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Clinical pathological and neurochemical changes in dementia A subgroup with preserved mental status and numerous neocortical plaques.

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Clinical, Pathological, and
Neurochemical Changes in Dementia:
A Subgroup with Preserved Mental Status
and Numerous Neocortical Plaques
Robert Katzman, MD,* Robert Terry, MD,” Richard DeTeresa, BS,” Theodore Brown, PhD,?
Peter Davies, PhD,*$ Paula Fuld, PhD,“ Xiong Renbing, MA,? and Arthur Peck, MDq
Postmortem examination was performed on 137 residents (average age 85.5 years) of a skilled nursing facility whose
mental status, memory, and functional status had been evaluated during life. Seventy-eight percent were demented
using conservative criteria; 55% had characteristic Alzheimer’s disease. Choline acetyltransferase and somatostatin
were significantly reduced in the brains of patients with Alzheimer’s disease as compared with age-matched nursing
home control subjects, although the degree of the reduction was less severe than found in subjects less than 80 years of
age. Ten subjects whose functional and cognitive performance was in the upper quintile of the nursing home residents,
as good as or better than the performance of the upper quintile of residents without brain pathology (control subjects),
showed the pathological features of mild Alzheimer’s disease, with many neocortical plaques. Plaque counts were 80%
of those of demented patients with Alzheimer’s disease. Choline acetyltransferase and somatostatin levels were intermediate between controls and demented patients with Alzheimer’s disease. The unexpected findings in these subjects
were higher brain weights and greater number of neurons (> !90 p,m2 in a cross-sectional area in cerebral cortex) as
compared to age-matched nursing home control subjects. These people may have had incipient Alzheimer’sdisease but
escaped loss of large neurons, or alternatively, started with larger brains and more large neurons and thus might be
said to have had a greater reserve.
Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A. Clinical, pathological,
and neurochemical changes in dementia: a subgroup with preserved mental status and
numerous neocortical plaques. Ann Neurol 1988;23:138-144
The modem era of biomedical interest in Alzheimer’s
disease is based on the assumption that the classical
markers of the disease in brain, neuritic plaques and
neurofibrillary tangles in neocortex and hippocampus,
are related to dementia, the clinical expression of the
disorder [9, 10). The relationship of dementia and
pathological changes received quantitative confirmation in the prospective clinical-pathological study of
patients in a nursing facility and chronic care hospital
in Newcastle-on-Tyne (UK) carried out by Blessed
and co-workers 12) and Tomlinson and associates 121).
These investigators found that scores on functional and
mental status assessments obtained in the year before
death correlated well (correlation coefficients 0.7 and
0.6, respectively; numbers confirmed by others [l 1,
12)) with the number of neuritic plaques in sections of
neocortex prepared for microscopy; they also found
that the presence of neurofibrillary tangles in neocortex correlated well with the presence of dementia. We
have had the opportunity to carry out a similar prospective study in a 500-bed skilled nursing facility, and
here we report the analysis of data on 137 subjects
who underwent postmortem examination. In addition
to mental status scores and plaque and tangle counts,
our analyses include memory and fluency scores,
computer-assisted counts of cells in neocortex, and
measures of the neurotransmitter markers choline
acetyltransferase (ChAT) activity and somatostatin-like
immunoreactivity.
There is a close relationship between the degree
of dementia measured during life and quantitative
neuropathological changes found post mortem, with
two important exceptions: (1) brains of nondemented
elderly patients sometimes contain pathological fea-
From the *Department of Neurosciences, University of California,
San Diego, La JoIIa, CA, the +Department of Computer Science,
Queens College, New York, the Departments of $Pathology,
$Neuroscience, and “Neurology, Albert Einstein College of
Medicine, Yeshiva University, New York,and the “Department of
Psychiatry, Jewish Home and Hospital, New York, NY.
Received June 16, 1987, and in revised form July 31. Accepted for
publication July 3 2 , 1987.
Address correspondence to Dr Katzrnan, Department of Neurosciences, M-024, UCSD School of Medicine, La Jolla. CA 92093.
