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Volume 16, Number 14,
Issue of July 15, 1996
pp. 4491-4500
Copyright ©1996 Society for Neuroscience
Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in
Very Mild Alzheimer's Disease
Teresa Gómez-Isla1,
Joseph L. Price2,
Daniel W. McKeel Jr.2,
John C. Morris2,
John H. Growdon1, and
Bradley T. Hyman1
1 Neurology Service, Massachusetts General Hospital,
Boston, Massachusetts 02114, and 2 Departments of Anatomy
and Neurobiology, Pathology and Neurology, and the Alzheimer's Disease
Research Center, Washington University, St. Louis, Missouri
63110
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
The entorhinal cortex (EC) plays a crucial role as a gateway
connecting the neocortex and the hippocampal formation. Layer II of the
EC gives rise to the perforant pathway, the major source of the
excitatory input to the hippocampus, and layer IV receives a major
hippocampal efferent projection. The EC is affected severely in
Alzheimer disease (AD), likely contributing to memory impairment. We
applied stereological principles of neuron counting to determine
whether neuronal loss occurs in the EC in the very early stages of AD.
We studied 20 individuals who at death had a Clinical Dementia Rating
(CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were
carried out on sections representing the entire EC. In the cognitively
normal (CDR = 0) individuals, there were ~650,000 neurons in
layer II, 1 million neurons in layer IV, and 7 million neurons in the
entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia
(CDR = 0.5), all of whom had sufficient neurofibrillary tangles
(NFTs) and senile plaques for the neuropathological diagnosis of AD,
had 32% fewer EC neurons than controls. Decreases in individual lamina
were even more dramatic, with the number of neurons in layer II
decreasing by 60% and in layer IV by 40% compared with controls. In
the severe dementia cases (CDR = 3), the number of neurons in
layer II decreased by ~90%, and the number of neurons in layer IV
decreased by ~70% compared with controls. Neuronal number in AD was
inversely proportional to NFT formation and neuritic plaques, but was
not related significantly to diffuse plaques or to total plaques. These
results support the conclusion that a marked decrement of layer II
neurons distinguishes even very mild AD from nondemented aging.
Key words:
entorhinal cortex;
stereology;
neuronal loss;
perforant
pathway;
Alzheimer's disease;
aging
INTRODUCTION
Distinguishing Alzheimer's disease (AD) from
normal aging has been a recurring nosological and diagnostic problem
(Drachman, 1983 ; Berg, 1988; Morris et al., 1991). From a clinical
point of view, the idea that mild memory loss is a common concomitant
of aging raises a theoretical model whereby AD and aging lie on a
continuous spectrum (Bartus et al., 1982; Brayne and Calloway, 1988).
According to this idea, AD represents exaggerated aging rather than a
true ``disease'' (Drachman, 1994).
Controversy also exists about whether aging and AD represent a
neuropathological continuum or are dichotomous (Terry et al., 1981,
1987; Coleman and Flood, 1987; West et al., 1994). Neurofibrillary
tangles (NFTs) and senile plaques (SPs), the two chief
neuropathological hallmarks of AD, are reported to occur frequently in
aging brains (Tomlinson et al., 1968; Dayan, 1970; Ball, 1977;
Arriagada et al., 1992a; Bouras, 1993). NFTs are nearly universal in
the hippocampal formation in nondemented individuals over the age of
~60 years, and the number increases with age (Price et al., 1991;
Arriagada et al., 1992a; Price, 1993). Numerous SPs also may be present
in many nondemented individuals (Delaere et al., 1990). The
distribution of NFTs and SPs in various brain regions in the elderly
matches the pattern of hierarchical vulnerability seen in AD and Down
syndrome (Mann et al., 1987; Arnold et al., 1991; Price et al., 1991;
Arriagada et al., 1992a,b; Hof et al., 1995; Hyman et al., 1995). On
the basis of these observations, it can be argued that only
quantitative differences separate AD from healthy aging and, thus, AD
might represent an accelerated aging process.
An alternative point of view is that AD and normal aging are not a
continuum but are two well-differentiated processes from both clinical
and pathological perspectives. One of the most difficult and crucial
issues in this problem is the clinical determination of normality as
distinguished from very mild or even presymptomatic disease. Recent
studies suggest that in truly healthy aging, intellectual performance
remains unimpaired over time, whereas sustained decline of even modest
proportions may represent a pathological condition rather than
representing benign senescence (Roth, 1986; Morris and Fulling, 1988;
Morris et al., 1991, 1996; Linn et al., 1995). This second point of
view implies that a line of demarcation based on qualitative
differences separates the pathological condition of AD from healthy
aging.
