Zhurnal Nevropatologii i Psikhiatrii imen~S.S. Korsakova~ vol. 72~ no. 7, pp. 1024-I029~ 1972.
ABSOLUTE NUMBER OF NEURONS AND THICKNESS
OF THE CEREBRAL CORTEX DURING AGING,
SENILE AND VASCULAR DEMENTIA, AND
PICK'S AND ALZHEIMER'S DISEASES
V.F.
SHEFER
D e p a r t m e n t of E x p e r i m e n t a l Diagnosis and
L a b o r a t o r y of B r a i n Pathomorphology,
Bekhterev R e s e a r c h Institute,
Leningrad
The absolute n u m b e r of n e u r o n s and thickness of the cortex were
studied in a r e a s 6, 10, 18, 21, 21/38 and 40 and in the subieulum of
m e n t a l l y healthy p e r s o n s of different ages and in patients with s e n i l e
and v a s c u l a r d e m e n t i a or with P i c k ' s or A l z h e i m e r ' s d i s e a s e . In old
age the m e a n absolute n u m b e r of n e u r o n s in m e n t a l l y healthy p e r s o n s is
reduced by 20%, while the thickness of the cortex on the free surface
of the gyri r e m a i n s unchanged. In p e r s o n s with senile and v a s c u l a r d e m e n t i a the n u m b e r of n e r v e c e l l s is reduced by 35-38 %, but t h e r e is no
d e c r e a s e in the t h i c k n e s s of the cortex on its free s u r f a c e . In A l z h e i m e r ' s
d i s e a s e the n u m b e r of n e r v e cells is reduced by half and the thickness of
the cortex by 6% o P i c k ' s d i s e a s e is c h a r a c t e r i z e d by m a s s death of n e r v e
c e l l s in the affected a r e a s , leading to a r e d u c t i o n of 14-30 in their n u m ber, and to a d e c r e a s e in thickness of the c o r t e x by half. The s u b i c u l a r
c o r t e x thickness in old age is reduced by 28 % and in d i s e a s e s leading to
d e m e n t i a by 4 7 - 7 1 % .
It is generally considered that in old age and, in particular, in diseases leading
to dementia some of the nerve cells in the cortex die, as a result of which atrophy
of the brain develops and its cortex becomes thinner. However,
it is not known
which portion of the total number of nerve cells dies or whether there is a relationship between the severity of diseases leading to dementia and the number of nerve
cells found in the cortex. I found no reference to any- investigation in which the
absolute numbers of nerve cells in the cerebral cortex were compared in young and
old or in patients with various types of dementia.
Methods of determining the absolute number of nerve cells in the cerebral cortex are also undeveloped; I know of
three papers describing studies of the thickness of the cortex and its layers
during normal aging of the brain, but of no similar study of the dementias.
319
NEURONS
AND
THICKNESS
OF
CEREBRAL
CORTEX
DURING
AGING
Dalakashvili (1) concluded that in all a r e a s (1, 4, 9 and 19) the cortex thickness in
the middle-aged is reduced by 1-4% and in old p e r s o n s by 2 . 7 - 1 0 . 7 % compared
with the b r a i n of a m a n aged 35 y e a r s used as the control (one case~. S1~einina (2)
who m e a s u r e d the thickness of a r e a 45 in p e r s o n s 7 to 105 y e a r s old found that the
c o r t e x b e c o m e s t h i n n e r in old age. However, her value for the thickness of the c o r tex in a p e r s o n 105 y e a r s old (2.34 mm) lies within n o r m a l l i m i t s ( 2 . 5 - 2 . 3 ram) as
given in (3). Haug (4) states that t h e r e is no difference in the thickness of the c o r tex and its l a y e r s in a r e a s 17 in p e r s o n s 15 to 75 y e a r s old. Unfortunately these
w o r k e r s do not d e s c r i b e the c o r t i c a l surface where the m e a s u r e m e n t s were made.
