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Clinically diagnosed Alzheimer's disease Autopsy results in 150 cases.

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Clinically Diagnosed Alzheimer’s Disease:
Autopsy Results in 150 Cases
C. L. Joachim, MD,*t J. H. Morris, BM, BCh, DPhil,” and D. J. Selkoe, MDI-
One hundred fifty autopsy brains from patients with clinically diagnosed Alzheimer’s disease (AD) were examined
pathologically. The brains were received consecutively over a +year period from numerous sources as part of a
research program in which one brain half was frozen for biochemical studies and the other half was fixed in formalin.
One hundred thirty-one (87%) of the 150 cases fulfilled histological criteria for AD, with or without additional
findings, such as Parkinson’s disease or stroke. At least a minimal degree of amyloid angiopathy was found in every
brain showing histopathological abnormalities of AD. Twenty-three (18%) of the 131 AD brains had Lewy bodies in
neurons of the substantia nigra. Thirteen of the 19 non-AD cases were diagnosed as other neurodegenerative disorders.
In only 2 cases was no histological correlate for the patient’s dementia found. We conclude that (1)the many physicians
who diagnosed these cases did so highly accurately; (21 degenerative changes in the substantia nigra were more
common in patients with AD than has been reported for the general aged population; (3) amyloid angiopathy was a
constant accompaniment of AD, although its severity varied widely; (4) vascular dementia was rarely clinically
misdiagnosed as AD; (5) neuropathological findings were insufficient to account for the clinical syndrome of dementia
in less than 2% of cases; (6) the histological criteria established by the National Institutes of HealtWAmerican
Association of Retired Persons Research Workshop on the Diagnosis of Alzheimer’s Disease worked well in assessing
this large series.
Joachim CL, Morris JH, Selkoe DJ. Clinically diagnosed Alzheimer’s disease:
autopsy results in 150 cases. Ann Neurol 1988;24:50-56
The diagnosis of Alzheimer’s disease (AD) can be
made with certainty only by histological examination
of brain tissue, either on biopsy or at autopsy. Because
of its invasiveness and low likelihood of altering the
patient’s treatment, brain biopsy is rarely part of the
workup of idiopathic chronic dementia. Clinical studies involving AD patients must therefore wait until
autopsy tissue is available to confirm the diagnosis,
which may take years. A knowledge of the likelihood
that a clinical diagnosis of AD will be confirmed at
autopsy would assist in such areas as planning trials
of therapeutic agents, assessing the relative frequencies
of associated findings such as Parkinson’s disease or
strokes, counseling the patients’ families, evaluating results from studies using new radiological or clinical
laboratory techniques, and assessing any change in the
relative frequencies of causes of dementia over time.
We have reviewed the neuropathological findings in
150 brains from patients with the clinical diagnosis of
AD. The brains were consecutively received from
multiple sources in several states, and the diagnoses of
AD had been made by many different community and
academic physicians. What the patients whose brains
From the *Department of Pathology, and the ?Center for Neurologic Diseases, Brigham and Women’s Hospital, and the Departments of ?Neurology (Neuroscience) and *Pathology, Harvard
Medical School, Boston, MA.
we examined had in common was a family who requested an autopsy to confirm the clinical diagnosis of
AD and who wished to donate the tissue for research.
Detailed clinical information was not available in all
cases, and therefore no attempt was made to correlate
clinical and pathological findings beyond diagnosis of
the cause of the progressive late-life dementia. Instead,
the aim of the study was to determine the accuracy
of the clinical diagnosis of A D made by a wide range of
physicians in diverse clinical settings in a large patient
population, and also to define the range and frequency
of other conditions that have a similar clinical presentation.
Materials and Methods
Only limited clinical information was available on many of
the patients whose brains were received. However, minimal
data on all patients included sex, age, and a clinical diagnosis
of AD (presenile or senile dementia of the Alzheimer rype).