In an attempt to distinguish these two possibilities, we compared
quantitative neuropathological features of individuals known to be
cognitively normal before death, individuals with the earliest
clinically detectable signs of dementia of the Alzheimer type, and
individuals with well-established AD. We used stereologically based
cell-counting techniques to assess the structural integrity of the
entorhinal cortex (EC). The EC was chosen because it is highly
selectively vulnerable in AD (Hyman et al., 1984, 1986; Arnold et al.,
1991; Braak and Braak, 1991; Price et al., 1991; Arriagada et al.,
1992a; Fukutani et al., 1995; Solodkin and Van Hoesen, 1996). Moreover,
layers II and IV of the EC are among the first regions affected with
tangles in Down syndrome and in normal aging (Mann and Esiri, 1989;
Price et al., 1991; Arriagada et al., 1992b; Hyman et al., 1995). The
EC lies in a critical path in neural systems related to memory; it
receives afferents from widespread association and limbic areas,
projects to the dentate gyrus of the hippocampal formation, receives
afferents from the hippocampus, and sends afferents back to association
neocortex (Rosene and Van Hoesen, 1987; Zola-Morgan et al., 1994).
Damage of the EC and related structures is associated with memory
impairment (Leonard et al., 1995). Because memory impairment
frequently is the earliest symptom of AD, we reasoned that
neuropathological changes and neuronal loss in the EC might contribute
to memory impairment at the very mild stages of AD.
MATERIALS AND METHODS
We performed neuronal counts in the EC from 20 individuals whose
cognitive status before death was known. Clinical and neuropathological
observations from these cases have been published previously (Morris et
al., 1991, 1996; Price et al., 1991; Berg et al., 1993; McKeel et al.,
1993; Price, 1993). All cases were evaluated clinically in the Memory
and Aging Project of the Washington University Alzheimer's Disease
Research Center (ADRC).
Of the 20, 9 (2 CDR = 0, 3 CDR = 0.5, 4 CDR = 3) were
part of a longitudinal study and had undergone enrollment procedures
that included validated inclusionary and exclusionary criteria to
diagnose dementia of the Alzheimer type (Berg et al., 1982; Morris et
al., 1988) and assess cognitive status according to the Washington
University Clinical Dementia Rating (CDR) (Morris, 1993). Control
subjects met all exclusionary criteria but were not demented.
Recruitment, entry characteristics, and assessment methods have been
described previously (Berg et al., 1982). In brief, subjects were
recruited from the greater St. Louis metropolitan community and
examined by experienced physicians at entry and at ~12-18 month
intervals thereafter. Of the nine cases, seven were assessed within 1 year of their death and one was assessed 2 years before death. The
ninth case (rated CDR = 0) was assessed 6.4 years before death; in
this case, an extensive retrospective interview with close relatives
shortly after the subject's death was used to confirm the CDR. Of
note, the two CDR = 0 individuals were among the oldest examined,
ages 80 and 89. In three of the four cases with a CDR score = 0.5, there was slight initial disagreement between the examining clinicians
and the reviewer; these cases were rated as CDR = 0/0.5 to denote
``questionable'' dementia. These cases were treated as CDR = 0.5 subjects, because clinical evaluation raised the question of ``very
mild'' dementia.
The standardized clinical assessment included semistructured interviews
with the subject and a collateral source (usually the spouse or other
close relative) and several brief cognitive scales, including the
collateral source-derived Dementia Scale of Blessed (Blessed et al.,
1968), the Aphasia Battery (Faber-Langendoen et al., 1988), and the
Short Portable Mental Status Questionnaire (Pfeiffer, 1975). Symptoms
of depression in the subject were solicited both by self-report and
from the collateral source at each time of evaluation (Knesevich et
al., 1983). The assessment protocol provided information sufficient for
the clinician to determine the presence of dementia and, when present,
to stage dementia severity according to the CDR, in which a score of 0 indicates no cognitive impairment and a score of 0.5, 1, 2, or 3 indicates very mild, mild, moderate, or severe dementia (Hughes et al.,
1982; Morris, 1993). The CDR is a global measure of dementia severity
and is scored solely on clinical information without reference to
psychometric performance. Reports by the collateral informant of
functional decline in the subject's performance of usual activities
can indicate accurately the earliest symptoms of AD at the CDR 0.5 stage (Morris, 1991). At entry and every 2 years thereafter, the
collateral and subject interview portions of the assessment were
videotaped for review by another clinician who provided a second CDR
score.
The remaining 11 cases (8 CDR = 0, 1 CDR = 0.5, 1 CDR = 1, 1 CDR = 3) were evaluated postmortem only. Their cognitive
status before death was established with a structured Retrospective
Collateral Dementia (RCD) interview with a close relative, administered
via telephone by a Memory and Aging Project physician. This interview
is similar to the collateral interviews used in the premortem
assessments and has been validated, allowing a CDR score to be assigned
with reliability (Davis et al., 1991). All CDR determinations were made
before neuropathological examination.
From the clinical assessments, the 20 subjects included in this study
were subdivided into two groups. The AD group included the 10 clinically demented individuals rated CDR = 0.5 to 3 (mean
age ± SD = 84.2 ± 9.9 years; range, 67-95 years). All of
them had a subsequent neuropathological diagnosis of definite AD
(Khachaturian, 1985; Mirra et al., 1991). The control group was formed
by the 10 individuals who were rated CDR = 0 and therefore were
believed to be cognitively normal (mean age ± SD = 75 ± 9 years; range 60-89 years). Although some of these cases had a few NFTs
in the EC or scattered SPs, none of them met criteria for AD by
neuropathological examination (Khachaturian, 1985; Mirra et al.,
1991).
