti Rao from the Division of Neuropathology for autopsy data. Mrs. Margaret Forbes, Ms. Annette Grechen, and Mrs. Paula Gent helped in the preparation of the manuscript.
References
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Organic Dementia Disorders, 3rd ed. Washington DC, APA, 1983:101-161.
2. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Dis-ease. Neurology 1984;34:939-944.
3. Khachaturian Z. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105.
4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston: Butterworths, 1983.
5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7:486-488.
6. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11.205-242.
7. Todorov A, Go R, Constantinidis J, Elston R. Specificity of the clinical diagnosis of dementia. J Neurol Sci 1975;26:81-98.
8. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13.
9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua-tion of banked brain specimens submitted with clinical diagnosis of Alzheimer's disease. In: Wirtman R, Corkin S, Growdon J, eds. Alzheimer's disease: advances in basic research and therapies. Proceedings of the Fourth Meeting of International Study Group on the Treatment of Memory Disorders Associated with Aging. Zurich, January 1984. Cambridge, MA: CBSM, 1984:463. Molsa PK, Paljarvi L, Rinne JO, Rinne UK, Sako E. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 1985;48:1085-1090.
11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn-dromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986;49:163-174.
12. Wade J, Mirsen T, Hachinski V, Fismm~ M, Lau C, Merskey H. The clinical diagnosis of Alzheimer disease. Arch Neurol 1987;44:24-29.
13. Alafuzoff I, Igbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinicalpathological correlation and classification by multivariate data analysis. Acta Neuropathol (Berl) 1987,74:209-225.
14. Kokmen E, Offord K, Okazaki H. A clinical and autopsy study of dementia in Olmsted County, Minnesota, 1980-1981. Neurology 1987;37:426-430.
15. Joachim CL, Morris JH, Selkoe D. Clinically diagnosed Alzheimer's disease: autopsy neuropathological results in 150 cases. Ann Neurol 1988;24:50-56.
16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology 1987;37:1201-1204.
17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann Neurol 1987;22:122.
18. Moossy J, Martinaz J, Hanin I, Rao G, Yonas H, Boiler F. Thalamic and subcortical gliosis with dementia. Arch Neurol 1987;44:510-513.
19. Huff J, Becker J, Belle S, Nebes R, Holland A, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology 1987;37:1119-1124.
20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The neurological examination in patients with probable Alzheimer's disease. Arch Neurol 1987;44:929-932.
21. Moossy J, Zubenko G, Martinez AJ, Rao G. Bilateral symmetry of morphologic lesions in Alzheimer's disease. Arch Neurol 1988;45:251-254.
22. Heilig CW, Knopman DS, Mastri AR, Frey W II. Dementia without Alzheimer pathology. Neurology 1985;35:762-765.
From the Departments of Neurology (Drs. Boller, Lopez, and Moossy), Psychiatry (Dr. Boller), Pittsburgh (University Drive) Veterans Administration Medical Center (Dr. Boller), Department of Pathology (Division of Neuropathology) (Dr. Moossy), and the Pittsburgh Alzheimer Disease Research Center (Drs. Boller, Lopez, and Moossy), University of Pittsburgh Medical School, Pittsburgh, PA.
Supported in part by NIH Grants nos. AG05133 and AG03705, NIMH Grant no. MH30915, by funds from the Veterans Admin., and by the Pathology Education and Research Foundation (PERF) of the Department of Pathology, University of Pittsburgh.
Presented in part at the fortieth annual meeting of the American Academy of Neurology, Cincinnati. OH, April 1988.
Received April 7, 1988. Accepted for publication in final form July 20, 1988.
Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261.
January 1989 NEUROLOGY 39 79
TSS
http://www.vegsource.com/talk/lyman/messages/9249.html
From: TSS (216-119-130-151.ipset10.wt.net)
Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia
Date: May 8, 2001 at 6:27 pm PST
Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia Date: Tue, 8 May 2001 21:09:43 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To:
[email protected]
#### 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 accountsfor approximately 60% of cases.1-3
Interest in the accuracy of the diagnosis of dementia is a relatively recent phenomenon, reflecting both an increase in physicians' awareness of multiple specific causes of dementia and a marked increase in both the incidence and prevalence of dementia associated with the increase in the elderly population.4' The clinical evaluation remains the key to the differential diagnosis, and in most cases dementia can be diagnosed accurately by clinical criteria. However, the definitive diagnoses of AD.1'5'7 Pick's disease,8'10 Creutzfeldt-Jakob disease (CJD),11-16 Binswanger's disease,17'18' and diffuse Lewy body disease19-22 still require histologic examination of the cortex to identify characteristic structural changes.