More than 100 physicians diagnosed these cases, and the
criteria that they used were not assessed in this study. The
brains were received over a 3-year period from January 1984
through December 1986. Donation of the brain tissue was
initiated by the family in almost all instances. The fresh
Received Aug 26, 1987, and in revised form Nov 3, 1987, and Jan
28, 1988. Accepted for publication Jan 30, 1988.
Address correspondence to Dr Joachim, Center for Neurologic Diseases, Thorn Research Building, Room 1226, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 021 15.
50 Copyright 0 1988 by the American Neurological Association
brains were halved sagittally; one half was frozen for biochemical studies and the other half formalin fixed. Following at least 2 weeks of fixation, each brain half was photographed, weighed, and cut coronally.
Sections of medulla, pons, midbrain, cerebellum, basal
forebrain (2 sections), hippocampus, basal ganglia, thalamus,
and neocortex from frontal, temporal, parietal, and occipital
lobes were taken on every brain. Other sections were taken
as indicated. The tissue blocks were manually dehydrated,
paraffin embedded, and sectioned at a thickness of 6 p.
Hematoxylin-eosin and modified Bielschowsky silver stains
[l] were done on every section. Two or more sections, one
of which was always occipital lobe, were stained with Congo
red and examined with a Zeiss polarizing microscope. Many
cerebral hemispheric sections were larger than the 3” X 1”
standard size (e.g., 3” x 1.5” or 3” x 2“ slides). If indicated,
portions of the frozen brain half were fixed in formalin and
examined pathologically.
Histological criteria used for the diagnosis of A D were
those outlined by the National Institutes of Health/
American Association of Retired Persons (NIHAARP) Research Workshop on the Diagnosis of Alzheimer’s Disease
[2], with the following two modifications: (1) plaque counts
were performed in frontal, temporal, and occipital neocortex; and (2) regions of primary motor, auditory, and visual
cortex were excluded from the counted areas. Cases that
were examined before the N I H A A R P criteria were published were reevaluated in light of these criteria. The
Bielschowsky silver stain was used because of its sensitivity
in detecting a large variety of plaque appearances (1-31.
All cases fulfilling histological criteria for AD, regardless
of the patient’s age, were labeled as AD. There was no separate category for senile dementia of the Alzheimer type.
Some age-related differences in A D pathological findings
were examined, however (see Results).
Histological criteria for the diagnosis of Parkinson’s disease were (1) the loss of pigmented neurons in the substantia nigra with reactive gliosis, to an extent that was clearly
greater than that seen in normal aging; and (2) the presence
of Lewy bodies in some remaining pigmented neurons (and
often in basal forebrain neurons). Brains with Lewy bodies
but only mild loss of pigmented neurons (not obviously
worse than that seen in normal aged brains) were reported as
having incidental Ltwy bodies.
In those brains where Lewy bodies were found in the
substantia nigra, insular cortex at the level of anterior commissure and parahippocampal cortex were examined for the
presence of cortical Lewy bodies.
Since most authorities regard the presence of Lewy bodies
as an essential feature for the diagnosis of Parkinson’s disease
[4], brains with extensive loss of pigmented neurons and
gliosis in the substantia nigra similar to that seen in Parkinson’s disease but in which Lewy bodies were not found on 3
separate levels of midbrain were designated as having substantia nigra degeneration without Ltwy bodies. In these brains,
Lewy bodies were also absent in basal forebrain, locus ceruleus, and vagal nucleus.
The histological criteria for the diagnosis of dementia due
to vascular causes were: (1) the presence of 1 or more large,
remote strokes (occupying most or all of a major vascular
territory in the examined hemisphere) in a patient known to
have had stroke(s) in the opposite hemisphere and/or (2) the
presence of severe cerebral lobar white matter ischemic damage (with diffuse loss of myelin and axons) accompanied by
severe and widespread changes of arteriosclerosis (Binswanger’s disease or subcortical arteriosclerotic leukoencephalopathy, IS]). Strokes were considered to have contributed
to the clinical dementia if sufficiently remote or larger in size
than lacunae (i.e., attributable to arterial rather than arteriolar occlusion), or if the vascular damage involved hippocampus, amygdala, thalamus, or basal forebrain.