The brains were fixed within 36 hr after death by immersion in buffered
10% formalin for 2 weeks before the sectioning at 1 cm intervals in
the coronal plane. For neuropathological diagnosis, tissue blocks were
selected from standardized regions of the left cerebral hemisphere.
Tissue blocks were embedded in paraffin, sectioned at 6 µm, and
stained with a battery of conventional and immunohistochemical stains
(McKeel et al., 1993; Mirra et al., 1994; Morris et al., 1996). Blinded
counts of total diffuse, neuritic, and cored SPs and NFTs were made in
midfrontal, superior temporal, and inferior parietal lobule neocortex,
in hippocampal area CA1, and in the EC, using modified Bielschowsky
silver methods (Berg et al., 1993; McKeel et al., 1993).
For neuronal counts and other research purposes, large blocks
(~3 × 5 cm) were taken from the right cerebral hemisphere for serial
sectioning. The blocks included the ventral half of the brain from the
orbital cortex, rostrally, through the basal forebrain, amygdala, and
insula, including the entire hippocampal formation and adjacent
temporal neocortex, caudally. The blocks were soaked in a
cryoprotective solution (30% sucrose or 10% glycerin) and serial
sectioned at 50 µm on a freezing microtome. All sections, including a
complete series through the hippocampus and EC, were collected and
divided into series of 1 in 22. Adjacent series were stained using the
Nissl and Bielschowsky methods and immunohistochemically with
antibodies against paired helical filaments (Price et al., 1991).
To count neurons within the EC, the boundaries of this cortical area
were marked on Nissl-stained sections through its full rostro-caudal
extent. The description of the EC by Amaral and Insausti (1990) was
used to define the medial and lateral boundaries of the EC. No attempt
to identify EC subdivisions was made. Following a systematically random
scheme and based on stereological unbiased techniques, five
50-µm-thick sections were selected, taken at equally spaced intervals
(3 mm) along the entire length of the EC on each brain (Gundersen,
1992; West, 1993). The volume of the entire EC (reference volume) in
each brain was estimated according to the principle of Cavalieri
(Cavalieri, 1966), using the Bioquant Image Analysis System (Nashville,
TN) that allows the delineation of the layers on each section. To
ensure that the estimation was unbiased, the first section plane was
placed randomly within the first interval length (West and Gundersen,
1990). Within each section, a systematically random sampling scheme was
applied to count neurons. The number of neurons in the entire EC and in
each of its laminae was estimated by using ~1500 optical dissectors
in each case. Each optical dissector was a 50 × 100 micrometer
sampling box with extended exclusion lines. This intensive sampling was
necessary to obtain an adequate representation of each of the layers,
because the laminar densities in the EC are markedly heterogeneous.
Using a 100× oil-immersion objective lens, neurons that had a visible
nucleolus were counted if they were not present in the initial plane of
focus but came into the focus as the optical plane moved through the
tissue. Detailed descriptions of these techniques have been presented
elsewhere (West and Gundersen, 1990). The appropriateness of the
sampling scheme chosen was evaluated by calculating the precision of
the estimates made in each individual, expressed as the coefficient of
error (CE) as described previously (West and Gundersen, 1990). In all
cases, the CE was <0.06, suggesting that a minimal amount of variance
in the counts is from the technique. The estimation of total number was
performed by multiplying the volume density of neurons in the layers by
the volume of the layers. All counts were carried out by one examiner
(T.G.I.) without knowledge of the age, gender, or neuropathogical
status of the material being analyzed.
NFTs and SPs were mapped from the immunostained or Bielschowsky-stained
50 µm frozen sections with the aid of a microscope digitizer coupled
to a computer, as described previously (Price et al., 1991). The
computerized maps then were transferred to a computer-aided design
program, and the boundaries of brain structures were added. The density
of tangles and plaques within the EC as a whole was measured by
outlining the EC and then measuring the area and counting the number of
items within it.
Statistical comparison of neuron number (in each layer) to age among
controls was by linear regression analyses. Comparison of neuronal
number, density, and volume in each layer in AD compared with controls
was by ANOVA. Comparison of neuronal number to NFT density and SP
density was made by rank ordering the cases and comparing the rank
orders by Spearman rank correlation coefficient, because the NFT and SP
counts were obtained at a representative level rather than throughout
the entire anterior-posterior extent of the EC. Differences were
considered to be significant if p < 0.05.
RESULTS
Neuron number in the EC is unchanged in cognitively
normal aging
We first examined whether a change in neuronal number occurs with
increasing age in individuals who are believed to be cognitively normal
(CDR = 0). When the number of neurons in the entire EC and in each
lamina was compared within this group (n = 10), no
statistically significant differences were observed according to age
(Tables 1, 2).The total number of neurons
in the EC, as well as neuronal densities and volumes, remained stable
between the sixth and ninth decades (Fig. 1). When the
same parameters were estimated per layer, again the analysis showed no
significant change in number of neurons with increasing age in the
nondemented group (Fig. 2).