The objective of m y i n v e s t i g a t i o n was to calculate the r a t i o s between the absolute n u m b e r s of n e r v e cells in l a y e r III of c e r t a i n c o r t i c a l a r e a s of the b r a i n and to
m e a s u r e the thickness of the cortex and its l a y e r s in the same a r e a s in the following groups: 1) young p e r s o n s f r o m 19 to 28 y e a r s old with no m e n t a l d i s e a s e and
dying from accidental causes (5 p e r s o n s ) . This group will subsequently be named
the control; 2) ten m e n t a l l y healthy old p e r s o n s (mean age 77 y e a r s ) ; 3) six
patients (mean age 79 years) who suffered from s e n i l e dementia; 4) six p e r s o n s
(mean age 71 years) i n whom a v a s c u l a r d e m e n t i a had been diagnosed clinically;
5) six patients (mean age 67 years) with A l z h e i m e r ' s d i s e a s e ; 6) six patients (mean
age 55 years) with P i c k ' s d i s e a s e . In two patients with P i c k ' s d i s e a s e only the
t e m p o r a l lobes were affected; in the other four patients the frontal and t e m p o r a l
lobes were affected.
The b r a i n s were fixed in formalin, embedded in celloidin, and sections were
stained by N i s s l ' s method. The r a t i o s between the absolute n u m b e r s of n e r v e cells
i n l a y e r III of the free c o r t i c a l s u r f a c e of the left h e m i s p h e r e were d e t e r m i n e d in
a r e a s 6, 10, 18, 21, 21/38 and 40 and also in the s u b i c u h m (the a r c h i c o r t e x in the
depth of the hippocampal f i s s u r e ) .
To calculate the absolute n u m b e r of n e r v e cells in c o r t i c a l l a y e r III in a given
a r e a it is n e c e s s a r y to know the volume of this l a y e r (V) and the m e a n n u m b e r of
cells (a) in a known volume of this l a y e r (v). C l e a r l y the absolute n u m b e r of n e r v e
c e l l s (A) in l a y e r III of the a r e a studied can be e x p r e s s e d by the equation:
A = V--- • a
V
V can be calculated by the equation:
V=L•
where L is the length of the layer; M its width; H its height. The volume of b r a i n
s u b s t a n c e in one field of v i s i o n of the section u n d e r c o n s t a n t m a g n i f i c a t i o n was taken
as v. Its value is found by the equation:
v=S•
where S is the a r e a of a field of v i s i o n of the m i c r o s c o p e under constant m a g n i f i c a tion; h the thickness of the s e c t i o n in the s a m e field of vision. The n u m b e r of n e r v e
c e l l s (a) is then counted. By substituting the values of V and v in the equation for
calculating the absolute n u m b e r of n e r v e cells it a s s u m e s the following form:
A=Vxa
v
LxMxH
SYh
xa
However, to c o m p a r e absolute n u m b e r s of n e r v e cells in the v a r i o u s groups of
s u b j e c t s , an equation can accordingly be deduced. A s s u m e that the absolute n u m b e r of n e r v e c e l l s in one p a r t i c u l a r group of subjects is At (all t e r m s in the equation are marked by the c o r r e s p o n d i n g s u b s c r i p t 1), and that the absolute n u m b e r
320
NEURONS
AND
THICKNESS
OF
CEREBRAL
CORTEX
DURING
AGING
i n the group taken for c o m p a r i s o n is A2 (all other t e r m s a r e given the c o r r e s p o n d i n g
s u b s c r i p t ) . The equation for d e t e r m i n i n g the r a t i o between the absolute n u m b e r of
n e r v e c e l l s (K) will then be:
K = A i:A2=
Vl• ai :
)
• a2
V2• a2• Vl.