The 150 patients ranged in age from 53 to 97 years
(average, 77 years). There were 81 men and 69
women. All carried a clinical diagnosis of AD, although 2 patients were considered to have combined
AD and vascular dementia, and 7 patients had the
additional diagnosis of Parkinson’s disease. Postmortem intervals ranged from 2 hours to 5 days. In 72
cases the right brain half was formalin fixed, in 67 cases
the left brain half was formalin fixed, in 10 cases the
entire brain was put into fixative, and in 1 case both
brain halves were frozen.
Gross Anatomical Findings
The fixed whole-brain weights, calculated by doubling
the measured weight of the fixed half, are shown in
Table 1. The lowest brain weight in the series, 700 g,
belonged to a woman with Pick’s disease, and the highest brain weight, 1,980 g, was from a man with Parkinson’s disease. Although the mean brain weight of
patients with Parkinson’s disease (with or without accompanying AD) was higher than that of patients with
AD alone, none of the mean brain weights listed in
Table 1 fali outside published 95% confidence ranges
for brain weights of aged normal subjects [6]. Individual brain weights were outside the 95% confidence
ranges, however, and the number of such brains in
each major disease category is shown in Table 1.
Remote strokes larger in size than lacunae were seen
in 14 of 150 cases, 11 of which also fulfilled histological criteria for A D and 3 of which were diagnosed as
vascular dementia. In only 1 case was there a macroscopic hemorrhage in the examined brain half. That
brain was from a 75-year-old man with extensive amyloid angiopathy, moderate cerebral atherosclerosis, and
remote temporal lobe hemorrhagehnfarction.
Malignant tumor was found in only 1 brain, which
was from a patient with severe histological changes of
A D and massive metastatic melanoma. Two small incidental meningiomas (less than 0.8 cm) were seen in
another A D brain.
No cases were considered to be due to normal pressure hydrocephalus alone. Two brains were received
with intraventricular shunts in place, but both showed
sufficient numbers of neocortical plaques and tangles
to warrant the diagnosis of AD. The possibility that
Joachim et al: Autopsy Diagnosis of Dementia
Table 1. Brain Weightsa and Number of Brain Weights Outside the 95% Confidence Limits for the A ge Groupb
Number of
Weights Outside
95% Limits“
Number of
Weights Outside
95% Limitsd
Patient Group
Brain Weight‘ (g)
Brain Weight‘ (g)
150 patients with clinical history
of A D
131 patients with pathological
findings of AD
23 patients with pathological findings of Parkinson’s disease, with
or without concomitant A D
980- 1,980
040- 1,600
1 (1)
24 (16)
16 (11)
20 (15)
900- 1,360
15 (11)
1 (4)
“Twice the measured weight of the half of bran fixed.
bSee reference [ b ]
‘Values are expressed as the range, mean values are in parentheses
“Values in parentheses indicate percent of total number of patients in the group.
A D = Alzheimer’s disease
Table 2. Microscopic Diagnoses in 150 Cases of Clinically Diagnosed Alzheimer‘s Disease
No. of
Alzheimer’s disease
Alzheimer’s disease and Parkinson’s disease
Alzheimer’s disease with contributing strokes
Alzheimer’s disease with incidental Lewy bodies
Alzheimer’s disease and spongiform encephalopathy
Total number of cases fulfilling histological criteria for A D
Parkinson’s disease
Vascular dementia
Nigral degeneration without Lewy bodies
Severe frontotemporal atrophy with neuronal loss and gliosis
Progressive supranuclear palsy
Pick‘s disease
Chronic meningoencephalitis
No abnormality beyond age-related lesions
these were cases of A D accompanied by treated normal pressure hydrocephalus cannot be ruled out.