Brain tissue is almost invariably obtained at autopsy, and the vast majority of pathologic diagnoses are thus made post mortem. Alternatively, an antemortem histologic diagnosis can be provided to the patient and his or her family if a cerebral biopsy is performed while the patient is still alive. Because brain biopsies for dementia are not routinely performed, we sought to define the spectrum of pathologic changes seen in a retrospective unselected series of adult patients undergoing cerebral biopsy for the diagnosis of atypical dementing illnesses and to determine the patient selection criteria most likely to result in a definitive diagnosis.
MATERIALS AND METHODS
Cerebral biopsies performed solely for the diagnosis of dementia in adult patients were identified by a manual search of the patient files of the Division of Neuropathology, Duke University Medical Center Durham, NC, and by a computerized search of discharge diagnoses of patients undergoing brain biopsies. Fourteen cases were identified from the period 1980 to 1989. Patients undergoing biopsies for suspected tumor, inflammation, or demyelinating disease were excluded. A clinical history of dementia was an absolute requirement for inclusion in the study. Diagnosis was based on Dignostic and Statistical Manual of Mental Disorders, Third Edition, and on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for probable AD.23
The published recommendations for handling tissue from patients with suspected CJD were followed in every case.24-26 Briefly, tissue was transported in double containers clearly marked "Infectious Disease Precations." Double gloves, aprons, and goggles were used at all times. Tissue was fixed in saturated phenol in 3.7% phosphate-buffered formaldehyde for 48 hours25 and subsequently hand processed for paraffin embedding. At least 1 cm(to 3 power) of tissue was available for examination from each patient, except for patient 7, who underwent bilateral temporal lobe needle biopsies. Patient 14 underwent biopsy of both frontal and temporal lobes.
One paraffin block was prepared for each biopsy specimen, and sections were routinely stained with hematoxylin-eosin, luxol fast blue, Congo red, alcian blue, periodic acidSchiff, and modified King's silver stain27 in every ease, except for case 7, in which the diagnosis was made by frozen section. Portions of both gray and white matter were primarily fixed in glutaraldehyde and embedded in epoxy resin (Epon). Tissue was examined by electron microscopy if abnormalities, such as neuronal storage or other inclusions, were seen in routine paraffin sections.
Khachaturian's5 National Institute of Neurological and Communicative Disorderers and Stroke/ADRDA criteria for quantitation of senile plaques and the diagnosis of AD were used in all cases after 1985. At the time of our, study, these criteria were also applied retrospectively to cases accessioned before 1985. No attempt was made to grade the severityof other abnormalities (eg, gliosis and spongiform change), and the original pathologic diagnoses were not revised.
RESULTS
The clinical presentations, biopsy findings, and follow-up data, including postoperative complications, are summarized in Table 1 for all 14 patients. Their biopsy findings are summarized in Table 2.
The ages of this unselected group of 14 patients who underwent cerebral biopsies for dementia ranged from 32 to 78 years (mean, 51.6 years). There were seven men and seven women. Duration of symptoms ranged from 1 month to 6 years (mean, 2.3 years). No differences were noted between the group with diagnostic biopsies (cases 1 through 7) and the group with nondiagnostic biopsies (cases 8 through 14) with regard to age at the time of biopsy or duration of symptoms. However, five of seven patients in the nondiagnostic group had hemiparesis, chorea, athetosis, or lower motor neuron signs. None of these findings was present in the patients with diagnostic biopsies. Visual disturbances, abnormal eye movements, and ataxia were present in four of seven cases with diagnostic biopsies but were absent in the group with nondiagnostic biopsies.
In this series of 14 patients, two experienced postoperative complications, one of which was severe. Patient 2 developed an intraparenchymal parietal cortex hemorrhage and was mute after biopsy. Patient 9 developed a subdural hygroma that was treated uneventfully.