138 Copyright 0 1988 by the American Neurological Association
tures in a degree diagnostic of Alzheimer’s disease; and
(2) conversely, there are occasional brains of demented
subjects that do not contain markers of Alzheimer’s
disease or of other disorders known to produce dementia that can be detected by neuropathological examination. The discovery of such exceptions led some
neuropathologists in the 1950s to doubt the importance of Alzheimer brain changes as a cause of dementia in the elderly 1161. In this study we present data
that help explain the first of these exceptions.
Methods
Subjects
We report data on 137 subjects who were interviewed at
least once during life and in whom postmortem examination
was performed. All of the subjects resided at the Jewish
Home and Hospital for the Aged, a skilled nursing home in
New York. The average age of the 137 subjects was 85.4
years; 111 were women, 26 were men. The subjects were
predominantly lower middle class and Jewish; median education was 9 years of school. The study had been approved by
the human subjects committees at both the Albert Einstein
College of Medicine and the Jewish Home and Hospital.
Clinical Data
Mental status was evaluated annually using an informationmemory-concentration (IMC) test described by Blessed and
colleagues [ 2 } and adapted for use in the United States {7}.
This modified test includes 26 items with 33 possible errors.
The test-retest reliability over intervals of 1 to 6 weeks is
0.86 120); the remarkable stability of this test on annual
retesting is reported elsewhere [3}. We score the Blessed
IMC as the number of errors made. Memory was tested
using the Fuld object memory test 17, 87, in which the subjects are asked to recall 10 physical objects, each one of
which had been handled manually, observed, and named.
After a distracting task (category fluency), the subject was
asked to recall the 10 objects; the number of correct recalls
was scored as the first retrieval. The subject was then reminded verbally of the objects not recalled; again recall was
sought after an intervening task. This procedure of selective
reminding was repeated a total of five times, and the total
number of correct recalls across the five retrievals was scored
as the total recall. Category fluency is the number of words in
a specified category retrieved in 1 minute. In this analysis we
report the sum of the retrievals for three categories. Twenty
of the patients were too demented to give their own name
and could not be tested.
New York State required that all patients entering a
skilled nursing home must evidence functional impairment
according to a strict scoring system. In addition, we assessed
functional ability yearly using a scoring system based on a
modification of the functional evaluation of Blessed and coworkers [2}. The score (Fl) was based upon subjects’
difficulty with eating, dressing, incontinence (each scored 0
to 3); help needed to find objects in their room; and ability
to find their way around the nursing home floor (each scored
0 to 2), with a maximum score of 13 for the most impaired.
A second score (F2) was based on the floor aide’s evaluation
of the behavior of the patient, modified from the behavioral
evaluation of Blessed and co-workers [Z]; there were 11
questions scored 0 to 2, with a maximum score of 22 for the
most disturbed. In addition to the mental status and functional evaluations, clinical diagnoses and medications were
recorded during each annual survey.
Patients were arbitrarily classified as clinically demented or
nondemented without regard to pathological findings. The
diagnosis of dementia was made if the Blessed IMC score
was 10 or higher. The diagnosis of dementia requires evidence of both functional and cognitive impairment: The fact
that the overwhelming majority of subjects had been admitted to a skilled nursing facility under New York State
rules was evidence per se of functional impairment; the score
of 10 errors on the mental status test was evidence of cognitive impairment. This cutoff is consistent both with the experience of Blessed and associates [Z] and the finding in two
independent studies that apparently nondemented, active,
elderly persons living in the community score fewer than 8
errors (n = 54 [7); n = 488 [Katzman and colleagues, in
preparation)). Because the classification of demented or
nondemented is dichotomous and based upon a mental
status examination score, there were likely to be subjects
who were incorrectly classified. The cutoff at 10 errors on
the IMC was deliberately conservative so that all of these
subjects were likely to have been demented. Moreover, in
80% of the subjects classified as demented, the dementia
had been noticed by the medical staff. Diagnoses by the
medical staff included organic brain disease, chronic organic
brain syndrome, cerebral arteriosclerosis, senility, dementia,
and primary degenerative dementia. In regard to the variety
of diagnostic terms used, it should be noted that this study
began 3 years before publication of the Diagnostic and Statistical Manual III [I} diagnostic criteria.
