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Dendritic atrophy in children with Down's syndrome.

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Dendritic Atrophy in CMdren
with Down’s Syndrome
L. E. Becker, MD, D. L. Armstrong, MD,’ and F. Chan, MSc
~
Dendritic branching was evaluated in the visual cortex of 8 children with Down’s syndrome and 10 controls, ranging
in age from 4 months to 7 years and divided into infantile, late-infantile, and juvenile groups. Camera lucida drawings
of Golgi-impregnated neurons were used for examining the following dendritic aspects: dendritic intersections as a
function of distance from the cell body, point of maximum dendritic branching, number of branch orders, total
number of branch segments, and total dendritic length. The number of intersections and the total dendritic length
were above normal in the infantile period (6 months old or less) and dropped steadily to significantly below normal in
the juvenile group (older than 2 years). These reductions contrasted with expanding dendritic arborization in normal
children. The results suggest that the dendritic tree atophies in early childhood in Down’s syndrome.
Becker LE, Armstrong DL, Chan F: Dendritic atrophy in children with Down’s syndrome.
Ann Neurol 20:520-526, 1986
Although a variety of abnormalities may occur in subjects with Down’s syndrome, only mental retardation
and an extra chromosome 21 are seen in all patients
C20). The morphological basis for the mental retardation is not known, but cytoarchitectural abnormalities
may be important. Davidoff [S], Colon 161, and Ross
and co-workers i: 171 have described a reduction in the
number of neurons. Marin-Padilla i: 131 reported morphological changes in the dendritic spines of a 19month-old child with Down’s syndrome, including unusually long spines, very short spines, and a reduced
number of spines. Similarly, Purpura [ 151 investigated
2 cases of Down’s syndrome in children at 8 and 9
months of age, respectively, and found notable alterations in the dendritic spine structure of the hippocampal neurons. Suetsugu and Mehraein {23} examined
the hippocampus and cingulate gyrus in 7 patients with
Down’s syndrome aged 7 to 23 years and found no
significant reduction in the number of spines on the
apical dendrites. In children with Down’s syndrome
who are over 4 months of age, we found a markedly
reduced number of spines in the neurons from the
visual cortex [24].
In this report we examine the growth of the dendritic tree in children with Down’s syndrome and compare it with that in control patients.
Materials and Methods
The brains of 8 patients with Down’s syndrome confirmed
by chromosomal analysis and of 10 neurologically normal
From the Division of Neuropathology, University of Toronto, and
The Hospital for Sick Children, Toronto, Ontario, Canada.
Received Sept 24, 1985, and in revised form Feb 21, 1986. Accepted for publication Feb 22, 1986.
5 20
patients from The Hospital for Sick Children, Toronto, were
obtained at postmortem examination less than 24 hours after
death. The ages in the patients with Down’s syndrome were:
4 months (1 patient), 6 months (l), 11 months (2), 16
months (2), and 5 years (2). Death was caused by cardiac
arrest after cardiac catheterization (2 patients), cardiac arrest
after cardiac operation ( 3 ) , aspiration ( l ) , bacterial endocarditis (I), and bronchopneumonia (1). Age-matched control
patients were studied; their ages were 4 , 6 , 9 , 10, 11, 12, and
18 months (1 patient each), 5 years (2), and 7 years (1). The
controls had no neurological disease and their brains were
anatomically normal. Death in the control group had resulted
from sudden infant death syndrome, hemolytic uremic syndrome, congenital heart disease, or drowning. The subjects
and controls were divided into three groups: infantile (6
months old or under), late infantile (more than 6 months to 2
years old), and juvenile (more than 2 years old).
Tissue from the visual cortex (area O A of Von Economo)
was stained by a modification of the rapid Golgi method,
embedded in paraffin, and sectioned at 50 y m [I, 24, 25).
These sections were compared with 100-ym sections to determine whether there was any significant difference in the
completeness of the analysis of dendritic arborization.