Eight patients died 1 month to 9 years after biopsy. An autopsy was performed in five of these eight patients. One of these patients (patient 4) had a firm diagnosis of presenile AD on biopsy, which was confirmed at autopsy. Patient 3 had a biopsy diagnosis of CJD, which was also confirmed at autopsy. Two patients with only white-matter gliosis diagnosed at biopsy had autopsy diagnoses of amyotrophic lateral sclerosis with dementia (patient 8) and CJD (patient 9). One patient in whom a biopsy specimen appeared to be normal had Huntington disease identified at autopsy (patient 14). At the time of this writing, four patients are still alive, two are in clinically stable condition 1 to 2 years after biopsy, and two are severely demented 2 to 3 years after biopsy. Two patients (one with a definite and one with a possible diagnosis of CJD) have been unavailable for follow-up.
COMMENT Our study of patients presenting with atypical dementia reaffirms the diagnostic utility of cerebral biopsy. In selected cases, cerebral biopsy results in a high yield of definitive diagnostic information. A wide variety of disorders may be encountered, including CJD, AD, diffuse Lewy body disease, and storage disorders, such as Niemann-Pick disease.28-30 The diagnosis of Niemann-Pick disease type C was confirmed by assay of cholesterol esterification in cultured fibroblasts31'32' with markedly abnormal results in one patient, who was described in detail elsewhere.33
One example of an unsuspected anaplastic astrocytoma (case 7) was also encountered. This case was unusual in light of currently used sensitive imaging techniques. This patient may have been suffering from gliomatosis cerebri.
Table 1.--Summary of Clinical Presentation and Course*
Case/Age,y/Sex
Duration of Symptoms, y
Clincial Findings
Biopsy
Follow-up ==========
1/60/F
0.1
Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral synchronous discharges
CJD
Unavailable ==========
2/57/M
0.4
Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal EEG
CJD
Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy ==========
3/59/M
2
Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic sharp waves
CJD
Dead at 61 y, autopsy showed CJD =========
4/32/M
1
Dementia, myclonus, ataxia, family history of early-onset dementia
AD
Dead at 40 y, autopsy showed AD =========
5/78/M
6
Dementia, paranoia, agitation, rigidity
Diffuse Lewy body disease
Dead at 78 y, no autopsy =========
6/37/F
6
Dementia, dysarthria, abnormal eye movements, ataxia
Neuronal storage disorder, adultonset N-P type II
Stable at 39 y =========
7/58/F
0.3
Dementia, amnesia, depression, partial complex seizures
Anaplastic astrocytoma
Dead at 58 y, no autopsy ==========
8/37/M
2
Dementia, dysarthria, upper-extremity atrophy and fasciculations
Gliosis
Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter gliosis =========
9/45/F
2
Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis
Gliosis
Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD =========
10/56/F
2
Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic sharp waves
Consistent with CJD
Unavailable ==========
11/60/F
2
Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic resonance image showing small vessel disease
Plaques, gliosis
stable at 61 y =========
12/52/F
2
Dementia, aphasia, right-sided hemiparesis
Gliosis
Bedridden, severely demented at 54 y =========
13/40/M
0.5
Dementia, mild bifacial weakness, concrete thinking, altered speech
Normal
Stable at 41 y =========
14/52/M
6
Dementia, choreoathetosis, family history of senile dementia, computed tomographic scan showing normal caudate
Normal
Dead at 61y, autopsy showed Huntington's disease, grade II/IV ========== * EEG indicates electroencephalogram; CJD, Creutzfeldt-Jakob disease; AD, Alzheimer's disease; and N-P, Niemann-Pick disease.
