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Neuron Number in the Entorhinal Cortex and CA1 in Preclinical Alzheimer Disease
Joseph L. Price, DPhil;
Andy I. Ko, BA;
Marcus J. Wade, BA;
Sarah K. Tsou;
Daniel W. McKeel, MD;
John C. Morris, MD
Arch Neurol. 2001;58:1395-1402.
ABSTRACT
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Objectives To determine whether nondemented subjects with pathological evidence
of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal
cortex and hippocampus, and whether the onset of cognitive deficits in AD
coincides with the onset of neuronal degeneration.
Methods Preclinical AD cases have been defined by the absence of cognitive decline
but with neuropathological evidence of AD. The hippocampus and entorhinal
cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR]
0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild
symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only).
The volume and number of neurons were determined stereologically in 2 areas
that are vulnerable to AD—the entorhinal cortex (as a whole and layer
II alone) and hippocampal field CA1.
Results There was no significant decrease in neuron number or volume with age
in the healthy nondemented group and little or none between the healthy and
preclinical AD groups. Substantial decreases were found in the very mild AD
group in neuron number (35% in the entorhinal cortex, 50% in layer II, and
46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and
29% in CA1). Greater decrements were observed in CA1 in the severe AD group.
Conclusions There is little or no neuronal loss in aging or preclinical AD but substantial
loss in very mild AD. The findings indicate that AD results in clinical deficits
only when it produces significant neuronal loss.
INTRODUCTION
SEVERAL clinicopathologic studies of older adults with slight cognitive
decline before death, just at the threshold for clinical detection, demonstrated
large numbers of neurofibrillary tangles and amyloid plaques, sufficient for
the diagnosis of Alzheimer disease (AD).1, 2, 3, 4, 5, 6, 7, 8
Reasoning that these pathological lesions develop over time, the pathobiological
processes that underlie AD must begin in a preclinical stage that precedes
clinically detectable cognitive change, probably by years. This preclinical
AD stage would be a critical target for therapeutic intervention.
As used herein, "preclinical AD" indicates a stage in which there is
no impairment in memory or other cognitive functions. Although this term has
been used in other studies9, 10, 11, 12, 13
for slight cognitive decline before dementia, results of careful clinicopathologic
studies14 indicate that such decline, in the
absence of known explanation, consistently indicates a neuropathological disorder,
usually AD. Indeed, subtle cognitive decline before dementia diagnosis often
includes deficits in multiple cognitive domains that are sufficient to cause
functional interference.1, 9, 10, 11
A previous study8 by 2 of us (J.L.P.
and J.C.M.) reported cases of preclinical AD that did not have any clinical
indication of cognitive decline (Clinical Dementia Rating [CDR] 0) but had
substantial pathological changes indicative of AD. These cases were defined
specifically by the presence of neuritic plaques, but they also had high numbers
of total senile plaques and neurofibrillary tangles comparable to the density
of these markers in very mild AD cases. Preclinical cases represent the earliest
definable stage of AD, between healthy aging and clinically detectable AD.
Subsequent analyses15 of longitudinal psychometric
assessments from preclinical AD cases confirmed that they were free from subtle
cognitive decline.
Several studies16, 17, 18, 19, 20
of neuronal number in the hippocampus and entorhinal cortex have shown that
there is essentially no neuronal loss with aging but substantial cell and
volume loss in AD. In the entorhinal cortex, in particular, marked cell loss
was found even in very mild AD cases (CDR 0.5, mild cognitive impairment [MCI]).16, 20 This study sought to determine whether
similar neuronal loss could be detected in the preclinical stage of AD. The
results also test the hypothesis that the onset of cognitive decline corresponds
to the onset of cell loss.
