close

Вход

Забыли?

вход по аккаунту

?

Cortical peptide changes in Huntington's disease may be independent of striatal degeneration.

код для вставкиСкачать
/
l
.
1
n
- 1
-1
0
T T
.
7
Lortical l’eptide Lhanges in Huntington’s
Disease Mav Be IndeDendent of
Striatal Degeneration
Michael F. Mazurek, M D , FRCP(C),*t$ Sarah Garside, MD,fS and M. Flint Beal, MDS
Patients with Huntington’s disease (HD) develop pathological changes in cerebral cortex as well as in striatum. We
studied levels of neuropeptide immunoreactivity in 13 areas of postmortem cerebral cortex dissected from 24 cases of HD
and 12 controls. Concentrations of immunoreactive cholecystokinin (CCK-LI) were consistently elevated 57 to 153% in
HD cortex. Levels of vasoactive intestinal polypeptide (VIP-LI) and neuropeptide Y (NPY-LI) were significantly increased
in 10 and 8 of the 13 cortical regions, respectively. Concentrations of somatostatin (SRIF-LI) were increased in only 3
areas, while substance P (SP-LI) was, for the most part, unchanged. Detailed analyses of the CCK-LI and VIP-LI data
showed there to be no relationship between the increased cortical peptide levels and the degree of striatal atrophy. We
studied the same cortical peptides in rats with long-standing striatal lesions and found no significant changes of CCK-LI,
NPY-LI, VIP-LI, or SRIF-LI in any of the 8 cortical regions that were examined. These results indicate that there are
widespread and differential changes in cortical neuropeptide systems in HD and that these changes occur independently
of the striatal pathology that characterizes the illness.
Mazurek MF, Garside S, Beal MF. Cortical peptide changes in Huntington’s disease may be
independent of striatal degeneration. Ann Neuroi 1997;41:540-547
Huntington’s disease (HD) is characterized clinically
by a relentlessly progressive movement disorder and a
range of neuropsychiatric problems, including cognirive impairment. While the abnormal movements can
with some confidence be ascribed to the degeneration
of spiny projection neurons in the striatum, the pathophysiology of the neuropsychiatric deterioration remains unclear. The cognitive changes, in particular, are
of a type generally associated with dysfunction of the
cerebral cortex, especially the dorsolateral prefrontal
cortex (reviewed in Reference 1).
There has been renewed attention in recent years to
the neocortical changes associated with HD. A series of
neurochemical and histological studies has shown there
to be hypometabolism and a distinctive pattern of neural degeneration in HD cortex, with depletion of pyramidal projection neurons and relative preservation of
locally projecting interneurons [2-121.
Cholecystokinin (CCK) and vasoactive intestinal
polypeptide (VIP) are markers for two of the subpopulations of intrinsic cortical neurons that appear to be
spared in H D . We have studied concentrations of
CCK and VIP in control and HD postmortem cerebral
cortex, with particular attention to the frontal lobes,
which receive much of the basal ganglia feedback from
striatum. To assess the relationship between cortical
peptide changes and striatal pathology, we studied two
groups of HD brains, those with mild-to-moderate
striatal atrophy and those with severe striatal atrophy.
T o clarify whether different subpopulations of morphologically similar peptidergic local circuit neurons
may be differentially affected in H D , we directly compared the changes in immunoreactive CCK and VIP
with alterations in neuropeptide Y (NPY), somatostatin, and substance P (SP) measured in the same tissue
samples. Finally, to further explore whether the cortical
changes in HD are related to the aberrant striatal output, we studied the neurochemical profile of cerebral
cortex in rats with long-standing striatal lesions, compared with that found in HD.
From the Departments of *Medicine (Neurology), tPsychiatry, and
*Biomedical Science (Neuroscience), McMaster University Medical
Centre, Hamilton, Ontario, Canada; and SDepartment of Neurology, Massachusetts General Hospital, Boston, MA.
Received Apr 22, 1996, and in revised form Sep 25. Accepted for
publication Sep 26, 1996.
540
Materials and Methods
Postmortem Studies of Human Tissue
Brains were obtained postmortem from
12 control subjects with no history or clinical evidence of
TISSUE SAMPLES.
Address correspondence to Dr Mazurek, Neurology 4U2, McMaster
University Medical Centre, 1200 Main St West, Hamilton, Ontario