Table 2.--Pathologic Findings at Biopsy *
Case Site of Biopsy Type of Biopsy Tissue Examined Spongiform Change Neuritic Plaques per X 10 Field Tangles White Matter Gliosis Other
1 R temporal Open 1 cm3 + 0 0 0 0 =====
2 L temporal Open 1 cm3 + 0 0 0 0 =====
3 R temporal Open 1 cm3 + 0 0 0 0 =====
4 R frontal Open 1 cm3 0 >100 + + Amyloid angiopathy =====
5 R temporal Open 1 cm3 0 9 0 0 Lewy bodies =====
6 R temporal Open 1 cm3 0 0 0 0 Neuronal storage =====
7 R temporal/L temporal Needle/needle 1 X 0.3 X 0.3 cm / 1 X 0.3 X 0.1 cm 0/0 0/0 0/0 +/0 0/anaplastic astrocytoma =====
8 R frontal Open 1 cm3 o o o + 0 =====
9 L parietal Open 1 cm3 0 0 ± + 0 =====
10 R temporal Open 1 cm3 ± 0 0 0 0 =====
11 L temporal Open 1 cm3 0 23 0 + 0 =====
12 L temporal Open 1 cm3 0 0 0 + 0 =====
13 r frontal Open 1 cm3 0 0 0 0 0 =====
14 L temporal/L frontal Open/open 1 cm3/ 1 cm3 0/0 0/0 0/0 0/0 0/0 ===== * Plus sign indicates present; zero, absent; and plus/minus sign, questionably present
Positron emission tomography showed multiple areas of increased uptake, even though the magnetic resonance image was nondiagnostic and showed only subtle increased signal intensity on review. Bilateral temporal lobe needle biopsies yielded abnormal findings. Biopsy of the right side showed only reactive gliosis, which may have been adjacent to tumor. Biopsy of the left side, performed 3 days later, was diagnostic for anaplastic astrocytoma. Unfortunately, permission for an autopsy was refused, and complete evaluation of the underlying pathologic process thus must remain speculative.
The high incidence of definite and probable CJD in our series indicates that it is imperative that appropriate precautions are taken to prevent the transmission 0f disease to health care workers when biopsy tissue from patients with dementia is handled.24-26
At our institution, cerebral biopsy for the diagnosis of dementia is reserved for patients with an unusual clinical course or symptoms that cannot be diagnosed with sufficient certainty by other means. In most instances, cerebral biopsy is unnecessary and is clearly not a procedure to be proposed for routine diagnostic evaluation. In all cases, extensive clinical, metabolic, neuropsychological and radiologic evaluations must be performed before cerebral biopsy is considered. In addition, preoperative consultations among neurologists, neurosurgeons, neuroradiologists, and neuropathologists are necessary to ascertain the optimal biopsy site given the clinical data to ensure that maximal infornmtion is derived from the biopsy tissue.
An optimal biopsy specimen is one that is taken from an affected area, handled to eliminate artifact, and large enough to include both gray and white matter.34 Open biopsy is generally preferred because it is performed under direct visualization and does not distort the architecture of the cerebral cortex. This method also provides sufficient tissue (approximately 1 cm3) to perform the required histologic procedures.
Some physicians question the utility of diagnostic cerebral biopsies in dementia, stating that the procedure is unlikely to help the patient. While it is frequently true that the diagnoses made are untreatable with currently available therapeutic modalities, this is by no means universally true. Kaufman and Catalano35 noted that cerebral biopsy has revealed specific treatable illnesses, such as meningoencephalitis and multiple sclerosis. Our patient with anaplastic astrocytoma (patient 7) underwent radiation therapy, although she quickly died of her disease. Furthermore, when a definitive diagnosis can be made, even of incurable illnesses, such as CJD and AD, it is often possible to give an informed prognosis to the family and to help them plan for the future.
The formulation of indications, for diagnostic cerebral biopsy raises difficult and complex issues. In 1986, Blemond36 addressed the clinical indications and the legal and moral aspects of cerebral biopsy, and his recommendations remain valid today: (1)The patient has a chronic progressixe cerehral disorder with documented dementia. (2) All other possible diagnostic methods have already been tried and have failed to provide sufficient diagnostic certainty. (3) The general condition of the patient permits cerebral biopsy. (4) Several specialists are in agreement regarding the indication. (5) Informed consent is obtained from relatives. (6) Modern diagnostic tools, such as immunocytochemistry and electron microscopy, are used to the fullest capacity in the examination of the material obtained.
As with any intracranial surgical procedure involving the cerebral cortex, the risks of cerebral biopsy include anesthetic complications, hemorrhage, infections, and seizures. Guthkelch37 stated that the mortality associated with brain biopsy is not greater than that associated with general anesthesia. Cerebral biopsy, however can result in substantial morbidity. In our series, two of 14 patients suffered operative complications, intraparenchymal hemorrhage in one patient (patient 2) resulted in aphasia, while another patient (patient 10) developed a subdural hygroma, which was successfully treated, and recovered her baseline status.