If the subjects classified in this study as nondemented
were compared with a group of active volunteers residing in
the community who were aged 75 to 85 years, 90% of the
community sample would be found to have a score of 5
errors or less, whereas 55% of those in our group classified
as nondemented were found to have a score of 5 errors or
less. However, it must be recognized that the mental status
scores used in this analysis of an autopsy series were the last
scores obtained before death; therefore the likelihood of
intercurrent illnesses affecting the score was much greater in
the nursing home than in the community sample. None of
the subjects classified as nondemented was clinically diagnosed as demented using any of the above diagnoses. Nevertheless, it is likely that some of the subjects classified as
nondemented did in fact have a mild dementia.
Pathology
Details of the pathological workup have been reported previously [197. Postmortem examinations were carried out
within 24 hours of death. The brain was divided sagittally
and the right hemibrain frozen at - 70” C for chemical analysis; the left hemibrain was fixed in 10% buffered formalin.
Total brain weight was calculated by doubling the left hemibrain value, measured after at least 7 days of fixation.
Histopathological evaluation of each of these specimens
involved examination of 8 - ~ mhematoxylin-eosin-stained
Katzman et al: Normal Cognition with Plaques
139
sections obtained from midfrontal, superior temporal, and
inferior parietal cortex, cingulate gyrus, visual cortex, hippocampus, amygdala, substantia innominata, substantia nigra,
locus ceruleus, and cerebellar vermis. Neocortical and hippocampal neuritic plaques were counted on 10+m sections
stained with 1% thioflavine S and viewed with ultraviolet
illumination at x 125; tangles were counted in the same
sections at x 500 magnification. Plaques and tangles were
counted in sections from the cortical ribbon along the sides
of the gyri that were examined morphometrically or in the
pyramidal cell layer of hippocampus, predominantly in CA 1.
In some instances, silver impregnations were used in addition to the thioflavine S, and in most cases multiple additional sections of neocortex were examined. Cells were
counted on 20-pm cresyl violet preparations from midfrontal, superior temporal, and inferior parietal cortex, using a
Quantimet for morphometry. Contiguous cells were separated from each other and blood vessels were eliminated
from the counting procedure by a combination of manual
and automatic editing. Cells were detected by their cytoplasmic density as compared to neuropil and cell numbers were
determined by size class in an area 600 pm wide by the full
thickness of the cortex. Size classes used in these analyses
were 5 to 40 pm', 41 to 90 pm2, and greater than 90 pm2.
Cells smaller than 40 pm2 were almost all glia, whereas those
larger than 40 pm2 were almost all neurons.
Plaques and tangles were counted in 8-pm sections stained
with thioffavine S. Using a 10 x objective lens, plaques were
counted in three fields along the side of the gyrus, and the
numbers were averaged. Tangles were assayed in the same
way, but using a 40 x objective lens.
Pathological diagnoses were made by one of us (R. T.)
taking into account all of the available gross and microscopic
data, including counts of plaques and tangles but not including morphometric or neurotransmitter data. Most of the
diagnoses were made before publication of the recent pathological criteria [ 131, but diagnoses in borderline cases have
been reviewed since those criteria became available. A few
subjects who did not meet the diagnostic criteria in terms of
the number of plaques in neocortex still received a diagnosis
of mild senile dementia of the Alzheimer type (SDAT)
based on the numbers of plaques or tangles observed in
other regions such as amygdala and hippocampus. Diagnosis
of vascular changes causing dementia required evidence of
infarction of at least 50 cm3 of cerebral hemisphere or the
presence of numerous lacunes and white matter changes.
Acute cerebral infarctions occurring terminally were not included in this category.
Cbemistty
Analyses for ChAT and somatostatin were performed on
samples from the right hemibrain that had been frozen at
- 70" C. Reported here are data from midfrontal, superior
temporal, and inferior parietal cortex and hippocampus, the
regions analogous to those in the left hemibrain that had
been used for morphometry and neuritic plaque count.
ChAT activity was determined by the method of Fonnum
after homogenization of tissue samples in 1 m~ ethylenediaminetetraacetic acid containing 0.1% Triton X-100.
Protein concentration was determined by the Lowry method.