MATERIALS AND METHODS
The brains used in this study were taken from a previous clinicopathologic
series8 and included all cases that had sufficient
sections through the structures to be counted. The cognitive status of most
subjects (including all of the preclinical AD cases) was assessed within a
year of death using the CDR as part of a longitudinal study.21, 22
These cases were supplemented with others that were assessed by a validated
postmortem interview with an informant who knew the subject well.23
Twenty-two brains were available with sections through the entorhinal
cortex that were rated CDR 0 (nondemented) or 0.5 (very mild AD) (Table 1). Cases assessed as CDR 0/0.5 (reflecting
a less certain stage of CDR 0.5) have been shown in previous studies to have
no pathological distinction from the CDR 0.5 group8
and were included in the very mild AD group in this study. The CDR 0 cases
had no indication of any cognitive impairment or decline. An overlapping group
of 29 brains rated CDR 0, 0.5, or 3 (severe AD) was available with sections
through hippocampal field CA1 (Table 1).
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Table 1. Summary of Cases*
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Frozen sections were cut at 50 mm from 1-cm-thick coronal blocks. Series
of 1 in 22 sections were stained using the Bielschowsky silver method, immunohistochemical
stains for ß-amyloid and paired helical filaments, and the Nissl method.
The Nissl-stained sections were used in this study for volume measurements
and cell counts. The Bielschowsky and immunohistochemical stains were used
in the previous study8 to analyze neurofibrillary
tangles and amyloid plaques.
Cases were divided into healthy nondemented brains (CDR 0), preclinical
AD brains (CDR 0), and very mild AD brains (CDR 0/0.5 or 0.5) (Table 1). Because the extreme cell loss in severe AD was documented
previously in the entorhinal cortex16 but not
in CA1, a fourth group of severe AD (CDR 3) cases was added for CA1 (Table 1). The criteria for the groups were
the same as in the previous study.8 Healthy
nondemented brains were rated CDR 0 and had either no amyloid plaques or cortical
patches of diffuse plaques only. These brains also had a variable number of
tangles, especially in the entorhinal and perirhinal cortex.8
Preclinical AD brains were defined as CDR 0 cases that had neuritic and diffuse
plaques widely distributed throughout the neocortex; when so defined, the
cases also had substantial numbers of tangles.8
In the entorhinal cortex analysis, there was no significant difference in
age between the healthy nondemented and preclinical AD groups, but the very
mild AD cases were significantly older. There was no significant difference
in age between the groups analyzed for CA1.
All cases were assessed using 4 pathological standards for AD: (1) a
modified version of the Khachaturian criteria,24, 25
which has been used in other studies from the Alzheimer Disease Research Center
(ADRC) of Washington University, St Louis, Mo14, 22;
(2) the Braak stages for neurofibrillary and amyloid change26;
(3) the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)
neuropathological criteria27; and (4) the National
Institute on Aging/Reagan Institute criteria for likeliness of AD28 (Table 1). Preclinical AD and very mild AD cases were rated similarly, although more
of the very mild AD cases were rated as "probable AD" by the CERAD criteria
because of their positive clinical history of dementia. Other aspects of some
of the cases studied here have been analyzed in previous studies.1, 2, 4, 8, 15, 16, 22
Two separate analyses of the entorhinal cortex, as a whole and layer
II alone, were done by 2 different examiners (A.I.K. and M.J.W., respectively).
The boundaries of the entorhinal cortex were delineated by the sharply defined
layer II, often grouped into cell islands, and the lamina dissecans deep to
layer III, using the criteria of Amaral and Insausti.29
Layer II was distinguished by its greater cellular density compared with layer
III and included the cell islands and intervening cells.
A third investigator (S.K.T.) measured hippocampal field CA1. Because
of tissue demands for diagnostic and other purposes, sections through the
entire extent of CA1 were not available. A counting region was defined in
the middle portion of CA1, bounded rostrally where field CA2/3 was first distinguished
by its narrower pyramidal cell layer and caudally by the posterior edge of
the entorhinal cortex. The values therefore do not represent the total volume
or neuronal number in CA1. The boundaries of CA1 with CA2/3 and the subiculum
were demarcated as defined by Amaral and Insausti.29
All counts were done on coded slides, with investigators masked to the
age, cognitive status, and neuropathological diagnosis of the case. Measurements
were made using a stereological system (C.A.S.T.-Grid; Olympus, Albertslund,
Denmark), which includes a computer-linked microscope with a motorized stage
for automated selection of counting fields and a z-axis sensor to determine
depth within the section. A video camera on the microscope and interfaced
to the computer allowed accurate marking of cells within the counting volume.