By s u b s t i t u t i n g the values of V and v i n the equation it a s s u m e s the following form:
K = (Li • M1 • Hi) • al • (S2 • h2)
(L 2 • M2 • H2) • a 2 • (Si • hi)"
Since S is a constant, the final equation is:
K = L1 • MI•
a l • h2
L 2 • M2• H2 • a 2• h l"
To calculate the r a t i o s between the n u m b e r s of n e r v e cells in the groups of
s u b j e c t s it is e s s e n t i a l to know the length, width and thickness of l a y e r III of the
c o r t e x a r e a investigated, the m e a n n u m b e r of n e r v e cells in the m i c r o s c o p i c field,
and the m e a n t h i c k n e s s of the s e c t i o n where the n e r v e c e l l s were counted. Evidently
the width and length of the free s u r f a c e of l a y e r III in a p a r t i c u l a r gyrus a r e d i r e c t l y
p r o p o r t i o n a l to its width and length. The r a t i o s between the length and width of
the gyri of a given a r e a of c o r t e x will thus be equal to the s a m e r a t i o s between the
width and length of the free s u r f a c e of l a y e r III. When the value of K is d e t e r m i n e d
for the c o r t e x a r e a and not for a n individual gyrus, the n u m b e r of gyri i n that a r e a
m u s t be taken into account. However, s i n c e the n u m b e r of gyri in the b r a i n is on
the a v e r a g e constant, and evidently unchanged with age, it was decided that this
value could be d i s r e g a r d e d . Simple c a l c u l a t i o n shows that the length of a wavy line
(the gyri have approximately this form) v a r i e s d i r e c t l y p r o p o r t i o n a l l y to the d i s t a n c e s between the e x t r e m e points of the wavy Hne p e r p e n d i c u l a r l y to the axis. The
r a t i o s will thus be equal to the r a t i o s between the lengths of the c o r r e s p o n d i n g wavy
l i n e . To judge the length of the gyri, t h r e e basic m e a s u r e m e n t s were used: 1) the
s h o r t e s t d i s t a n c e from the frontal pole (the most a n t e r i o r point) to the p r e c e n t r a l
g y r u s at the l e v e l of the f i r s t frontal f i s s u r e . This d i s t a n c e is a sufficiently o b j e c t ive c r i t e r i o n of the change in length of the frontal gyri; 2) the s h o r t e s t d i s t a n c e
from the frontal pole to the occipital (after deduction of the p r e c e d i n g value from it).
This was used as the c r i t e r i o n of a change in length of the occipital and p a r i e t a l g y r i ;
3) the s h o r t e s t d i s t a n c e from the t e m p o r a l to the occipital pole. This value was used
to e s t i m a t e changes in length of the t e m p o r a l gyri. To d e t e r m i n e the m e a n width
of a gyrus or of the gyri of a p a r t i c u l a r lobe (NI) the width of all gyri of the frontal
lobe and t e m p o r a l lobe and of the s u p r a m a r g i n a l and p r e c e n t r a l gyri was m e a s u r e d .
Up to 400 such m e a s u r e m e n t s were made on the left h e m i s p h e r e of each b r a i n . The
t h i c k n e s s of l a y e r III (H) on its free s u r f a c e was m e a s u r e d in histological sections
u n d e r the m i c r o s c o p e by an o c u l a r m i c r o m e t e r . Under a magnification (90x7~1.5)
the n e r v e c e l l s were counted in 20 fields of v i s i o n of l a y e r III~ of the free c o r t i c a l
s u r f a c e . The m e a n n u m b e r of n e r v e cells (a) in the field of v i s i o n was d e t e r m i n e d .
The fields of v i s i o n counted formed a continuous s e r i e s . Only those n e r v e c e l l s in
which a n u c l e u s and nucleolus could be distinguished were counted. In each field of
v i s i o n in which the n u m b e r of n e r v e c e l l s was counted t h i c k n e s s of the s e c t i o n was
m e a s u r e d . The m e a n thickness of the s e c t i o n was then calculated (h). To d e t e r m i n e the t h i c k n e s s of the s e c t i o n the upper and lower points of the s e c t i o n were
focussed and the d i s t a n c e m e a s u r e d by the v e r n i e r of the m i c r o m e t e r screw. As a
r e s u l t of these m e a s u r e m e n t s values e x p r e s s e d in different units of m e a s u r e m e n t
were
obtained.