140 Annals of Neurology Vol 2 3
N o 2 February 1988
Table I. Clinical and Pathological Diagnoses
SDAT Pathology
Pathological
Diagnosis
N o SDAT Pathology
Pathological
Diagnosis
n
n
CLINICALLY NONDEMENTED
Group A
SDAT only
Group A'
SDAT
Park
SDAT + Vasc
SDAT Other
Total
+
+
5
2
3
0
10
Group B
No brain lesions
Group B'
Park
Vasc
Other
Total
CLINICALLY DEMENTED
Grow c
SDAT only
Group C'
SDAT
SDAT
SDAT
+ Park
+ Vasc
+ Other
Total
51
4
8
13
76
No brain lesions
Group D'
Park
Vasc
Other
Total
SDAT = senile dementia of the Alzheimer type; Park
son's disease; Vasc = vascular disease.
12
5
8
7
32
=
Parkin-
ChAT activity is expressed as nmol acetylcholine/hr/lOO mg
protein.
Somatostatin assays were carried out using a radioimmunoassay in which the antibody to somatostatin, '251-Tyrlsomatostatin, was incubated with sample or standard for 48
hours at 4" C, and free and bound labeled somatostatin were
separated by absorption of free tracer on dextran-coated
charcoal. The assay, which has been previously described [4],
could detect 5 pg of somatostatin per tube and gave a linear
response over the range of 12 to 500 pg. Somatostatin is
expressed as n g h g protein.
Statistical Analyses
Descriptive statistics, including mean and standard deviation,
are reported for many of the data. Significance tests reported
for the individual items were based on rank order using the
Kruskal-Wallis statistic. To compare several numbers between the groups, we summed the k individual KruskalWallis values and tested against a x2 distribution with k degrees of freedom.
Results
Classification of Clinical and Pathological Diagnoses
Table 1 shows the clinical and pathological diagnoses.
Of the 137 patients, 108 (79%)met the clinical criteria
for dementia; 76 patients (55%) met both clinical and
pathological criteria for Alzheimer's disease. Thus,
70% of the clinically demented subjects were shown
to have Alzheimer's disease. The number of patients
with clinical dementia who had Parkinson's disease and
vascular disease were in each case approximately
equally divided between those with coexistent Alzheimer changes and those without. The category of
Table 2. Clinical MeaSm-eJa
Nondemented
Demented
B
A
n
Mean
86.7 f 3.9
19
83.8
?
17
16
17
3.5
3.5
4.3
?
?
10
1.2 t 2.0
2.0 ? 2.6
3.8 ? 3.3
10
10
10
29.9 ? 12.8
5.3 f 2.5
24.9 f 8.0
17
17
16
26.8
5.1
29.4
&
-t
Measure
n
Mean
Age (yr)
Function
Flb
F2
Blessed IMCb
Retrieval
Five trialsb
First trialb
Fluency(threecategories)b
10
8
8
?
SD
D
C
?
-t
n
M e a n ? SD
7.1
32
85.7 t 6.6
?
?
4.5
4.0
?
6.9
26
25
26
7.6 f 5.2
4.1
3.7
18.6 t 5.8
18
18
17
17.2
3.4
14.4
n
Mean
8.4
76
85.5
?
4.1
4.1
2.8
63
59
60
8.5
6.2
22.7
14.2
2.1
11.3
46
46
41
8.4 2 10.3
1.8 5 2.0
13.1 ? 7.4
?
SD
?
SD
*
10.5
1.8
f 6.4
f
?
“Patients in Groups A, C = Alzheimer’s pathology; B = no brain lesions; D = no Alzheimer’s pathology.
”p < 0.001, comparison of groups using rank order (Kruskal-Wallis).
IMC
=
information-memory-concentration test.
“other” diagnoses included astrocytoma, cerebellar
cyst, cerebellar degeneration, hydrocephalus, laminar
necrosis of Sommer’s sector, multiple sclerosis, and
thalamic gliosis.
We compared data on the subjects in Group A with
those in Group A’ (Table 1) and so on in regard to
clinical measures, brain weight, plaques, tangles, cell
counts, ChAT, and somatostatin and found no significant differences except in the demented patients
with Parkinson’s disease who had lower frontal ChAT
(n = 3). We therefore collapsed our data into four
groups: Group A, nondemented with SDAT pathology (n = 10); Group B, nondemented without SDAT
or other brain lesions (n = 19);Group C, demented
with SDAT pathology (n = 76); and Group D, demented without SDAT pathology (n = 32).