Table 1.
Neuronal counts in the entire EC for control
subjects
| Case |
CDR |
Age |
Sex |
Number of neurons × 106 |
Reference volume (cm3) |
Neuronal
density (neurons/ mm3 × 103) |
|
| 1 |
0 |
60 |
F |
6.18 |
1.04 |
59 |
| 2 |
0 |
61 |
M |
7.14 |
1.30 |
55 |
| 3 |
0 |
70 |
F |
6.89 |
0.90 |
77 |
| 4 |
0 |
73 |
F |
8.70 |
0.96 |
91 |
| 5 |
0 |
75 |
F |
5.89 |
0.80 |
74 |
| 6 |
0 |
76 |
F |
7.64 |
1.17 |
65 |
| 7 |
0 |
80 |
M |
5.06 |
0.83 |
61 |
| 8 |
0 |
83 |
M |
8.46 |
0.99 |
85 |
| 9 |
0 |
83 |
F |
6.90 |
0.84 |
82 |
| 10 |
0 |
89 |
M |
6.26 |
0.91 |
69 |
|
| Average
|
|
75 |
|
6.91 |
0.97 |
72 |
| SD |
|
9 |
|
1.13 |
0.15 |
12 |
|
Table 2.
Neuronal counts per lamina for control
subjects
| Case |
CDR |
Number of neurons × 106
|
| Layer I |
Layer II |
Layer III |
Layer
IV |
Layers V,
VI |
|
| 1 |
0 |
0.031 |
0.54 |
3.03 |
0.79 |
1.80 |
| 2 |
0 |
0.059 |
0.65 |
3.09 |
1.40 |
1.93 |
| 3 |
0 |
0.025 |
0.79 |
3.32 |
1.24 |
1.51 |
| 4 |
0 |
0.024 |
0.65 |
4.71 |
1.23 |
2.09 |
| 5 |
0 |
0.011 |
0.70 |
3.18 |
0.78 |
1.22 |
| 6 |
0 |
0.044 |
0.81 |
4.19 |
0.86 |
1.74 |
| 7 |
0 |
0.043 |
0.31 |
2.69 |
0.91 |
1.11 |
| 8 |
0 |
0.019 |
0.68 |
3.88 |
1.22 |
2.66 |
| 9 |
0 |
0.022 |
0.61 |
3.92 |
0.94 |
1.41 |
| 10 |
0 |
0.022 |
0.73 |
3.24 |
0.95 |
1.32 |
|
| Average |
0.03 |
0.65 |
3.52 |
1.03 |
1.68 |
| SD |
|
0.014 |
0.14 |
0.62 |
0.22 |
0.47 |
|
Fig. 1.
No statistically significant differences in the
total number of neurons in the EC were observed in the nondemented
group (CDR = 0; n = 10) according to age
(r = 0.0001, p = 0.98, NS).
[View Larger Version of this Image (14K GIF file)]
Fig. 2.
No statistically significant differences in the
number of neurons per layer in the EC were observed in the nondemented
group (CDR = 0; n = 10) according to age (layer
II, r = 0.001, p = 0.91; layer III,
r = 0.04, p = 0.57; layer IV,
r = 0.05, p = 0.54; layers V, VI,
r = 0.03, p = 0.60, NS).
[View Larger Version of this Image (21K GIF file)]
Neuron number in the EC is decreased substantially in AD
The averages of the total number of neurons in the entire EC and
in each lamina, along with neuronal densities and reference volumes
corresponding to each CDR category in the AD group, are shown in Tables
3 and 4. A highly significant difference
was observed when the AD group as a whole was compared with the
nondemented group. The average total number of neurons in the EC was
3.64 ± 1.51 × 106 in AD versus 6.91 ± 1.13 × 106 in controls. The difference represents a 48%
reduction in total number of EC neurons in the AD group compared with
controls (p < 0.001) (Fig. 3).
The volume of the EC in AD was ~40% less than controls
(p < 0.001) (Fig. 4). When
volume densities were compared, only layer II reached statistical
significance, 4.4 × 103 versus 7.3 × 103 neurons/mm3
(p < 0.001). No significant differences were
found in terms of neuronal densities in the remaining layers,
suggesting that density measures are not as sensitive as estimates of
total neuronal number in identifying neuronal loss.
Table 3.
Neuronal counts in the entire EC for AD
subjects
| Case |
CDR |
Age |
Sex |
Total number of
neurons × 106 |
Reference volume
(cm3) |
Neuronal density (neurons/ mm3 × 103) |
|
| 1 |
0.5 |
85 |
M |
4.83 |
1 |
48 |
| 2 |
0.5 |
86 |
M |
4.45 |
0.71 |
63 |
| 3 |
0.5 |
95 |
F |
4.73 |
0.66 |
72 |
| 4 |
0.5 |
95 |
F |
4.81 |
0.70 |
69 |
| 5 |
1 |
86 |
F |
5.82 |
0.79 |
74 |
| 6 |
3 |
67 |
M |
2.47 |
0.38 |
65 |
| 7 |
3 |
71 |
F |
2.47 |
0.40 |
60 |
| 8 |
3 |
77 |
M |
3.08 |
0.50 |
62 |
| 9 |
3 |
85 |
F |
0.90 |
0.14 |
64 |
| 10 |
3 |
95 |
F |
2.84 |
0.56 |
51 |
|
| Average |
|
84.2 |
|
3.64 |
0.59 |
63 |
| SD |
|
9.9 |
|
1.51 |
0.24 |
8 |
|
Table 4.