The current diagnostic accuracy of cerebral biopsy in the evaluation of dementia is unknown. Most of the larger general series 34'38-41 were reported before computed tomography was available and included many pediatric cases presenting with genetic neurodegenerative disorders that are now more readily diagnosed by other means. For adults with dementia, less information is available. Katzman et al4 recently reviewed the literature concerning the diagnostic accuracy of cerebral biopsy for dementia and concluded that 75% of these procedures result in diagnostic material. Patient selection is very important, and the literature is heavily weighted toward patients with a clinical diagnosis of AD.35'42-44 Our study thus provides documentation of the diagnostic accuracy of cerebral biopsies in unselected patients with atypical dementia.
Autopsy follow-up is imperative in any dementia program,2 as a definitive diagnosis will not be made in a substantial proportion of patients. In our series, three patients died without a diagnosis, and autopsy was performed in all three. The diagnostic features were not present in the cortical area in which the biopsy was performed. In case 8, examination of the spinal cord revealed amyotrophic lateral sclerosis. Diffuse gliosis of the white matter was noted, which was the pathologic basis of the patient's dementia. In case 9. the spongiform change of CJD was focal, according to the pathologist's report; unfortunately, the tissue was not available for our review. In case 14, the diagnosis of Huntington's disease grade II/IV was made after close examination of the caudate nucleus. As one might predict, fewer autopsies were performed in the group with diagnostic biopsies; only two of five deaths in this category were followed by postmortem examinations. The diagnosis of AD was confirmed in case 4. In ease 3, the biopsy diagnosis of CJD was confirmed.
In summary, a series of 14 unselected cerebral biopsies performed for the diagnosis of atypical dementia was reviewed to define the spectrum of pathologic changes seen and to estimate the likelihood of obtaining diagnostic tissue. Histologic diagnoses of CJD, AD, diffuse Lewy body disease, Niemann-Pick disease type C, or anaplastic astrocytoma were made in seven patients. The high incidence of CJD in this population (four of 14 cases) emphasizes the need to use appropriate precautions when tissue from patients with unusual dementing illnesses is handled. Consultation among neurologist, neurosurgeons, neuroradiologists, and neuropathologists is essential to select appropriate patients and to choose the proper biopsy site. Demented patients with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs are unlikely to benefit from cortical biopsy.
This investigation was supported by Clinical Investigator Award PHS AG-00446 from the National Institute on Aging (Dr. Hulette) and by grant PHS SP50AG05128-03 from the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (Drs Earl and Crain). Dr Hulette is a College of American Pathologists Foundation Scholar, Northfield, Ill.
The Authors thank Ms Bonnie Lynch and Ian Sutherland, PhD, for thier assistance.
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14. Masters CL, Richardson EP: Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease): the nature and progression of spongiform changes. Brain 1978;101:333-344.
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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
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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.
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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.
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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
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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.
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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.
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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
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1996). Stanley Prusinger, the scientist who coined the term prion, speculates Alzheimer's may in fact turn out to be a prion disease (Prusiner, 1984). In ...
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MULTIMODAL EVOKED POTENTIALS IN MOUSE MODELS OF NEURODEGENERATION
Transmissible spongiform encephalopathies and Alzheimer's disease are neurodegenerative disorders in which neuropathologic changes are associated with accumulation of prion protein and deposition of amyloid ß-protein, respectively. Recently, transgenic mice that overexpress a mutant human ß-amyloid precursor protein and mice devoid of prion protein were generated. However, few electrophysiologic studies in intact freely moving...
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Causes of Alzheimer's and "Mad-Cow" Diseases
Alzheimer's and "mad-cow" diseases are unique in that their infectious agents are not viruses or germs, but rather proteins. The brains of patients who suffered from Alzheimer's or cows that died of "mad-cow" disease show deposits of abnormal tissue called amyloid plaques. The primary component of these plaques is a protein called prion protein or PrP. Chemical and biochemical analysis showed that there was no difference in composition or primary structure between the normal, cellular form of PrP (PrPC, shown at right) and the disease form of PrP (PrPSc). Further analysis showed that PrPC can change into PrPSc when two of the a helices (shown in green) change into ß sheets. This ß sheet can then induce a similar change in another molecule of PrPC and hydrogen bond to it. The PrPSc 's then polymerize and come out of solution, forming the plaques found in Alzheimer's patients and mad cows. How the plaques cause the symptoms of the diseases is still not clear, but the prion protein holds the unique distinction of causing a disease solely through a small alteration in secondary structure.