More than 20 serial sections from each brain were examined for dendritic development. From each brain, 10 representative Layer 3 and Layer 5 pyramidal cells were chosen
randomly from completely impregnated cells with the soma
lying near the center of the thickness of the section and
unobscured by other tissue elements. These cells were drawn
at 270 x with the assistance of a camera lucida. Cells from all
brains ‘were coded and the identity was not known until after
quantirations were complete. Neurons were examined in
both layer 3 and Layer 5 pyramidal cells: 20 were invesAddress reprint requests to Dr Becker, Department of Pathology,
The Hospital for Sick Children, 5 5 5 University Ave, Toronto, OnM5G 1x8‘
“Present address: Department of Pathology, Baylor College of
Medicine, Houston, TX 77030.
tigated in the infantile group (control, 20), 40 in the late
infantile group (control, 50), and 20 in the juvenile group
(control, 30).
Dendritic branching was examined from two main perspectives: quantitation of dendritic intersections relative to
the distance to the cell body using Sholl’s concentric circle
method [ l , 2 11, and measurements of length and numbers of
dendritic branches in centrifugal ordering systems [ l , 4, 7).
The 50- or 100-pm sections permitted the measurement
of some but never all of the dendrites of any given neuron.
No correction was used for the portion of dendritic tree that
was lost by sectioning or that was required to complete the
three-dimensional structure; Coleman and Riesen 151 found
that the relative difference between neurons remains essentially constant without such correction.
Dendritic intersections relative to the distance to the cell
body were analyzed by counting the number of dendrites
intersecting each circle of a series of concentric shells at 20p m intervals from the cell body. A radius of 300 p m from
the center of the neuron was analyzed. The number of intersections was then plotted as a function of the distance from
the cell body [l].
Data from this analysis were expressed as the number of
intersections from apical and basal dendrites. For each set of
cells in each age category, the mean and standard deviation
of the total number of dendritic intersections within the 300p m radius were computed. In addition, distribution of the
number of intersections as distances from the center of the
cell was fitted to a normal curve by square-root transformation of the distance; hence, we computed the point of maximum branching and its confidence limits. One-way analysis
of variance and Duncan’s multiple-range test were used to
determine the significance of differences between ages. Twosample Student’s t tests were done to determine individual
differences between p i r e d groups of subjects add controls.
Dendritic branch segments were analyzed in a centrifugal
ordering system, with numbering beginning with the first
projection from the cell body (order number 1). Each branch
segment for all cells was measured by placing the camera
lucida drawing o n the surface of an Apple I1 graphic tablet
interfaced with a programmed Apple I1 computer. Measure-
ments were recorded for each cell as the number of branch
orders, the total number of branch segments, and the total
dendritic length. The means for the set of cells in each layer
for each of the above aspects were compared berween patients and controls for each age group. Student’s t test was
used to determine statistical significance.
Results
A comparison of 50- and 100-ym sections showed no
significant differences in the number of dendritic intersections or branch segments of pyramidal neurons in
Layers 3 and 5 of the visual cortex.
Dendritic Intersections
The infantile groups in general showed a higher number of intersections in patients than in controls (Table
1). The difference was significant in Layer 3 cells (p <
0.05), specifically at 140 to 220 y m from the cell body
on the apical dendrite and at 60 to 200 ym on the
basal dendrite (Figs 1, 2). The difference was reversed
in the late-infantile period, as the number of intersections decreased with increasing age in patients and increased in controls. This was especially significant in
Layer 5 neurons in basal dendrites at 60 to 240 pm.
In the juvenile groups, the change became highly
significant in Layers 3 and 5 (p < 0.001) in both apical
and basal dendrites. The most active regions of the
dendrite, defined as the regions where the differences
were significant, were between 60 and 200 ym on the
basal dendrite and between 140 and 240 ym on the
apical dendrite.