Neuronal counts per lamina for AD
subjects
| Case |
CDR |
Number of neurons × 106
|
| Layer I |
Layer II |
Layer III |
Layer
IV |
Layers V,
VI |
|
| 1 |
0.5 |
0.014 |
0.36 |
3.71 |
0.60 |
1.46 |
| 2 |
0.5 |
0.022 |
0.22 |
2.61 |
0.56 |
1.04 |
| 3 |
0.5 |
0.022 |
0.19 |
2.63 |
0.52 |
1.37 |
| 4 |
0.5 |
0.025 |
0.36 |
2.65 |
0.76 |
1.00 |
| 5 |
1 |
0.021 |
0.28 |
3.11 |
0.63 |
1.78 |
| 6 |
3 |
0.010 |
0.14 |
1.16 |
0.57 |
0.59 |
| 7 |
3 |
0.003 |
0.11 |
1.15 |
0.44 |
0.77 |
| 8 |
3 |
0.013 |
0.05 |
1.89 |
0.18 |
0.94 |
| 9 |
3 |
0.010 |
0.014 |
0.61 |
0.05 |
0.21 |
| 10 |
3 |
0.016 |
0.12 |
1.33 |
0.34 |
1.00 |
|
| Average |
|
0.02 |
0.18 |
2.09 |
0.47 |
1.02 |
| SD |
|
0.007 |
0.12 |
1.01 |
0.22 |
0.45 |
|
Fig. 3.
The average total number of neurons in the EC was
reduced by 48% in the AD group (n = 10) when compared
with the nondemented group (n = 10)
(p < 0.001).
[View Larger Version of this Image (44K GIF file)]
Fig. 4.
The volume of the EC was reduced by 40% in
the AD group (n = 10) when compared with the
nondemented group (n = 10)
(p < 0.001).
[View Larger Version of this Image (30K GIF file)]
Significantly fewer neurons were present in each layer in the AD group
(Fig. 5). The degree of neuronal change in layer II was
substantially larger than in any other layer (layer II, 72%,
p < 0.001; layer III, 41%, p < 0.01;
layer IV, 55%, p < 0.001; layers V, VI, 40%,
p < 0.01).
Fig. 5.
Significant decreases in neuronal number were
present in all layers of EC in the AD brains (n = 10)
when compared with the nondemented group (n = 10).
Decrease in cell number in the AD group was highest in layer II
compared with other layers (layer II, 72%, p < 0.001;
layer III, 41%, p < 0.01; layer IV, 55%,
p < 0.001; layers V, VI, 40%, p < 0.01).
[View Larger Version of this Image (30K GIF file)]
Neuronal number decreased most dramatically in layers II and IV in
very mild AD
Neuronal number decreased from 68% of control values in the
CDR = 0.5 subgroup to 31% of control in the CDR = 3 subgroup
(Fig. 6). The same correlation between the severity of
neuronal loss and CDR score was observed when individual laminae were
analyzed in AD brains. Layer II followed by layer IV showed the highest
and earliest rates of neuronal depopulation. For example, in layer II
there were 647,360 ± 143,220 in controls, decreasing 57% to 282,290 ± 90,460 neurons in the individuals with the mildest cognitive
deterioration (CDR = 0.5, n = 4), and decreasing
further to 85,130 ± 50,260, only 13% of control, in the most severe
cases (CDR = 3, n = 5). In layer IV, a 41%
decrease from the number of neurons in the CDR = 0 group was
estimated in the CDR = 0.5 subgroup, and a 69% decrease was
observed in the CDR = 3 subgroup. The remaining layers all
together (I, III, V, and VI) showed a 25% decrease from control levels
in the CDR = 0.5 subgroup and 63% decrease from control levels in
the CDR = 3 subgroup (Fig. 7).
Fig. 6.
The number of neurons in the EC in the AD group
(n = 10) compared with CDR = 0 controls
(n = 10), correlated with the clinical severity of
dementia. The difference increased from 32% in the CDR = 0.5 subgroup (n = 4) to 69% in the CDR = 3 subgroup
(n = 5).
[View Larger Version of this Image (18K GIF file)]
Fig. 7.
The number of neurons in the EC of AD brains
(n = 10) compared with CDR = 0 controls
(n = 10), negatively correlated with clinical severity
of dementia in all layers. Layers II and IV, in particular, showed the
highest and earliest changes. In layer II, a difference of 57% was
estimated in the CDR = 0.5 subgroup (n = 4) and
87% in the CDR = 3 subgroup (n = 5). In layer IV,
differences of 41 and 69%, respectively, were estimated in the same
CDR subgroups.