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importantly, recent findings indicating that the cellular accumulation of incorrectly folded proteins is the molecular basis of many diseases, including Alzheimer's Disease, Prion Diseases and Huntington Disease, underscore the importance of understanding the mechanisms of folding in vivo. Alzheimer's and prion disease appear to be caused by the generation of a "pathological" conformation in the newly translated protein that would otherwise fold to a normal conformation that does not produce the disease. In some model systems, molecular chaperones appear to play a role in this conformational change. Thus, developing approaches to study protein folding under physiological conditions is essential to understand how folding defects can lead to disease.
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Implications for Alzheimer's disease
Harris also has recently expanded his research to include Alzheimer's disease, which shares several features with prion diseases despite being non-infectious. Leonard Berg, M.D., professor of neurology and former director of the Alzheimer's Disease Research Center at the medical school, and other colleagues say Harris readily applies his extensive knowledge of cell biology to this area as well.
http://record.wustl.edu/archive/1998/02-12-98/3678.html
RESEARCH LETTERS
Early-Onset Familial Alzheimer Disease With Coexisting [beta] -Amyloid and Prion Pathology
To the Editor: Familial Alzheimer disease (AD) with early onset has been linked to 3 different genes with an autosomal dominant mode of inheritance: [beta] -amyloid, protein precursor, and the presenilins 1 and 2, representing not more than 50% of all cases of early-onset AD cases.1 Thus, the genetic defect remains unexplained in at least half of the families with histories of early onset of AD. We have recently described such a Swiss family whose members presented with a standard clinical and neuropathologic profile of AD.2 In particular, severe neurofibrillary tangle degeneration was present in the hippocampus and in several cortical areas, together with a large amount of [beta] -amyloid deposits and senile plaques (SPs). However, known mutations have not been found, either in the [beta] -amyloid precursor protein or in the presenilin 1 and 2 genes.2 We now report that the brains of 5 deceased members of this family, from 2 generations, present a coexisting [beta] -amyloid and prion protein (PrP) pathology.
Methods
Five available cases with clinical AD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. The age at onset of disease ranged from 43 to 64 years (mean, 55.8 years) and age at death ranged from 55 to 81 years (mean, 67.4 years). In addition, 4 of the 5 cases had epileptic features. Serial frozen sections (50 µm thick) through the temporal and frontal cortex of the 5 formalin-treated brains were pretreated with formic acid. They were then processed using monoclonal antibodies against amyloid- [beta] 40 peptide (1:100; [Sigma] ) and against PrP106-126 (1:200; produced by one of us).3 The latter antibody specifically marks the pathological isoform of the PrP and does not cross-react with [beta] -amyloid deposits. In addition, double immunostaining using successive anti- [beta] -amyloid and anti-PrP106-126 antibodies was performed.
Results
In all 5 cases, the cerebral cortex revealed spongiform changes, mainly in superficial layers, and some degree of gliosis. Neurofibrillary tangle and neuritic plaques revealed by Gallyas were numerous in all cortical regions including the primary visual area. In addition, frequent [beta] -amyloid-positive SPs were observed, together with SP stained by the monoclonal antibody against PrP106-126. Successive sections alternately stained with the 2 antibodies showed that both [beta] -amyloid and PrP106-126 positive SP are deposited in all layers of the frontal and temporal cortex. A population of SP, marked on 2 serial sections with both antibodies, was positive for both [beta] -amyloid and PrP106-126. Double-stained sections with [beta] -amyloid and PrP106-126 antibodies further demonstrate that 3 populations of plaques exist: only [beta] -amyloid, only PrP106-126 positive, or positive for both antibodies (Figure 1) and a majority of SPs (>50%) are immunopositive for both [beta] -amyloid and PrP106-126 antibodies. Comparatively, the relative proportion of SPs marked for each antibody alone is smaller. In particular, SPs marked for PrP106-126 represent approximately 5% to 10% of the whole population.