A regularly spaced series of 10 to 12 sections through the entire rostrocaudal
extent of the target structure was selected for random, systematic sampling,
beginning randomly with the first section available. The entorhinal cortex,
layer II, or CA1 was outlined on each section, and the Cavalieri principle
was used to determine the overall area. The total reference volume for each
structure was determined as the sum of areas of the counted sections divided
by the number of sections counted and then multiplied by the total number
of sections through the entorhinal cortex and the distance between sections
(1100 µm). Because tissue necessarily was lost between blocks, 1 to
3 sections were added for each transition between blocks. These extra sections
slightly increased the absolute number of cells but had little effect on relative
differences between groups.
The computer set counting fields that were regularly spaced but randomly
positioned within the outlined area. Approximately 100 to 150 fields were
counted for each brain. Cell numbers were estimated using the optical disector
method.30 The actual thickness of the sections
on the slide was measured and an optical disector depth was set to that thickness
minus 1-mm guard volumes on top and bottom. Because the 50-mm frozen sections
collapsed during dehydration, the measured section thickness was typically
10 to 12 mm and the disector depth was 8 to 9 mm. Neurons were distinguished
from glia by their stained cytoplasm and nucleolus and their generally larger
size and nonspherical shape. At least 100 neurons were counted for each brain.
The total number of neurons counted was divided by the volume sampled (number
of counting fields x shrinkage factor x disector depth x
counting field area) to calculate volumetric cell density. Shrinkage factor
is the thickness at which the sections were cut (50 mm) divided by the measured
section thickness. Cell density was then multiplied by the calculated reference
volume of the entire structure to give the total number of cells.
Data were analyzed across the 3 groups using 1-way analysis of variance
(ANOVA). Subsequently, post hoc analysis of differences between groups was
done using the Tukey "honestly significant difference" test for groups with
unequal numbers (Spjotvoll/Stonine test), which corrects for multiple comparisons.
Because of possible age effects, the ANOVAs were repeated with age as a covariant.
The Spearman rank order correlation (r) was also
calculated for the relation between age and volume or neuron number in the
healthy nondemented brain group.
RESULTS
ENTORHINAL CORTEX
Correlational analysis of the relation between age and neuron number
in the healthy nondemented group indicated that there was a nonsignificant
0.7% per year decrease in total numbers of neurons with age (slope = -85 000
neurons per year, r = -0.4, P = .12) (Figure 1A). A similar
but significant 1% per year decrease in the volume of the entorhinal cortex
was also found with age (slope = -12.7 mm3 per year, r = -0.69, P = .01).
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Figure 1. Relation between age and neuron
number in the whole entorhinal cortex (A) and layer II only (B) in individual
cases. The linear regression lines relate age to neuron number in healthy
nondemented cases. Although the lines have a slight downward slope, neither
correlation is significant. AD indicates Alzheimer disease.
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Because layer II of the entorhinal cortex previously has been shown
to be among the most severely affected structures in AD,8, 16, 26
it was analyzed separately. The correlation with age again indicated nonsignificant
decreases with age in layer II in neuronal number (slope = -16 000
neurons or 1.2% per year, r = -0.45, P = .15) (Figure 1B)
and tissue volume (slope = -0.4 mm3 or 0.4% per year, r = -0.27, P = .4).
For all measures, preclinical AD cases were intermixed with healthy
nondemented cases (Figure 1). The
mean volume and number of neurons in the entorhinal cortex also showed essentially
no difference between the preclinical AD and healthy nondemented groups in
either the whole cortex or layer II (P = .71-.97
for all comparisons) (Table 2
and Figure 2). In contrast, most
very mild AD cases had fewer neurons and smaller volume than most healthy
nondemented or preclinical AD cases (Figure
1). The mean volume and number of neurons were substantially decreased
in the very mild AD group (by 21% to 50%) (Table 2 and Figure 2).