[View Larger Version of this Image (31K GIF file)]
Neuronal changes paralleled NFTs and plaque neuritic formation but
not amyloid deposition
We also compared EC neuron number to NFT and SP densities in the
same cortex (Tables 5, 6). Figure
8 represents maps of NFTs in the EC and CA1 zone of the
hippocampus of representative cases of each CDR category (CDR = 0, 0.5, and 3). In general, NFTs were predominant in layers II and IV with
fewer numbers in III, V, and VI, whereas SPs were more scattered,
although amyloid plaques tended to occur in layer III. A significant
negative correlation between the number of neurons and the degree of
NFTs (Z =  2.24, p = 0.02) and
neuritic plaques was observed (Z = 2.44,
p = 0.01) (Figs. 9 and
10b), but no significant correlation was
found between either of these two parameters and the number of total
SPs (Z = 0.17, p = 0.86, NS) or
diffuse plaque subpopulations in the same area
(Z = 1.72, p = 0.09) (Fig.
10a,c).
Table 5.
Tangle and plaque densities for control
subjects
| Case |
Sex |
Age |
Plaque
and tangle densities (no./mm2)
|
Hippocampus
(CA1)
|
Entorhinal
|
Lateral temporal
cortex
|
| SP |
NFT |
SP |
NFT |
SP |
NFT |
|
| CRD-0 |
| 1 |
F |
60 |
0 |
0.4 |
0 |
1.5 |
0 |
0 |
| 2 |
M |
61 |
0 |
N/A |
0 |
N/A |
0 |
N/A |
| 3 |
F |
70 |
0 |
14.4 |
2.3 |
0 |
0 |
0 |
| 4 |
F |
73 |
0 |
N/A |
0 |
N/A |
0 |
N/A |
| 5 |
F |
75 |
0 |
0.1 |
0 |
8.7 |
0 |
0 |
| 6 |
F |
76 |
0.1 |
16.8 |
1.1 |
3.7 |
0.6 |
0.1 |
| 7 |
M |
80 |
0 |
5.2 |
0 |
16.1 |
0.1 |
0.1 |
| 8 |
M |
83 |
0 |
1.3 |
0 |
3.4 |
0.4 |
0 |
| 9 |
F |
83 |
0.3 |
0.1 |
7.1 |
0.9 |
5.0 |
0 |
| 10 |
M |
89 |
0 |
35.3 |
0.5 |
37.6 |
0.2 |
0.1 |
|
|
N/A, Not available.
|
|
Table 6.
Tangle and plaque densities for AD
subjects
| Case |
Sex |
Age |
Plaque
and tangle densities (no./mm2)
|
Hippocampus
(CA1)
|
Entorhinal
|
Lateral temporal
cortex
|
| SP |
NFT |
SP |
NFT |
SP |
NFT |
|
| AD
CDR-0.5 |
| 1 |
M |
85 |
6.7 |
6.5 |
5.9 |
17.7 |
17.7 |
0.4 |
| 2 |
M |
86 |
7.7 |
55.7 |
19.1 |
42.4 |
18.3 |
2.4 |
| 3 |
F |
95 |
0.2 |
9.3 |
6.5 |
29.7 |
13.7 |
0.2 |
| 4 |
F |
95 |
2.6 |
21.5 |
13.3 |
48.4 |
25.0 |
5.0 |
| AD
CDR-1 |
| 5 |
F |
86 |
9.7 |
6.1 |
14.3 |
4.2 |
5.7 |
0.0 |
| AD
CDR-3 |
| 6 |
M |
67 |
12.2 |
66.4 |
15.7 |
110.6 |
37.9 |
52.5 |
| 7 |
F |
71 |
8.8 |
143.0 |
11.1 |
111.1 |
22.0 |
53.2 |
| 8 |
M |
77 |
7.4 |
12.7 |
9.7 |
25.4 |
45.0 |
0.3 |
| 9 |
F |
85 |
6.2 |
40.5 |
16.3 |
N/A |
16.9 |
33.7 |
| 10 |
F |
95 |
10.4 |
43.1 |
15.7 |
42.0 |
22.9 |
9.3 |
|
|
CDR, Clinical dementia rating, where CDR-0.5 indicates
questionable dementia; N/A, not available.
|
|
Fig. 8.
The topographical distribution of NFTs assessed by
PHF-1 immunostaining (Price et al., 1991) in the EC and CA1 zone of the
hippocampus is illustrated in each CDR category (CDR = 0, 0.5, and
3).
[View Larger Version of this Image (47K GIF file)]
Fig. 9.
The rank order of cases for NFT density in
the EC was negatively correlated with the number of neurons (Spearman
rank correlation test n = 17, Z = 3.40, p < 0.001). We also calculated the relationship
between the rank order of NFT densities and the number of neurons in
the AD group alone (n = 9, Z = 2.24,
p = 0.02). The graph represents data from nine AD
brains. In one case, the PHF-1 immunostaining for NFTs was not
available.