The subjects in each group were similar in regard to
age and sex. The respective mean ages were 86.7 years
in Group A, 83.3 years in Group B, 85.6 years in
Group C, and 85.7 years in Group D. All groups were
predominantly female (81% for entire sample; 7 in
Group A, 17 in Group B, 62 in Group C, and 25 in
Group D).
The frequency distribution of IMC error scores was
essentially flat over the range of error scores from 0 to
19, with 1 to 5 subjects for each error score, and then
increased at error scores of 20 and above, with 4 to 7
subjects for each score. In particular, there were only 4
subjects with a score of 0, 3 with a score of 1 error,
and 1 with a score of 2 errors, so only 5% of the entire cohort fell within this range. In regard to clinical measures (Table 2), Group A (nondemented with
plaques) is significantly different from Group C (p <
0.001; demented, with plaques) on all six measures of
functional and cognitive performance. It is also important to note that the performance of Group A sur-
passed that of Group B control subjects on five of
these measures and was similar on the sixth measure
(fluency to three categories).
In regard to brain weights (Table 3), it is noteworthy
that Group A brains were heavier than those of any
other group. In regard to measures of plaques and
tangles, Group A is intermediate between B (lower)
and C (higher). This order for plaques and tangles is
significant at p < 0.001 for all eight regions counted.
The means of plaque counts of Group A are, however,
closer to those of Group C; the means of tangle counts
are closer to those of Group B.
The unexpected finding in this series (Table 4 ) is
that the number of large neurons in Group A exceeds
that in Groups B, C, and D in three regions in which
cells were counted. However, this finding is significant
only in the parietal region. A similar order was observed in brain weight. The probability of this particular order occurring by chance on these four measures
is 6-*, less than l o p 3 . Using the Kruskal-Wallis statistic for the sum of the values of large cell types and
brain weight, Group A differs from Group B at p <
0.05, and Group A differs from Group C a t p < 0.001.
Tables 5 and 6 show neurotransmitter markers in
the four groups. It can be seen that in general the
average values for neurotransmitter markers in Group
A are intermediate between the average values of the
control group, Group B, and the values in the Alzheimer demented group, Group C, in all seven sets
of values. The probability of this particular ordering
occurring randomly is 6-’, which is less than lo-*.
In comparison of the neurotransmitter markers for
Groups A and B, the summed Kruskal-Wallis statistic
(7.36) is not significant, but Group A differs from
Group C at a probability o f p < 0.01 (summed Kruskal-Wallis value 16.9).
Katzman et al: Normal Cognition with Plaques
141
Table 3. Pathological Markers”
~
B
* SD
n
Mean
Brain weight (gm)d
Neuritic plaquesb
Frontal‘
Parietal‘
Temporal‘
Hippocampal‘
Neurofibrillary tanglesc
Frontal‘
Parietal‘
Temporal‘
Hippocampal‘
10
1184.8 ? 174
~~
Demented
A
Marker
~~
~
Nondemented
C
n
Mean
19
1084.4
f
SD
?
D
n
M e a n ? SD
n
Mean
108
75
1055.5
112
32
1104.6 ? 110
1.1 2
0.9 ?
1.0 f
0.4 ?
2
10
10
10
8
17.1 Ifr 10.8
14.6 ? 11.2
12.5 7.6
1.2 f 3.5
*
19
19
19
19
0.6 ? 1.5
1.2 f 2.3
0.6
1.6
0.05 f 0.2
69
69
68
63
20.2 2
19.3 2
17.8 ?
3.9 %
13.2
13.1
12.1
5.6
30
28
29
29
10
10
10
9
0.0 ? 0.0
0.0 ? 0.0
0.20 ? 0.42
1.88 f 2.85
19
19
19
19
0.0
0.0
0.05
1.74
69
69
68
63
0.68 2 1.89
0.95 2 1.94
2.49 ? 4.11
6.63 t 7.15
30
28
29
28
?
I+_
?
0.0
0.0
0.23
3.62
?
0.0
0.04
0.03
1.25
SD
f
f
?
?