Microscopic Findings
Microscopic diagnoses are shown in Table 2. Of the
150 cases, 131 fulfilled histological criteria for AD,
with or without additional abnormalities. The great
majority of these 131 cases easily fulfilled the A D
criteria; neocortical plaque counts were considered
borderline in only 6 cases, 4 of which had histological
findings of other conditions associated with dementia.
Of the remaining 19 cases in the series, 13 showed
pathological changes of other neurodegenerative diseases: there were 7 cases of Parkinson’s disease (4 of
which had neocortical plaques but not in sufficient
numbers to fulfill diagnostic criteria for AD); 2 cases of
Annals of Neurology
Vol 24
N o 1 July 1988
of Total
nigral degeneration without Lewy bodies (and no other
apparent abnormality); 1 case of progressive supranuclear palsy; 1 case of Pick‘s disease; and 2 cases of
severe focal frontotemporal atrophy with histological
findings of marked neuronal loss, gliosis, and neuropil
sponginess unaccompanied by Pick bodies or ballooned neurons {7]. There were 3 cases of dementia
attributable to vascular causes; all 3 brains showed extensive bilateral vascular damage and none fulfilled histological criteria for AD. One case was diagnosed as
chronic meningoencephalitis of unknown cause; the
pathological changes appeared to be long-standing, and
ongoing inflammation with microglial nodules was evident, although no organisms or inclusion bodies could
be found. The remaining 2 cases were considered to
show no changes beyond those associated with aging;
both had some neocortical plaques, but the numbers
were too low to warrant the diagnosis of AD.
There were 7 cases clinically diagnosed as both AD
and Parkinson’s disease. O n pathological examination,
4 of these showed only the pathological changes of
Parkinson’s disease, 2 fulfilled histological criteria for
both A D and Parkinson’s disease, and 1 showed only
A D with no pathological change in the substantia nigra
beyond that expected with aging.
At least 1 amyloid-bearing vessel was seen in all 131
cases fulfilling histological criteria for AD. The extent
of amyloid angiopathy varied widely. In some cases
affected vessels were seen in every cerebral cortical
section examined, whereas in others, up to 8 Congo
red-stained sections had to be evaluated before a single positive vessel was found.
There were no cases that fulfilled criteria for both
AD and vascular dementia; however, pathologically
documented strokes were considered to have contributed to the clinical dementia in 11 of the 131 cases of
Histological Szlbtypes among A D Cases
Histological features observed in AD cases-including
neocorticai plaque and tangle densities, degree of amyloid angiopathy, and presence of accompanying nigral
among the 131 cases fulfilling
histological criteria for AD. Two subtypes warrant further discussion.
Twentythree (18%) of the 131 cases fulfilling histological criteria for AD had Lewy bodies in neurons of the substantia nigra. In 14 of these (11% of AD cases), the
accompanying neuronal loss and gliosis in the substantia nigra were sufficiently severe to warrant a separate
pathological diagnosis of Parkinson’s disease (see Table
2). The remaining 9 cases were considered to be A D
with incidental Lewy bodies. Ten of the 23 AD cases
with nigral Lewy bodies had very low neocortical tangle numbers (all but 3 of the patients were 75 years
of age or older). In 3 of these 10 cases plaque numbers
were also low, and these cases barely fulfilled histological criteria for A D (see below).
Cortical Lewy bodies were found in varying numbers in 14 of 14 cases of combined A D and Parkinson’s disease, 7 of 8 cases of A D with incidental Lewy
bodies (1 case was excluded on technical grounds, as
the specimen had been frozen prior to fixation and the
ensuing freezing artifacts were judged to be too great
for accurate visuahzation of cortical Lewy bodies), and
5 of 7 cases of Parkinson’s disease. There was a very
large variation in the number of cortical Lewy bodies
present in the examined areas, and no clearly defined
group of cases with large numbers of cortical Lewy
bodies could be distinguished in any of the pathological subgroups.