All the decreases were significant (P = .004 for
neuron number and P = .01 for volume in the whole
entorhinal cortex, and P<.02 for neuron number
in layer II), except that in volume of layer II, which showed a strong trend
toward significance (P = .055). When age was inserted
in the ANOVA as a covariant, the difference in neuronal number between groups
remained significant but the volume decreases only showed a trend toward significance
(P = .07).
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Table 2. Neuron Number and Volume in the Entorhinal Cortex*
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Figure 2. The average number of neurons
(A) and tissue volume (B) in the entorhinal cortex as a whole and in layer
II alone in the healthy nondemented, preclinical Alzheimer disease (AD), and
very mild AD groups. There was no significant difference between the first
2 groups, but the very mild AD group had significantly fewer neurons than
all the other groups. Asterisk indicates P<.05 vs the healthy
nondemented group; dagger, P = .055 vs the healthy nondemented
group. Error bars represent SE.
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The small numbers of cases reduced the power for statistical comparison
between the healthy nondemented and preclinical AD groups. A power analysis
of the data, however, indicated that decreases would have been statistically
detectable in preclinical AD cases if they approached those in very mild AD
cases (Table 2).
HIPPOCAMPAL FIELD CA1
There was considerable variance in the neuronal count in hippocampal
field CA1 within each group, probably owing to the difficulty in identifying
the boundaries of CA1. There was one outlying case in each of the healthy
nondemented, very mild AD, and severe AD groups that deviated from the mean
by 2 SDs or more (Figure 3A). To
reduce the variance and allow comparisons between groups, these outliers were
eliminated from further analyses and from Table 1.
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Figure 3. Analysis of neuron numbers in
hippocampal field CA1. A, The number of neurons counted in CA1 in the healthy
nondemented, preclinical Alzheimer disease (AD), very mild AD, and severe
AD cases to show variation within each group. Values marked with white diamonds
were 2 SDs or more from the mean (indicated by dashes) and were excluded from
further analyses. B, Relation of neuron number to age in healthy nondemented,
preclinical AD, very mild AD, and severe AD groups. The linear regression
line relates neuron number to age in the healthy nondemented group. No change
was found as a function of age. C, The average number of neurons in hippocampal
field CA1 in the healthy nondemented, preclinical AD, very mild AD, and severe
AD groups. There was no significant difference between the first 2 groups,
but the very mild AD and severe AD groups had significantly fewer neurons
than the other groups. Asterisk indicates P<.02 vs the healthy
nondemented group. Error bars indicate SE.
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Correlational analysis indicated no change in the number of neurons
in CA1 with age within the healthy nondemented group (slope = 0) (Figure 3B). Individual preclinical AD cases
were distributed among healthy nondemented cases, whereas the very mild and
severe AD cases had fewer neurons than most nondemented cases.
The AD-related changes in CA1 were similar to those in the entorhinal
cortex. The mean number of neurons in preclinical AD cases decreased by only
11% compared with the healthy nondemented group (Table 3 and Figure 3C)
(P = .95). On the other hand, very mild and severe
AD cases decreased by 46% and 65%, respectively. These decreases were significant
(P<.02 for both), even when age was covaried out
(P = .02 for both). The small number of cases limited
the power for statistical comparison, but power analysis indicated that a
decrease in the preclinical AD group would have been detected if it approached
that in very mild AD (Table 3).
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Table 3. Neuron Number and Volume in Hippocampal Field CA1*
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Although the total volume of hippocampal field CA1 was not determined
(see the "Materials and Methods" section), the analyzed portion of CA1 showed
volume changes similar to those in the entorhinal cortex. There was virtually
no change (+6%) in the average volume of the preclinical AD group compared
with the healthy nondemented group (P = .95). In
contrast, volume decreased by 29% and 38% in the very mild and severe AD groups,
respectively. ANOVA indicated that there was a significant variation among
the groups (P = .047), but results of post hoc analysis
with the stringent Tukey honestly significant difference test for unequal
groups did not indicate significant differences between specific groups (P = .3). If age was used as a covariant, there was only
a trend toward significance among groups (P = .06).