2.0
2.6
2.6
1.3
0.0
0.19
0.18
3.02
‘Patients in Groups A, C = Alzheimer’s pathology; B = no brain lesions; D = no Alzheimer’s pathology.
bPer microscopic field, x 125.
‘Per microscopic field, X 500.
‘ p < 0.01; ‘ p < 0.001, comparison of groups using rank order (Kruskal-Wallis).
Table 4. Morphometric Analyses: Number of Neocortacal Cells as Function of Cell Size“
Nondemented
B
A
Area
Frontal cortex
Glia
Small neurons
Large neurons
Parietal cortex
Glia
Small neurons
Large neuronsb
Temporal cortex
Glia
Small neurons
Large neurons
Demented
n
Mean f SD
n
Mean
8
8
8
1570 ? 329
857 ? 274
137 f 64
19
19
19
9
9
9
1663 f 559
1103 ? 366
145 2 60
8
8
8
1724 ? 484
814 f 203
133 f 89
C
* SD
D
SD
n
Mean t SD
n
Mean
1941 ? 500
847 ? 225
111 f 49
63
63
63
1778 ? 577
840 ? 212
98.9 f 58
25
25
25
1752 f 526
804 f 212
120 75
18
18
18
1941 f 349
879 ? 216
99.8 rf: 34
59
59
59
1788 ? 508
863 f 216
74 ? 43
22
22
22
1806 f 678
844 ? 151
88 f 36
19
19
19
1878 f 415
788 217
99.6 f 65
57
57
57
1756 ? 513
796 ? 197
72.5 ? 43.5
19
19
19
1813 ? 374
785 f 229
91.6 62
*
f
*
*
“Patients in Groups A, C = Alzheimer’s pathology; B = no brain lesions, D = no Alzheimer’s pathology. Glia cells are less than 40 pm’; small
neurons are 40-90 pm’, and large neurons are over 90 pm’.
bp < 0.001, comparison of groups using rank order (Kruskal-Wallis).
Discussion
The subjects in this study were very elderly residents
of a skilled nursing facility; their average age was 85.5
years. It is interesting, in this very elderly sample, to
compare the histological, neurotransmitter, and morphometric data on the demented patients with Alzheimer’s disease relative to the control group. Reductions in ChAT and somatostatin in the demented
patients with Alzheimer’s disease (Group C) compared
to the controls (Group B) are significant; however, the
extent of the reduction is less than that reported in
series with younger subjects or wider age ranges, consistent with the reports of Rossor and co-workers [l5].
142 Annals of Neurology Vol 23 No 2 February 1988
Thus, Group C (demented with Alzheimer’s disease)
values for both ChAT and somatostatin are reduced to
38 to 55% of the values of the control Group B but in
younger subjects the reductions are usually 50 to 90%
[4, 67. In a preliminary analysis of the first half of the
subjects in the present series we found that there were
very high correlations of the mental status and retrieval
test scores with total number of cortical plaques and
with ChAT, particularly hippocampal ChAT [lZ},
similar to what has been found in series with younger
subjects [2, 141. In regard to the morphometric data,
Terry and co-workers [18) had found that the number
of large neurons was reduced 40 to 46%, whereas in
Tabh 5 . Neurotransmitter Markers”
Nondemented
B
A
Neurotransmitter
Choline acetyltransferaseb
Frontald
Parietale
Temporale
Hippocampal‘
Somatostatin‘
Frontald
Parietald
Temporald
Demented
C
D
n
Mean? SD
n
Mean
&
SD
n
8
8
8
6
357 f 191
295 f 156
433 f 220
1087 f 595
12
12
12
12
521 ?
512 ?
640 -r1501 ?
234
400
339
803
46
45
46
42
288 2 191
223 & 193
294 ? 293
753 2 823
19
19
19
17
411 -r- 159
371 ? 217
495 f 306
1166 ? 446
4
4
1.52 -r- 0.86
1.70 ? 0.79
1.76 ? 1.00
6
40
39
39
0.78 -+- 0.64
1.27 2 1.19
1.10 2 1.37
15
15
15
1.49 ? 0.89
2.05 ? 1.78
2.11 2 1.20
4
2.05 f 1.81
2.42 ? 3.22
2.33 ? 1.51
6
6
Mean
?