NUMBERS. According to Tomlinson and colleagues
[8], small numbers of neurons with tangles may be
seen in neocortex in some intellectually normal, aged
patients. Cases in which neocortical tangles were scant
or absent in our series were therefore examined separately. In 28 of 131 cases of AD (21%), neocortical
tangIes were very rare or absent (Table 3). In this subgroup, the proportion of cases with concomitant conditions contributing to the clinical dementia (13/28;
46%) was higher than for the remaining 103 AD cases
in the series (13/103; 13%). Also, a somewhat larger
proportion of patients (22/28; 79%) was 75 years of
age or older as compared with the remaining AD patients in the series (70/103; 68%).
The many physicians who diagnosed the patients examined here did so quite accurately. Of 150 cases clinically diagnosed as AD, 131 (87%) fulfilled histological
criteria for AD, with or without additional findings
such as Parlunson’s disease or stroke. Our study is
limited by the fact that detailed clinical information
was not always available; therefore no correlations
could be made between histological findings and clinical manifestations of dementia. Instead, our study gives
Table 3 . Characteristics of Groups with Low Versus Moderate to High Numbers of Neocortical Tangles
No. of patients
Age range (yr)
No. (and percent) of patients 75 years or older
No. (and percent) of patients with additional abnormalities
contributing to dementia
Scant Numbers of
Neocortical Tangles
Moderate to High Numbers
of Neocortical Tangles
22 (79)
70 (68)
13b (13)
“Ten with Parkinson’s disease, 2 with vascular lesions, 1 with spongiform encephalopathy.
bFour with Parkinson’s disease, 9 with vascular lesions.
Alzheimer’s disease.
Joachim et al: Autopsy Diagnosis of Dementia
an indication of the accuracy of a clinical diagnosis of
A D as made by a wide range of physicians in a large
patient population. Because the brain donations were
requested by the patients’ families (rather than the
physician) and were therefore not received in any standardized fashion, the cases studied here cannot be considered representative of clinically diagnosed A D as a
whole. In spite of these limitations, the diagnostic accuracy reported here compares favorably with reports
from Sulkava and colleagues (22127 cases, 82%) C73
and Wade and colleagues (35/37 cases, 70%) [lo],
both of which were studies in which all patients were
examined by 1 physician and diagnosed using strict
clinical criteria. These degrees of accuracy are less than
the 11 of 11 reported by Martin and colleagues 1111,
but in that small study only ‘‘typical‘’ clinical cases with
an otherwise negative workup were chosen.
An important factor contributing to our high frequency of diagnosis of A D (and low frequency of
unclassified cases) was the use of the Bielschowsky
method for silver staining. The Bielschowsky stain has
the advantage of clearly demonstrating a wide range of
plaque and tangle morphologic characteristics and
demonstrates lesions that are not apparent using the
Bodian method [I, 31. Primitive plaques are far more
evident on Bielschowsky than Bodian stain, a feature
that must be taken into account when comparing
plaque counts from various studies employing different silver staining techniques. The members of the
NIWAARP Research Workshop on the Diagnosis of
Alzheimer’s Disease 123 emphasized the importance of
using optimal staining techniques to visualize A D lesions, and the choice of technique varies among laboratories. Some rely on thioflavin S staining 1121, a
method that was not used in our study but that is
considered very sensitive in detecting tangles and
plaques {I, 3, 131. Extensive sampling of cerebral cortex also helped achieve accurate histological diagnoses
in our series.