Comment
Coexistence of Creutzfeldt-Jakob disease (CJD) and AD in some patients has been described but appears mainly related to age in patients proven to have CJD.4 However, since the individuals in the Swiss family died over a long interval and were all similarly affected, it is unlikely that CJD is purely coincidental. On the other hand, familial Gerstmann-Straüssler-Scheinker disease can present a variant with concomitant neurofibrillary tangle and prion-positive plaques, but not [beta] -amyloid-positive plaques. Within this variant, 2 mutations in the gene for the PrP have been identified in 2 different families, and the clinical profile with cerebellar ataxia and extrapyramidal signs5 differs from our findings.2 Base pair deletion in the prion gene segregating as an uncommon polymorphism has been described in a family with a history of late-onset AD, but there is no neuropathological confirmation and the genetic association is uncertain.6
Thus, the data presented herein support the existence of a possible new subtype of familial early-onset AD with a concomitant [beta] -amyloid and prion brain pathology, together with a massive neurofibrillary tangle degeneration. Although all known mutations have been excluded in the coding regions of the AD genes, numerous candidate chromosome sites, either in the AD genes outside the coding regions or in other genes including PrP, must be considered.
G. Leuba, PhD, PD K. Saini, PhD University Psychogeriatrics Hospital Lausanne-Prilly, Switzerland
A. Savioz, PhD Y. Charnay, PhD University of Geneva School of Medicine Geneva, Switzerland
1. Cruts M, Van Broekhoven C. Molecular genetics of Alzheimer's diease. Ann Med. 1998;6:560-565.
2. Savioz A, Leuba G, Forsell C, et al. No detected mutations in the genes for the amyloid precursor protein and presenilins 1 and 2 in a Swiss early-onset Alzheimer's disease family with a dominant mode of inheritance. Dement Geriatr Cogn Disord. 1999;10:431-436. MEDLINE
3. Boris N, Mestre-Frances N, Charnay Y, Tagliavini F. Spontaneous spongiform encephalopathy in a young adult rhesus monkey. Lancet. 1996;348:55. MEDLINE
4. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol (Berl). 1998;96:116-122. MEDLINE
5. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Straüssler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. 1994;8:41-48. MEDLINE
6. Perry RT, Go RCP, Harrell LE, Acton RT. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer's disease family. Am J Med Genet. 1995;60:12-18. MEDLINE
Funding/Support: This study was supported by grants 3100-045960.95 and 3100-043573.95 from the Swiss National Science Foundation.
http://jama.ama-assn.org/issues/v283n13/ffull/jlt0405-5.html
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Occasional PrP plaques are seen in cases of Alzheimer's Disease
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2 3 Once isolated, the agent must be capable of reproducing the disease in experimental animals. 4 The agent must be recovered from the experimental disease produced. 3. In the case of transmissible spongiform encephalopathies (TSEs), these postulates are not fulfilled in the following ways: 4. Unfulfillments of Postulate 1. 4.1 Transgenic mice with a codon 102 mutation involving a leucine substitution spontaneously develop spongiform encephalopathy with no detectable mutant prion protein (PrPsc). (Ref. Hsiao K.K. et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science (1990) 250: 1587-1590.) (J/S/250/1587) 4.2 Spongiform encephalopathy in zitter rats does not involved PrP. (ref. Gomi H. et al. Prion protein (PrP) is not involved in the pathogenesis of spongiform encephalopathy in zitter rats. Neurosci. Lett (1994) 166: 171-174.) (J/NSC/166/171) 4.3 Many viruses and retroviruses can produced spongiform encephalopathies without PrPsc involvement. (Ref. Wiley C.A. Gardner M. The pathogenesis of murine retroviral infection of the central nervous system. Brain Path (1993) 3: 123-128.) (J/BRP/3/123) 4.4 Experiments involving the transmission of the 'BSE agent' in mice produced symptoms of TSE, but in 55% no PrPsc could be detected. (Ref. Lasmesaz. C. et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science (1997) 275: 402- 405.) (J/S/275/402) 5. Unfulfillment of Postulate 2 5.1 Occasional PrP plaques are seen in cases of Alzheimer's Disease, where they coexist with the more usual beta amyloid plaques. (Ref. Baker H. F. Ridley R.M. Duchen L.W. Crow T.J. Bruton C.J. Induction of beta
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Wednesday, 23 August, 2000, 23:54 GMT 00:54 UK Alzheimer's and CJD 'similar' [Brain] Rogue proteins are thought to cause degenerative brain disorders Scientists have discovered striking similarities between Alzheimer's disease and the human form of mad cow disease, vCJD.
They believe the breakthrough could lead to drugs to treat both conditions.
Both are marked by a gradual and ultimately fatal deterioration of the brain and both are associated with rogue proteins.
Now Prof