It is unnecessary
to reduce them to the same
321
metric unit, however,
NEURONS
AND
THICKNESS
OF
CEREBRAL
CORTEX
DURING
AGING
for in accordance with the equation derived it is the r a t i o between these values
which m a t t e r s , and this would be unaffected by the i n t r o d u c t i o n of the same c o r r e c t i o n factor into both n u m e r a t o r and denominator. All the data were thus obtained for calculating the r a t i o s between the absolute n u m b e r s of n e r v e cells in
different groups in the cortex.
In the equation for d e t e r m i n i n g the absolute n u m b e r of n e r v e cells in a r e a 6
the index (M) reflected the m e a n width of the p r e c e n t r a l gyrus, while the t e r m L
was d i s r e g a r d e d for no sufficiently objective c r i t e r i o n for it was available. In a r e a
10 the index M was taken as the m e a n width of all the frontal gyri, and the index L
as the distance from the frontal pole to the p r e c e n t r a l gyrus. In a r e a 18 the index
M reflected the mean width of all the occipital gyri, while the index L reflected the
distance from the precentral gyrus to the occipital pole. In area 21, M represented
the mean width of the middle temporal gyrus and L the distance from the temporal
to the occipital pole. In area 21/38, M was taken as the mean width of the temporal
gyri and L as the distance from the temporal to the occipital pole. In area 40 the
factor M reflected the mean width of the supramarginal
gyrus and L the distance
from the p r e c e n t r a l gyrus to the occipital pole. When the n u m b e r of n e r v e cells in
the subiculum was d e t e r m i n e d the factors M and L were d i s r e g a r d e d and factor H
was taken as the thickness of the c o r t i c a l l a m i n a .
The method used is not p e r f e c t but it c a n provide approximate data for the a b s o lute n u m b e r of n e r v e c e l l s in different p a r t s of the c e r e b r a l cortex.
The r e s u l t s obtained for the absolute n u m b e r s of n e r v e cells in the c o n t r o l and
other groups a r e given in Table 1. The c o r r e s p o n d i n g data a r e p r e s e n t e d as r a t i o s
between the n u m b e r of cells in the control group and the n u m b e r of cells i n each of
the other groups.
C o m p a r i s o n of the n u m b e r of c e l l s in the cortex of m e n t a l l y healthy p e r s o n s
dying i n old age with the n u m b e r of cells in the b r a i n of the c o n t r o l subjects i . e . ,
p e r s o n s dying at the age of 19-28 y e a r s , r e v e a l s a d e c r e a s e in the absolute n u m b e r
of n e r v e cells in old age in all r e g i o n s of the cortex. This d e c r e a s e was p a r t i c u l a r l y
m a r k e d in a r e a s 6 (by 22%), 10 (by 28%) and 21 (by 23%) and the subiculum (29%),
with an a v e r a g e d e c r e a s e of 20% for all r e g i o n s (the index for the control group
was always 100%).
In senile d e m e n t i a the d e c r e a s e in the n u m b e r of n e r v e c e l l s was g r e a t e r than
in the previous group (on the average by 38 %). It was p a r t i c u l a r l y m a r k e d in a r e a s
10 (35%), 21 (by 47%) and 21/38 (by 37%) and in the s u b i c u l u m (by 60%). This
suggests that i n this d i s e a s e m o r e n e r v e cells die in the frontal and t e m p o r a l lobes
and i n the subiculum than in the p r e c e n t r a l gyrus (area 6) and the p a r i e t a l and occipi t a l lobes (areas 40 and 18).
In v a s c u l a r d e m e n t i a the m e a n d e c r e a s e in the n u m b e r of n e r v e cells was by
35%. The c o n s i d e r a b l e d e c r e a s e (by 36 %) in the n u m b e r of n e r v e cells in the motor
c o r t e x (area 6) in this d i s e a s e is noteworthy. On the whole, the c h a r a c t e r and degree of the changes have much in c o m m o n in s e n i l e and v a s c u l a r dementia.