The mean distance from the perikaryon to the point
of maximum branching on the apical and basal dendrites of both Layers 3 and 5 neurons decreased from
the infantile to the juvenile group in patients and increased in controls (Table 2). The difference in distance between patients and controls was significant in
Layer 3 apical dendrite neurons of the juvenile group,
Table I . Comparison of Mean (&SDi Total Number of Intersections Within a 300-pm Radius of Apical and Basal
Pyrumidul Neurons in Visual Cortex in Luyers 3 and 5 j a r Each Group of PatimtJ and Controls
~~
Layer 5
Layer 3
Patients
Neurons
Apical
Infantile
Late infantile
Juvenile
Basal
Infantile
Late infantile
Juvenile
Controls
Significance
Patients
Controls
Significance
Mean
SD
Mean
SD
(PI
Mean
SD
Mean
SD
(PJ
39.55
28.83
24.75
23.17
8.49
9.50
24.20
33.12
37.77
8.56
11.03
10.71
<0.01
<0.05
<0.001
34.50
36.58
20.60
16.63
16.50
8.06
31.85
35.70
35.17
10.28
11.90
16.34
NS
NS
<0.001
45.80
28.03
22.65
32.64
12.74
11.78
18.25
31.28
36.73
9.61
12.64
16.08
<0.01
NS
<0.001
54.10
42.90
28.75
35.13
27.43
14.26
48.35
57.88
40.80
28.17
27.58
24.55
NS
<0.05
<0.01
SD = standard deviation; NS = not significant.
Becker et al: Dendritic Atrophy in Down’s Syndrome
521
APICAL DENDRITES
LAYER 3
BASAL DENDRITES
LAYER 3
1
1
l01
8
6
4
2
0
20
60
100
140
180 220
260
300
20
60
100
140
180 220
260
300
DISTANCE FROM CELL BODY IN MICRONS
in Layer 3 basal dendrite neurons of the infantile
group, and in the basal dendrites of both Layers 3 and
5 of the juvenile groups.
Length and Numbers of Dendritic Brunches
In patients, the mean total apical and basal dendritic
length per neuron (Layers 3 and 5 ) decreased from the
infantile to the juvenile groups, whereas it increased in
the controls (Table 3). In Layer 3 the differences between patients and controls were significant in the infantile and juvenile groups, but not in the late-infantile
groups. In Layer 5 the differences were significant for
apical dendrites in the juvenile groups and for basal
dendrites in the late-infantile and juvenile groups.
The mean number of branch orders per cell in apical
and basal dendrites (Layers 3 and 5 ) did not differ
significantly from control values.
The number of dendritic branches followed the
same pattern as did the dendritic length (i.e., the number was greater in patients than controls in the infantile
group and decreased steadily from the infantile to the
522 Annals of Neurology
Vol 20
N o 4 October 1986
Fig I . Number of intersectionsfor apical and basal dendrites of
Layer 3 aJ a function of distance from the cell body in Downi
syndrome (black bar) and controL (white bar) snbjects at d&bent ages (upper, infantile; middle, late infantile; lower.juvenile).
Cross-batcbed bars indicate overlap.
juvenile groups). This was especially significant in the
basal dendrites of Layer 3 for the infantile group
(Table 4). Control neurons (Layer 3) in the lateinfantile and juvenile groups had an insignificant increase in dendritic branches. In Layer 5 , the number of
branches was significantly reduced in the juvenile
group for apical dendrites and in the late-infantile
group for basal dendrites.
In most of these quantitation studies, infantile patients not only showed higher mean values than did
controls but also exhibited much higher standard deviations. 'This was especially apparent in the number of
dendritic intersections of Layer 3 cells (Table 1) and in
the total dendritic length analysis of both Layers 3 and
5 neurons (Table 3).
lo
APICAL DENDRITES
LAYER 5
1
BASAL DENDRITES
LAYER 5
1
lo]
8
6
4
2
0
20
60
100
140
180 220 260 300
20
60
100 140
180 220
260
300
DISTANCE FROM CELL BODY IN MICRONS
Fig 2. Number of intersectionsfor apical and basaldendrites of
k y e r 5 as a function of distance from the cell body in Down's
syndrome (black bar) and control (white bar) slrbjects at d;fferent ages (upper, infantile; middle, late infantile; lower, juvenile).
Cross-hatched bars indicate overlap.
Table 2. Mean Distance (pm)from the Perikalyon t o the Point of Maximum Branching of Apical and Basal
Pyramidal Neurons in the Visual Cortex in Layers 3 and 5 for Each Group of Patients and Controls
Layer 5
Layer 3
Neurons
Apical
Infantile
Late infantile
Juvenile
Basal
Infantile
Late infantile
Juvenile
Patients
Controls
Significance'
Patients
Controls
Significance"
107.10
122.27
9 1.90
110.10
127.50
142.80
NS
NS
131.20
127.33
100.20
121.90
131.37
136.90
NS
60.80
46.10
57.17
70.00
71.70
63.00
45.10
73.05
79.03
91.20
NS
NS
48.87
39.10
0.05
0.05
NS
0.05
NS
NS
0.05
"Duncan's multiple-range test.