[View Larger Version of this Image (15K GIF file)]
Fig. 10.
a, Total SP density (neuritic and
cored plus diffuse plaques), as assessed from a Bielschowsky-stained
section in the EC, did not correlate with number of neurons in AD
brains (n = 10) (Spearman rank correlation test;
Z = 0.17, p = 0.86, NS).
b, The density of neuritic and cored plaques in the EC of AD
brains (n = 10), as assessed from a
Bielschowsky-stained section, negatively correlated with the number of
neurons (Spearman rank correlation test; Z = 2.44,
p = 0.01). c, The density of diffuse plaques
in the EC of AD brains (n = 10), as assessed from a
Bielschowsky-stained section, did not correlate with the number of
neurons (Spearman rank correlation test; Z = 1.72, p = 0.09, NS).
[View Larger Version of this Image (16K GIF file)]
DISCUSSION
The individuals included in this study were highly selected cases.
Half of them were carefully assessed cognitively intact subjects, and
four others had very mild stages of dementia. Although the number and
age span of the cases limit generalization of the findings, the
following four major conclusions can be drawn from the data: (1) There
are ~7 million neurons in the adult human EC. No significant loss of
neurons in the EC is detectable in cognitively normal subjects between
the sixth and ninth decades of life. (2) There is, by contrast, a very
severe neuronal loss in the EC even in very mild AD cases that are at
the threshold for clinical detection of dementia. This neuronal loss is
so marked that it must have started well before onset of clinical
symptoms. (3) The most dramatic neuronal loss selectively targets
layers II and IV of EC, paralleling the known susceptibility of cells
in these layers for NFT formation. As the clinical severity of dementia
progresses, the remaining layers of EC also are affected. (4) The
degree of neuronal loss in the EC parallels the incidence of NFTs and
neuritic plaques, but not to diffuse plaques without neuritic
changes.
Although individual variations were observed in our study, the neuronal
population in the EC, one of the regions that is known to be vulnerable
to AD changes, remained stable in nondemented individuals between the
sixth and ninth decades. Falkai et al. (1988) reported comparable
results in a group of 11 younger control cases. Trillo and Gonzalo
(1992) also found no significant neuronal loss in the lateral area of
the EC in 17 cases from age 35 to 75 years. Although these two latter
studies used counting procedures and sampling schemes that differ from
ours, their results are congruent with the data presented in this
series and support the conclusion that substantial neuronal loss does
not occur in the EC during healthy aging. Lippa et al. (1992), using
optical dissectors in single sections, showed no loss in EC in 10 nondemented cases between ages 42 and 87 years, although a 31-year-old
subject had higher numbers and a 97-year-old subject had lower numbers.
Losses in layer II were over 90% in nine AD patients, similar to our
data. Losses of ~75% of EC neurons in AD were reported by Fukutani
et al. (1995). In contrast to these data, Heinsen et al. (1994)
reported an age-related neuronal loss of 26-39% in EC among 22 individuals between 18 and 86 years of age. The apparent discrepancy
with the present results could be in part attributable to
case-selection procedures that may have resulted in contamination by
unsuspected early AD cases. In addition, Heinsen et al. counted only
partial thickness of thick histological sections, potentially creating
variability attributable to differential shrinkage during the staining
and mounting procedures of frozen sections.
Based on the same stereological unbiased methods used in the present
study, West et al. (1994) recently reported no change in neuron number
in several hippocampal subfields in normal aging, although they did
detect neuronal loss in the dentate hilus and subiculum. This pattern
of loss contrasted with loss primarily in the CA1 hippocampal region in
AD brains. Both our results and those of West et al. (1994) reinforce
the idea that there is a selective pattern of neuronal vulnerability in
AD that contributes to memory impairments: CA1 zone of the hippocampus
(West et al., 1994) and layers II and IV of EC (our study). The fact
that neuronal loss does not occur in these regions during the normal
aging process is consistent with the hypothesis that AD and aging are
not part of a continuous spectrum and suggests that normal aging and AD
can be differentiated from a neuropathological perspective.
The marked EC alterations in layers II and IV in clinically mild AD
highlight the relative selective vulnerability of these lamina. It
seems likely that these changes disrupt the recently described modular
organization of the EC and, hence, its contribution to memory-related
neural systems (Solodkin and Van Hoesen, 1996). It is important to note
that NFTs in these clinically mild cases also occur in the
CA1-subiculum of the hippocampus, the perirhinal cortex, inferior
temporal gyrus, the amygdala and posterior parahippocampal gyri,
cholinergic basal forebrain, and dorsal raphe, although in general to a
less dramatic extent than layer II of the EC (Arriagada et al., 1992a).