In A l z h e i m e r t s d i s e a s e the d e c r e a s e i n the absolute n u m b e r of n e r v e cells in
all r e g i o n s except the subiculum was g r e a t e r than in the groups of patients with
s e n i l e and v a s c u l a r dementia. The m e a n d e c r e a s e in the n u m b e r of n e r v e cells was
about 50%, falling to a p p r o x i m a t e l y 48% of t h e i r n u m b e r in the b r a i n of the control
group.
By c o n t r a s t with the groups with s e n i l e and v a s c u l a r dementia, in this
d i s e a s e t h e r e is a w e l l - m a r k e d deficiency of cells (a d e c r e a s e of 46% ) in a r e a 40
(the s u p r a m a r g i n a l gyrus). In a r e a 18 the absolute n u m b e r of n e r v e cells was r e duced by 39% and in a r e a 10 by 43%. In all r e g i o n s of the cortex the n u m b e r of
n e r v e c e l l s was reduced approximately by half.
In P i c k ' s d i s e a s e the changes o b s e r v e d were different and c o n s i s t e n t . In this
group the m e a n i n d e x a c r o s s b r a i n a r e a s was calculated (8.05), but is r e l a t i v e l y
u s e l e s s because it o b s c u r e s the local c h a r a c t e r of the changes in this d i s e a s e .
322
NEURONS AND THICKNESS OF CEREBRAL CORTEX DURING AGING
TABLE 1. Ratios between Absolute N u m b e r s of Nerve Cells in Groups Studied
Ratios between
Groups compared with
control
Cortical regions investigated
l
6
Old, mentally
healthy persons,
Senile dementia
Vascular dementia
Alzheimer's disease
Pick's disease
TABLE
numbers of nerve cells in control group and
all other groups
2.
18
i0
21
1.29 1.4
1.16
1.3
t.87
1.2 11.53 1.34
1.58 [ 1,45 1.26
1.75
2.04 1.74 1.65
1.96
1.32 5.17 1.1
14.0
Mean
Thickness
21/38
40
subiculum
for all c o r t i cal regions
1.14
1.59
1.35
2.02
29.8
1.18
1.3
1.44
1.86
1.7
1.41
2.46
1.94
2.16
3.26
1.27
i. 61
i. 54
I. 92
8.05
of Cortex (in conventional
units)
T h i c k n e s s of cortex
in l a y e r s
Group
Control
Old, m e n t a l l y
healthy p e r s o n s
Vascular dementia
Senile d e m e n t i a
Alzheimer's disease
Pick's disease 1
[ I
II
III
IV
V-Vli
3.1
2.5
11.7
3.2
19.3
39.8
3.2
3.7
3.1
3.2
3.0
2.0
2.5
2.8
2.7
2.5
2.4
1.8
12.2
11.8
11.0
10.8
10.2
7.4
3.4
3.5
3.8
3.3
3.5
2.4
18.6
18.7
18.6
17.4
15.3
9.3
40.0
40.5
39.2
37.2
34.4
22.9
1Top row of n u m b e r s -- m e a s u r e m e n t s in c o r t i c a l a r e a s 6, 18, and 40; bottom
row -- m e a s u r e m e n t s . i n a r e a s 10, 21 and 21/38.
TABLE 3.
I
T h i c k n e s s of Cortex in Subiculum (in conventional units)
Group
Control
IOld, m e n t a l l y
healthy p e r s o n s
Vascular dementia
Senile d e m e n t i a
Alzheimer's disease
Pick's disease
T h i c k n e s s of cortex
Change compared with
control group, in %
28.5
20.6
15.1
12.8
12.4
8.3
323
72
53
45
43
29
NEURONS AND THICKNESS O F CEREBRAL CORTEX DURING AGING
Pick's disease is characterized by mass death of the nerve cells in areas i0, 21,
and 21/38, with a resulting decrease in the absolute number of nerve cells in these
regions by 5, 14, and 30 times respectively.