SD = standard deviation; NS = not significant.
Becker et al: Dendritic Atrophy in Down's Syndrome
523
Table 3. Comparzson of Mean ( k S D ) Dendritic Length (@miof Apical and Bcrsal Pyramidal Neurons in Visual Cortex
in Layers 3 and 5 for Each Subgroup of Patients and Controls
Layer 3
Patients
Neurons
Apical
Infantile
Late infantile
Juvenile
Basal
Infantile
Late infantile
Juvenile
Layer 5
-
Controls
Patients
Significance
-
Cp)
M=an
Controls
Significance
(pi
Mean
SD
1092.32
824.48
618.04
751.36 664.72
325.67 955.09
250.30 986.81
265.53 c0.05
366.53 NS
345.41 <0.001
1275.08
1230.38
‘582.64
700.25
697.22
284.07
1246.64 425.44
1181.20 496.28
969.80 479.81
NS
NS
1213.21
689.08
506.08
982.33
312.11
273.38
229.60 <0.01
335.91 NS
380.50 <0.001
1102.62
1095.36
653.48
1011.42
686.22
320.20
1307.29 742.53
1447.85 769.48
746.54 589.28
NS
<0.05
<0.05
Mean
465.49
783.42
886.85
SD
SD
Mean
SD
<0.01
SD = standard deviation; NS = not significant.
Table 4. Comparison of Mean (?SD) Number of Dendrite Branches ofApir,zl and Basal Pyramidal Neurons
in Visual Cortex Layers 3 and 5 for Each Group of Patients and Controls
Layer 5
Layer 3
Patients
Neurons
Apical
Infantile
Late infantile
Juvenile
Basal
Infantile
Lateinfantile
Juvenile
Mean
SD
Controls
Significance
Patients
Controls
Significance
Mean
SD
(p)
Mean
SD
Mean
SD
(p)
21.50
16.73
16.40
8.30
5.48
7.37
17.70
19.10
20.10
5.44
8.35
5.73
NS
NS
NS
17.10
19.28
12.20
5.96
10.56
5.78
17.75
17.50
17.87
6.92
7.96
9.18
NS
NS
<0.01
25.85
20.13
16.75
14.20
5.95
7.41
17.60
21.34
20.97
6.72
7.08
8.18
<0.05
NS
NS
22.60
19.55
18.15
8.44
8.61
7.62
19.75
23.78
17.50
7.73
8.82
7.15
NS
<0.05
NS
SD = standard deviation; NS = not significant.
Discussion
Pyramidal neurons have a characteristic dendritic tree
shape. The degree to which this familiar morphology is
genetically determined or influenced by environmental
factors remains unknown. Using animal models, some
progress has been made in defining the factors that
control dendritic growth and organization {2, 5 , 9-1 1,
181. The structure, which may be genetically determined, is influenced by the mechanical adhesive or
repulsive forces that are exerted between the growth
cones of the neuron and ingrowing axons. Some remodeling of the dendritic tree can occur as a response
to functional influence { 191.
The degree of overlap between structural and functional factors is not always clear. In subjects with
Down’s syndrome, genetically determined structural
factors may predominate, but functional environmental factors may also play a role in dendritic development.
524 Annals of Neurology Vol 20 No 4 October 1986
We have compared the postnatal growth of neuronal
dendrites in the visual cortex of controls and subjects
with Down’s syndrome. The number of samples from
the Down’s syndrome group was small, but we were
able to observe the information from these patients in
the context of a larger population of normal samples
{ 11, from which we selected appropriate age-matched
control subjects. We have previously documented observations in dendritic spine development in Down’:$
syndrome 1241 and found no difference up to 40
weeks’ postconceptional age in the number, distribution, or (using electron microscopy) morphology { 161.
However, after 4 months of age, there was a significant
decrease in the spines, which tended to be long and
thin. Although it cannot be assumed that spines and
immature neurons necessarily make functional synaptic contacts [16, 211, the development of spines does
appear to be a major feature of postnatal maturation.
Wisniewski and co-workers [26] have shown de-
creased density and size of synapses in Down’s syndrome.