The inclusion of “plaque-only’’ A D in the histopathological criteria for older patients appears to be
appropriate, and such cases constituted 21% of the
total A D cases in our series. The NIWAARP criteria
for pathological diagnosis of A D are based on neocortical plaque counts and do not include assessment of
neocortical tangle numbers for all age groups; the committee noted that neurofibrillary tangles may not be
found in patients 75 years or older who fulfill clinical
criteria for A D and who have large numbers of neocortical plaques. Terry and coworkers examined 60
A D patients older than 74 years and found that 30%
lacked neocortical tangles 1121. After evaluating a wide
range of clinical, pathological, and biochemical factors,
the authors concluded that senile dementia of the Alzheimer type with and without neocortical neurofibrillary tangles are the same disease, though the pres54 Annals of Neurology Vol 24
No 1 July 1988
ence of tangles is associated with a tendency toward
greater severity. Our results are consistent with those
of Terry and coworkers in that 22 (24%’) of 92 A D
patients in our series aged 75 years or older had few or
no neocortical tangles. Because we lacked complete
clinical data on our patients, we were unable to use our
series to address the finding of Terry and coworkers
that there were no statistically significant differences in
degree of dementia or rate of progression in the
plaque-only A D group as compared with those patients who also had neocortical tangles.
Looking at the issue of plaque-only A D from another point of view, we examined patients of all ages
with scant or absent neocortical tangles (281131 A D
cases (see Table 3). Patients in this subgroup were
more likely to have additional conditions such as Parkinson’s disease or stroke ( 13/28, 46%) than pacients
with moderate to large numbers of both neocortical
plaques and tangles (13/103, 13%). A greater proportion of patients was aged 7 5 years or older (22128,
77%) as compared with the remaining A D patients in
the series (70/103, 689%).
Nigral Lewy bodies were seen in 23 (18%’)of 131
cases that fulfilled histological criteria for AD. i n I4
cases (11% of A D cases), the nigral neuronal loss and
gliosis were sufficiently severe to warrant the additional pathological diagnosis of Parkinson’s disease.
The remaining 9 cases were considered to have incidental Lewy bodies (nigral neuronal loss nor obviously
worse than that associated with aging). A clinical history of Parkinson’s disease was reported to us for only
2 of the 23 A D cases with nigral Lewy bodies (each of
which fulfilled histological criteria for both A D and
Parkinson’s disease). Since aged patients show a spectrum of nigral degenerative changes, including Lewy
bodies, the decision as to the degree of neuronal loss
and gliosis necessary for a pathological diagnosis of
Parkinson’s disease is necessarily arbitrary. Even so,
the presence of nigral Lewy bodies in 18% of AD
cases is clearly higher than the expected 3 to 7%’ reported for large series of normal subjects 114, 151. The
presence of A D histopathological abnormalities in
many demented patients with Parkinson’s disease is
well recognized 116- 191, but the frequency with
which nigral degenerative changes accompany the
pathological findings of A D has received less attention.
In one neuropathological study of 20 AD brains, Ditter and Mirra [20) found varying degrees of nigral
degenerative changes (Lewy bodies, neuronal loss,
gliosis) in 11 patients (55 %). The neuropathological
results from these studies and our own suggest that
A D and Parkinson’s disease occur together more frequently than would be expected by chance, regardless
of whether the patient presents with Parkinson’s disease or dementia.
Cortical Lewy bodies were found, in varying num-
bers, in 21 of 22 cases of A D with nigral Lewy bodies
(1 case of A D with nigral Lewy bodies was excluded
for technical reasons). Varying, but generally smaller,
numbers of cortical Lewy bodies were also seen in 5 of
7 cases diagnosed as Parkinson’s disease. No clearly
defined group of cases with a notably large number of
cortical Lewy bodies was identified in this series. The
role of cortical Lewy bodies as a histological correlate
of dementia still needs to be clarified, and the question
of which cases might merit the diagnosis of diffuse
Lewy body disease is complicated by the fact that reported cases of diffuse Lewy body disease frequently
have accompanying plaques and tangles [2 1, 22). This
adds a further dimension to the apparent association of
Alzheimer-related and parkinsonian changes discussed
Amyloid angiopathy of widely varying degree is, in
this series, an invariable accompaniment of AD. At
least 1 amyloid-bearing vessel was seen in each of 131
cases fulfilling histological criteria for AD. Glenner
and coworkers {23) found amyloid angiopathy in 47 of
51 cases (92%) of pathologically verified AD. Mandybur 124) observed this microvascular change in 13 of
15 AD cases. Present protein chemical and immunocytochemical studies indicate that the principal protein
subunit of amyloid filaments in A D (the beta protein)
is shared between amyloidotic meningeal vessels and
senile plaque cores, although the latter may contain a
more modified form of the protein [25, 261.