It is likely that neuronal loss occurs in these areas as well, and that
the net result of these multiple lesions in memory-related structures
accounts for the impairment in explicit memory function that occurs as
an early symptom in AD (Locascio et al., 1995). In contrast to the
marked loss of neurons in EC in patients with very mild dementia,
however, our recent studies in the superior temporal sulcus (STS)
association cortex suggest that the STS does not undergo neuronal loss
until a much later point in the disease process, when clinical symptoms
of a more advanced dementia are present (Hyman et al., 1995). In accord
with this, preliminary study of the STS in the CDR = 0.5 patients
in this study shows no difference in STS neuron number compared with
nondemented controls. Ultimately, the number of STS neurons decreases
by ~50% in advanced AD (Hyman et al., 1995).
The fact that the number of layer II neurons in the EC is fewer than
half of the control neuronal population at a time when only mild or
questionable clinical symptoms of AD become apparent supports the idea
of a large functional reserve in memory-related neural systems and is
consistent with a presymptomatic phase of AD. Clinical studies have
suggested that subtle cognitive changes might be present for years
before dementia can be detected reliably (Linn et al., 1995). It is
likely that a threshold of neuronal loss in the entorhinal region,
along with accompanying alterations in other memory-related structures,
must be reached before memory impairment becomes detectable clinically.
On the other hand, neuronal loss in layer II may well be maximal at a
time when global dementia rating scales reflect a moderate level of
impairment. The concept of such a substantial loss of EC neurons before
AD symptoms occur may be analogous to the observation that very
substantial neuronal losses are present in the substantia nigra before
extrapyramidal symptoms become apparent in Parkinson's disease (Hirsch
et al., 1988).
The neuronal loss in the entire EC is accompanied by a parallel
reduction of its volume, pointing to an associated loss of the
neuropil, presumably including synapses. Absolute synaptic loss is more
difficult than neuronal number to analyze, in part because of the
plastic renormalization of synaptic densities and the enlargement of
the remaining synaptic profiles (Coleman and Flood, 1988; De Kosky and
Scheff, 1990). However, there is a close correlation between loss of
synapses and synaptophysin immunostaining and cognitive deterioration
(Terry et al., 1991), and perhaps the neuronal loss we highlight
contributes to the synaptic alterations that have been observed in the
hippocampal formation (Hamos et al., 1989; Cabalka et al., 1992; Samuel
et al., 1994).
In addition to the estimate of total neurons in the EC, we calculated
the results obtained when we used only a single section (at the level
of the uncal hippocampus) from each case. The same trends are apparent
even sampling from only a single section, but because this estimate
does not take into account atrophy in the anterior-posterior
direction, the degree of loss in the AD cases is underestimated. For
example, had we used data from only one section, rather than a 32%
decrement in EC in the CDR 0.5 cases, we would have calculated only a
23% decrease in comparison to the average of the 10 controls. This
result may be of practical use in the design of future stereologically
based experiments in human cortices, given the difficulty of obtaining
serial sections throughout an entire structure in the human brain.
The results of this study show that the amount of neuronal loss in the
EC in AD brains parallels neuritic changes, including tangle formation
and neuritic plaques. In contrast, no correlation is found between cell
loss and amyloid deposition in diffuse plaques or in total plaques.
These observations are in agreement with previous morphometric studies
in other brain regions suggesting a strong correlation of NFTs with
clinical symptoms, but a less strong or no relationship between the
number of amyloid SPs and the duration or severity of illness
(Price et al., 1991; Terry et al., 1991; Arriagada et al., 1992a; Berg
et al., 1993; Bouras et al., 1993; Hyman et al., 1993; Nagy et al.,
1995; Gómez-Isla et al., 1996). These observations suggest that a
simple and direct correlation between A deposition and neurotoxicity
is unlikely. Given the relationship between tangle formation and cell
loss, it is surprising, at first glance, that cell loss does not
increase as a function of age, because there is an age-related increase
in tangles, in the absence of dementia (Price, 1991; Arriagada et al.,
1992b; Price, 1993). However, immunohistochemical stains for NFTs make
the presence of several dozen NFTs in a cortical area quite obvious,
whereas neuronal loss must be much more substantial before it can be
detected.
In summary, we demonstrate that neuronal loss does not occur in the EC
in the cognitively intact elderly, whereas there is a selective and
very dramatic loss of neurons in the same region even at the mildest
stages of dementia in AD. This finding supports a model in which AD and
normal aging are not part of a continuum and can be differentiated both
anatomically and clinically. The results highlight the need to develop
new diagnostic tests to predict the presymptomatic and very mild stages
of AD before massive neuronal loss in select neural populations has
occurred, when therapeutic intervention might be most effective.
FOOTNOTES
Received March 26, 1996; revised April 25, 1996; accepted May 1, 1996.
This work was supported in part by Grants AG05134, AG08487, AG03991,
and AG05681. We thank the physicians and staff of the Clinical Core of
the Alzheimer's Disease Research Center (ADRC) of Washington
University for the subject evaluations, the Neuropathology Core of the
ADRC for postmortem diagnosis of Alzheimer's disease, Dr. Elizabeth
Grant of the ADRC Biostatistics Core for clinical data analysis, and
Mr. Hieu Van Luu for the histological preparation of the sections.
Correspondence should be addressed to Bradley T. Hyman, Neurology
Service, Warren 407, Massachusetts General Hospital, Boston, MA
02114.
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