COMMENT
The main finding of this study is that preclinical AD cases resemble
healthy nondemented cases in the volume and number of neurons in the entorhinal
cortex and hippocampal field CA1. Preclinical AD cases do not show the decreases
that are seen in clinically detectable, very mild AD. Although preclinical
AD cases have substantial numbers of plaques and tangles, indicating the beginning
of the pathobiological process underlying AD,8
the disease has not yet progressed to the point of producing identifiable
neuronal degeneration.
The observations also confirm the results of previous studies16, 19, 31 that there is little
or no loss of neurons in the entorhinal cortex or CA1 during healthy aging.
A slight, nonsignificant decrease in neurons with age was found in the entorhinal
cortex but not in CA1. Absent a neurodegenerative condition such as AD, aging
is associated with little if any neuronal loss.
The 35% loss of neurons in the entorhinal cortex and 50% loss in layer
II in very mild AD cases agrees closely with results of previous studies.
Gomez-Isla et al16 reported that the number
of neurons decreased in very mild AD by 32% in the whole entorhinal cortex
and 57% in layer II. More recently, Kordower et al20
reported similar losses in layer II of 64% and 58% in MCI and "mild to moderate"
AD, respectively. They also reported 26.5% loss in volume of layer II in MCI,
which corresponds well to the 21% decrease reported herein. Cases of MCI are
generally rated CDR 0.5,32 and the Mini-Mental
State Examination scores reported by Kordower et al20
for MCI are comparable to those recently reported by Morris et al14 for CDR 0.5 (MCI) cases. That same study14 showed that MCI generally represents very mild AD.
In contrast to the relative decreases, the absolute number of cells
counted in the healthy entorhinal cortex in this study was higher than in
the other studies.16, 20 In a third
study, West and Slomianka initially reported31
numbers close to the present results but later reported33
a technical correction that reduced their values by 0.6, resulting in values
close to those of the other studies. Because the studies all used similar
stereological counting methods, it is difficult to explain the differences.
It is possible that an unrecognized technical correction should be made in
numbers obtained in this study, as in the study by West and Slomianka.31 Such a correction, however, would not change relative
values between groups or the primary conclusion that there is substantial
neuronal loss in very mild AD but little or none in aging or preclinical AD.
The definition and pathological analysis of preclinical AD cases were
previously described in detail,8 but the major
points are reviewed herein. Very mild AD cases consistently have extensive
diffuse and neuritic amyloid plaques throughout the neocortex and neurofibrillary
tangles in and around the hippocampus and meet pathological criteria for AD.1, 2, 3, 4, 5, 6, 7, 8
Because these cases are at the threshold for detection of cognitive decline,4, 34 and because the pathological lesions
develop over some time, the disease process must begin before it can be detected
clinically. Preclinical AD cases resemble very mild AD cases pathologically
but do not have cognitive impairment or decline.