The figures obtained for the frontal
lobe (area i0) do not reflect the true picture, for of six cases of Pick's disease
studied a characteristic lesion in the frontal lobes was observed in only four. If
one considers, however, only the cases with frontal lobe involvement, the decrease
in the absolute number of nerve cells in area i0 is approximately the same as in
area 21/38. In Pick's disease there was the greatest (threefold) decrease in the
number of nerve cells in the subiculum.
In area 40 it was greater than in senile
and vascular dementia and was approximately the same as that observed in Alzheimer's disease (a decrease of 41%).
The number of nerve cells in areas 6 and
18 in Pick's disease was the same as in the group of mentally healthy old persons,
i. e., it was evidently within the normal limits for that age group.
Changes in the thickness of the free surface of cortex and its layers are presented in Table 2. The mean thickness of the cortical layers on its free surface
are shown.
The results indicate that the thickness of the cortex and its layers in
young and old mentally healthy persons and in persons with senile and vascular
dementia are practically identical. In Alzheimer ts disease the thickness of the
cortex is reduced on the average by 6%.
In persons with Pick's disease, on the
other hand, in the less severely affected regions (areas 6, 18 and 40) the thickness
of the cortex is reduced by 14%, while in the most severely affected regions (areas
40, 21 and 21/38) it is reduced by almost half. When some of the nerve cells die
and t h e r e is no i n c r e a s e in the abso!ute n u m b e r
of g l i a l c e l l s (these also w e r e counted),
t h e r e is no d e c r e a s e in the t h i c k n e s s of the
c o r t e x on i t s f r e e s u r f a c e . A p o s s i b l e e x p l a n a t i o n of this fact is that the volume of
J
,i
c o r t e x on the free s u r f a c e is r e d u c e d mainly
~i. I ',
'
I Jl
through n a r r o w i n g of the g y r i (Fig. 1). In
A l z h e i m e r ' s and P i c k ' s d i s e a s e s , however,
this evidently does not c o m p e n s a t e for the
r e d u c t i o n in volume of the c o r t i c a l substance,
so that the c o r t e x b e c o m e s t h i n n e r .
M e a s u r e m e n t s of c o r t i c a l t h i c k n e s s in
Fig. I. Schematic representation
the subieulum (given in T a b l e 3) indicate
of changes in transverse section
1) a d e c r e a s e in the t h i c k n e s s of this l a y e r in
through gyrus.
old, m e n t a l l y healthy s u b j e c t s by 28 %, in
v a s c u l a r d e m e n t i a by 47 %, in s e n i l e d e m e n t i a by 55%, in A l z h e i m e r ' s d i s e a s e by 57%, and in P i c k ' s d i s e a s e by 71% and
2) a m a r k e d d e c r e a s e is c h a r a c t e r i s t i c of t h e s e d i s e a s e s .
The r e s u l t s d e s c r i b e d in this p a p e r r e f l e c t changes in the n e r v e c e l l s in l a y e r
III of the c o r t e x and in the subiculum only and without v e r i f i c a t i o n they cannot be
applied to o t h e r l a y e r s of the c o r t e x o r to o t h e r r e g i o n s of the b r a i n .
dJl! ",,1', /:
REFERENCES
1.
2.
3.
4.
DALAKASHVILI, S.M. The State of the S t r u c t u r e of s o m e C o r t i c a l A r e a s
of the B r a i n d u r i n g Aging. T b i l i s i , 1967.
SHEININA, L . I . Soobshch. Akad. Nauk Gruz. SSR. 35:413, 1954.
A t l a s of the C y t o a r c h i t e e t o n i c s of the Human C e r e b r a l C o r t e x . Moscow,
1955.
HAUG, H. Quantitative Untersuchungen an d e r Sehrinde. Stuttgart, 1958.
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