SD
n
M e a n ? SD
“Patients in Groups A, C = Alzheimer’s pathology, B = no brain lesions, D = no Alzheimer’s pathology.
nmol acetylcholine produced/hour/100mg protein.
‘In nglmg protein.
dp < 0.01; ‘p < 0.001, comparison of groups using rank order (Kruskal-Wallis).
Table 6. Neurotrammitter h e l as Percentage
of Control Group B”
~
~
~~
Demented
Nondemented
Neurotransmitter
Choline acetyltransferase
Frontal (%)
Parietal (%)
Temporal (%I
Hippocampal (%)
Somatostatin
Frontal (%)
Parietal (%)
Temporal (%)
C
D
55
30
79
72
77
77
38
52
47
73
85
91
A
68
58
68
72
74
70
76
44
46
”Patients in Groups A, C = Alzheimer’s pathology; B
lesions; D = no Alzheimer’s pathology.
=
no brain
the present series the reduction is about 25%. Thus,
reductions in ChAT, somatostatin, and large neurons
continue to be important features of Alzheimer brains
in the ninth decade of life. It should be noted, however, that in the Alzheimer brains in this series there
were many neuritic plaques in the neocortex but fewer
neurofibrillary tangles than would be found in a series
of brains from patients with Alzheimer’s disease who
died before age 80. We have shown that patients with
Alzheimer’s disease without neocortical neurofibrillary
tangles do not differ in other morphological or chemical measures from the more typical patient with both
c191.
In the present series, 79% were clinically demented
using very conservative criteria and 5 5 % had the clinical and histological changes characteristic of Alzheimer’s disease. The latter then represented 70% of
the demented subjects. These values are similar to
those reported by others in both clinical and posunortem studies of nursing home residents 117). Among
the demented subjects in our series, other pathological
diagnoses included Parkinson’s disease (5 %), cerebrovascular pathology (7%), and a variety of miscellaneous conditions (7%). In 11% of the clinically demented subjects there were no histological changes in
the cerebral hemisphere that could account for the
clinical state. There was no evident significant change
in the neurotransmitters, cell counts, or other postmortem measures that would explain the dementia.
We have reviewed the clinical charts and laboratory
data on these subjects and have not found evident
explanations of their cognitive impairment. The subjects in this group might have had metabolic or toxic
conditions not diagnosed during life or neuronal
changes not evident in light microscopic examinations,
but our data do not provide a reasonable explanation.
In contrast, our study does provide remarkable
findings in regard to Group A, subjects with preserved
mental status but definite histological changes of the
Altheimer type. These nondemented subjects with
Alzheimer changes were functionally and cognitively
as intact as those in the control group, the nondemented subjects who were free of histological markers
of brain pathology. In fifteen separate regional measures of plaques, tangles, and neurochemical markers,
the nondemented subjects with Alzheimer changes
were intermediate between this control group and the
demented patients with Alzheimer’s disease. However, in regard to the number of large neurons in the
three regions of cortex measured, these nursing home
residents surpassed the subjects in the control group as
well as the demented patients with Alzheimer’s disease. This was consistent with the finding that the brain
weights in Group A were greater than in other groups,
suggesting that there has been less atrophy than is normally found in the very elderly or that this group of
patients started with more neurons and a larger brain
Katzman et al: Normal Cognition with Plaques
143
and thus had a greater reserve. This implies that patients in Group A had incipient Alzheimer’s disease
but did not show it clinically because of this greater
reserve.
It can be concluded, therefore, that there is a group
of elderly subjects with preserved mental status and
Alzheimer changes, including a moderate number of
neuritic plaques with few tangles in neocortex, who
show an intermediate degree of loss of ChAT and
somatostatin but who have retained intact pyramidal
neurons and whose brains are heavier than agematched normal subjects. These persons may have escaped the shrinkage of large neurons that accompanies
normal aging 1197 and the loss of large neurons that
usually occurs in Alzheimer’s disease 1181, so mental
status is preserved in spite of beginning Alzheimer
changes. Alternatively, these people might have
started with a larger brain and more large neurons and
thus might be said to have had a greater reserve.
~
Supported in part by the National Institute on Aging (AG Pol-5386
and P5OAG05131).
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