Intracerebral hemorrhages were rare in our series.
Only 1 case with a macroscopic hemorrhage, possibly
attributable to amyloid angiopathy, was seen. This is in
contrast to other reports of hemorrhage in cases with
A D changes and cerebral amyloid angiopathy 127301. The reason for the low incidence in our series is
not clear. More hemorrhages may have been seen had
both brain halves been examined pathologically. Also,
it is possible that referring pathologists may not have
sent us brains with known intracerebral hematomas.
Clinically, dementia due to vascular causes was
rarely confused with AD. Only 3 (2%) of the 150
cases reported here were diagnosed pathologically as
vascular dementia, and none of these 3 fulfilled histological criteria for A D even though 1 of them had
been considered to be a case of combined A D and
vascular dementia by the referring clinician. None of
the A D cases in our series fulfilled pathological criteria
for both A D and vascular dementia; however, strokes
were judged to have contributed to the dementia in 11
(8%)of 131 cases of AD. Our evaluation of strokes in
this series was limited by the fact that only one brain
half was examined. However, other recent studies also
suggest a relatively low incidence of stroke as a sole or
contributing cause for Alzheimer-type dementia. For
example, of 39 patients with a clinical diagnosis of A D
in the study by Wade and colleagues {lo], 33 cases
(85%) were pathologically diagnosed as AD; 2 (5%) as
mixed AD/multiinfarct dementia; and 1 (3%) as multiinfarct dementia alone. In the study by Sulkava and
colleagues {9], no major strokes were seen in a group
of 27 cases. At least some of the decrease in frequency
of stroke in these patient groups can be attributed to a
general decline in the incidence of stroke {31). The
advent of computed tomography scanning has also allowed better visualization of strokes, and some patients with multiple infarcts on computed tomography
scan may be diagnosed as having vascular dementia
rather than A D and thus not included in a study such
as ours. Autopsy evaluation is essential in assigning
a cause for dementia, since patients with multiple
strokes may also have extensive histological findings of
A D {lo, 32).
The diagnostic criteria established by the NIW
AARP Research Workshop on the Diagnosis of Alzheimer’s Disease {2] worked well in assessing this large
series. The importance of using a highly sensitive histological method to identify plaques cannot be overemphasized. Using these criteria, as well as standard
criteria for other dementing diseases, some histological
correlate for dementia was found in all but 2 cases,
in which no abnormalities were seen beyond those
expected with normal aging. It is difficult to know
whether this small number of undiagnosed cases implies that the criteria are too lax, allowing some patients who have only age-related changes plus some
other undetected cause of dementia to be assigned the
diagnosis of AD. This question could be addressed by
the histological study of a group of aged normal subjects. However, to be most useful, such a control
group should be examined carefully for the presence
of dementia prior to death {8).
Histological examination of the brains of demented
patients remains a necessary adjunct to clinical evaluation. In view of the accelerating pace of biochemical
and molecular biological studies of postmortem AD
brain tissue, it is important that detailed histopathological results of A D brain tissue donation programs be
reported on a regular basis.
This work was supported in part by Physician Scientist Award
K12AG00294 (C. L. J.) and N I H grants AGO2741 and AGO6173
(D. J. S.). D. J. S. is the recipient of a Metropolitan Life Foundation
Award for Medical Research.
The authors thank Ruth Hoare and Marian Slaney, Neuropathology
Histology Technicians, for excellent work. We are grateful to Sharon Tramer for typing and editorial assistance.
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