Links to research with relevance to Alzheimers
another transmissible protein amyloidosis? what does this implicate with Alzheimer's and TSE, if anything?.........TSS
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
The pathogenesis of these diseases was compared to Alzheimer's disease at a
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.
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
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
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
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 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
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
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
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,
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
4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston:
5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification
of ischemic score in differentiation of dementias. Ann Neurol
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
11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn-dromes in
presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry
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
16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical
biopsy results in Alzheimer's disease: correlation with cognitive deficits.
17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of
clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann
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
20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The
neurological examination in patients with probable Alzheimer's disease. Arch
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
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,
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.
"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.
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
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
Table 1.--Summary of Clinical Presentation and Course*
Duration of Symptoms, y
Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral
Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal
Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy
Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic
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
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
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 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
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
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
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
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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
Occasional PrP plaques are seen in cases of Alzheimer's Disease
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
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??????