Virtually all healthy nondemented cases have neurofibrillary tangles,8, 35 and these increase exponentially with
age, overlapping with very mild AD cases.3, 8
Although tangles clearly are pathological, the pattern of tangle development
resembles an age-related process. By themselves tangles do not provide a criterion
that could be used to distinguish individual preclinical AD cases from healthy
aging cases8 (see also Schmitt et al36). In contrast, plaques are not found in all healthy
nondemented cases.8, 35 Many cases
have no plaques, and others have only diffuse plaques, but a few cases with
no cognitive impairment have neuritic and many diffuse plaques widely distributed
throughout the neocortex.8 When identified
by the presence of neuritic plaques, these cases approach the very mild AD
cases in tangle and plaque density and generally meet pathological criteria
for AD. These cases therefore satisfy strict criteria for preclinical (presymptomatic)
AD.8
When effective disease-modifying therapies for AD become available,
the preclinical stage as defined herein would be the ideal period for treatment
initiation because it precedes the stage of significant neuronal death. At
present, however, preclinical AD cannot be detected during life. By definition,
it cannot be detected even with sensitive clinical assessment. Structural
magnetic resonance imaging also might be insufficient because significant
volume loss was not found in the entorhinal cortex or hippocampus in preclinical
AD cases. Magnetic resonance imaging studies reporting volume reductions very
early in AD either found that the volume changes coincided with memory decline37 or included cases with MCI in their "preclinical"
group,38, 39, 40 indicating
that the subjects were symptomatic and not strictly preclinical. Functional
imaging might be better able to recognize AD before structural and cognitive
decline,41, 42 although a method
to detect ß-amyloid in vivo might best diagnose preclinical AD.
Cross-sectional psychometric analyses do not identify reliably the earliest
stages of AD in individuals because the range of normal performance is greater
than the decline in very mild AD.34 Longitudinal
analysis can detect decline in individuals but is not more sensitive than
careful clinical assessment.34 A recent study15 reported longitudinal psychometric data from 24 cases
analyzed in the present study. None of the individual preclinical AD cases
declined in psychometric performance with time; their mean performance was
close to that of the healthy nondemented group. The very mild AD group, on
the other hand, consistently showed a decline in psychometric performance,
and their mean performance was significantly below that of the healthy nondemented
and preclinical AD groups.
Our data indicate that the onset of cognitive decline correlates closely
with the onset of neuronal loss in the hippocampus and entorhinal cortex,
2 areas that are particularly critical for memory processing.43
Of course, this correlation does not mean that neuronal death is more important
than other causes of neuronal dysfunction, such as synapse loss.44, 45
It would be expected that synaptic dysfunction would precede neuronal death,
but, within the resolution of available data, neuron loss in the hippocampus
and entorhinal cortex and identifiable cognitive decline occur at the same
stage of AD.
These and previous results support a model in which AD has a subtle
transition from healthy aging, beginning before identifiable cognitive loss
(Table 4). In this model, neurofibrillary
changes occur in everyone during aging but affect relatively few neurons at
younger than 85 to 90 years. Although tangles and other neurofibrillary changes
undoubtedly indicate a degenerative process, age-related neurofibrillary change
is insufficient to cause significant cellular loss or cognitive impairment.
If substantial amyloid plaques develop, however, the rate and amount of neurofibrillary
change increases during the preclinical stage of AD. There is insufficient
neuronal degeneration to produce detectable cognitive impairment, but autopsied
cases in this stage generally meet pathological criteria for AD. Further amyloid
deposition and accelerated neurofibrillary change result in significant neuronal
dysfunction and death and associated MCI, which characterizes the earliest
clinically detectable stage of AD.
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Table 4. Summary of Findings*
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AUTHOR INFORMATION
Accepted for publication April 23, 2001.
This study was supported by grants AG03991 and AG05681 from the National
Institutes of Health, Bethesda, Md.
We thank Hieu Van Luu for his excellent technical assistance and the
physicians and staff of the Memory and Aging Project and the Alzheimer's Disease
Research Center of Washington University for case evaluations, brain collection,
and histopathological diagnosis.
From the Departments of Anatomy and Neurobiology (Dr Price, Messrs
Ko and Wade, and Ms Tsou), Pathology and Immunology (Drs McKeel and Morris),
and Neurology (Dr Morris) and the Alzheimer's Disease Research Center (Drs
Price, McKeel, and Morris), Washington University School of Medicine, St Louis,
Mo.
Corresponding author and reprints: Joseph L. Price, DPhil, Department
of Anatomy and Neurobiology, Campus Box 8108, Washington University School
of Medicine, 660 S Euclid Ave, St Louis, MO 63110 (e-mail:
PriceJ{at}Thalamus.wustl.edu).
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