Our analysis of dendritic branching development in
brains of patients with Down’s syndrome reveals that
the pattern of branching is different from that of control brains. in the infantile period, the total number of
intersections was greater in subjects with Down’s syndrome than in controls. By the juvenile period, the
number of intersections was significantly decreased in
both Layers 3 and 5 at almost all distances greater than
50 pm from the perikaryon. The mean distance from
the perikaryon to the point of maximum branching in
both apical and basal dendrites and of both Layers 3
and 5 neurons increased with age in controls and decreased in infants with Down’s syndrome.
Total mean dendritic length (apical plus basal) per
cell in Layer 3 decreased by almost 50% from the
infantile to the juvenile groups in patients. In controls,
total length increased by 65% over the same age span.
Thus, in patients we saw a dramatic cessation of growth
together with actual dendritic shortening or atrophy.
In Layer 5, the total mean dendritic length decreased
progressively in the first 5 years of life in patients.
However, the controls also showed a decrease of apical
and basal dendrites in the juvenile group.
The numbers and orders of branches were similar in
patients with Down’s syndrome and controls at all
ages. The controls showed an increase in number of
branches with increasing age in Layer 3 neurons. In
Layer 5, with increasing age control neurons showed a
constant number of branches in the apical dendrites
with an increase in basilar branches in the late-infantile
period and a decrease in the juvenile period. Few of
these differences are significant individually, but the
patients with Down’s syndrome show a decrease in the
number of branches at each site earlier than did control subjects.
With early growth and development, the normal
dendritic tree expands. This expansion is not seen in
Down’s syndrome. On each of the measures (i.e., total
mean dendritic length, number of intersections, number of branches, orders of branching, and points of
maximum branching to the center of the neuron), the
Down’s syndrome neurons showed decreased numbers with increasing age. Conversely, the control
neurons showed an initial increase in all values, and not
until the juvenile period (2 to 5 years of age) was there
a trend toward less expansion.
The Down’s syndrome neurons showed one other
striking difference from controls-a relatively expanded dendritic tree at 4 months of age. There are
several plausible explanations for the excessive early
outgrowth of dendritic branches followed by subsequent atrophy. The excessive dendrite branching may
be an abortive attempt by the neuron to compensate
for the decreased number of spines and synapses on its
receptive surfaces. The extra chromosome 21 may
produce excess RNA and protein that cannot be permanently incorporated into the dendritic membrane or
cytoskeleton, so membrane turnover is decreased.
This would prevent the dendritic tree from being
maintained, which would cause the neurons to become
“atrophic” relative to the control dendritic pattern.
The absence of growth in the dendritic branches
seen in brains from Down’s syndrome patients is interesting in relation to observations of Buell and Coleman
13,43. They examined adult brains in a healthy control
group, in normal elderly people, and in a demented
elderly group. They found that normal brains in elderly subjects showed two populations of nerve cells,
one able to expand its dendritic arborization and the
other with a dying cell population and a shrinking
dendritic tree. Although we have not documented the
cell populations, in our material this phenomenon was
suggested in patients with Down’s syndrome of the
infantile group, which showed a large standard deviation. With increasing age, only cells with less developed dendritic arborescence were found, resembling
those of the demented elderly group in the study of
Buell and Coleman C3, 43. This suggests that the spurt
of growth occurs as a possible compensatory response
to neuronal loss at the beginning, followed eventually
by a uniform “premature aging” of cells.
Like other investigators 112, 13, 15, 22, 231, we
have found quantitative differences between controls
and patients. Given that the mechanism by which the
extra chromosome in Down’s syndrome produces an
abnormal phenotype is overproduction of chromosome 21-specific RNA 1121, a quantitative change
should be expected. Indeed, Sichitiu and co-workers
f223 have shown, at least for the superoxide dismutase
gene on chromosome 21, that increased amounts of
RNA produce increased protein levels.
The observed reduction of dendritic spines C233 and
this abnormal dendritic branching may be the morphological basis of the mental retardation; however,
further work is required to demonstrate that the structural abnormality is directly related to the impaired
mental functioning.
We would like to thank Mr Roy Augustin, BSc, for his expert
technical assistance and the Medical Publications Department, The
Hospital for Sick Children, for editorial assistance.
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