L8N 325, Canada.
Copyright 0 1977 by the American Neurological Association
neurological or psychiatric disease and from 24 patients with
a family history, clinical findings, and neuropathological abnormalities indicative of HD. The patients with HD were
graded pathologically according to the degree of macroscopic
caudate atrophy, using the system of Vonsattel and colleagues [13]. Grade 1 cases showed no atrophy of the caudate macroscopically but were characterized by moderate astrocytosis and neuronal loss of up to 50% in the caudate
nucleus. Grade 2 cases showed neuronal loss, astrocytosis,
and mild macroscopic atrophy of the caudate, but the convexity of the caudate was retained. Grade 3 cases showed
severe neuronal loss with astrocytosis, and the atrophy was
such that the ventricular surface of the caudate was straight
in a coronal section. Grade 4 was assigned to severe cases
with marked atrophy in which the caudate had became concave, often being reduced to just a thin strip of gliotic tissue.
For the purposes of neurochemical analysis, grades 1 and 2
were combined into one group (“mild-to-moderate striatal
atrophy”; n = 11), and grades 3 and 4 were merged into a
second group (“severe atrophy”; n = 13).
The mean age of the controls (7 women, 5 men) was
67.8 i 2.1 (SEM) years; that of the H D patients (13
women, 11 men) was 58.0 5 2.3 years. The interval between time of death and storage of tissue at -70°C was
13.9 ? 1.6 hours for controls and 9.3 2 1.2 hours for the
HD cases. Causes of death among controls included pulmonary embolus (n = 3), myocardial infarction (n = 2), bronchopneumonia (n = 2), cardiac arrest with underlying carcinoma (n = 4), and cardiac arrhythmia (n = 1). Patients
with H D died of bronchopneumonia (n = 17), adenocarcinoma (n = I), myocardial infarction (n = I), respiratory
failure (n = l), or unknown causes (n = 4). Two of the
control subjects were receiving psychoactive drugs, while at
least 11 of the H D patients were taking neuroleptics, 7 were
receiving benzodiazepines, and 3 were on antidepressants.
All brains were bisected in the sagittal plane; one-half was
fixed in formalin for histopathological examination while the
other was frozen at -70°C. The frozen hemisphere was subsequently cut in 0.5-cm coronal slices and cortical regions
were dissected at -10°C according to Brodmann areas.
Frozen
tissue samples were boiled in distilled water (pH 7) for 10
minutes and an aliquot was taken for measurement of CCK
immunoreactivity. The tissue was then boiled for a further
10 minutes in 0.1 M HCI, aliquots of which were lyophilized and subsequently reconstituted in buffer for radioimmunoassay of VIP, NPY, somatostatin, and SP.
CCK-like immunoreactivity (CCK-LI) was measured by a
double-antibody radioimmunoassay [ 141. Antisera were
raised in New Zealand rabbits by immunizing with sulfated
CCK-8 conjugated to thyroglobulin with carbodiimide. The
antiserum was diluted 1:200,000 and incubated with sulfated
CCK-8 standards (Peninsula) and ‘251-CCK-8 (SO,) (Du
Pont). The ED5, for the assay is 4 pg/tube with an ED,, of
1.25 pg and ED,, of 13 pg/tube. Cross-reactivity of the antiserum is 9% with CCK-4, 14% with nonsulfated CCK-8,
and 23% with human gastrin (picomolar equivalents in each
case). A host of other peptides show cross-reactivity of less
than 0.001%. Serial dilutions of aqueous extracts of human
TISSUE PROCESSING AND RADIOIMMUNOASSAY.
cerebral cortex produce an inhibition curve parallel to that
obtained with synthetic CCK-8 (SO,).
VIP-like immunoreactivity (VIP-LI) was measured by a
double-antibody radioimmunoassay using an antiserum
raised in rabbits and diluted 1:800,000. The diluted antiserum was incubated with VIP-28 standards (Peninsula) and
125
I-VIP-28 (Du Pont). When run under disequilibrium
conditions the assay has an ED,, of 24 pg/tube with an
ED,, of 9 pg/tube and an ED,, of 64 pg/tube. The antiserum shows negligible cross-reactivity with numerous other
peptides. Serial dilutions of acid extracts of human cerebral
cortex produce an inhibition curve parallel to that obtained
with synthetic VIP-28 (Peninsula).
NPY-like immunoreactivity (NPY-LI), somatostatin-like
immunoreactivity (SRIF-LI), and substance ]’-like immunoreactivity (SP-LI) were measured as previously described [5, 61.
For each peptide, control and H D samples from a particular brain area were extracted together and measured in duplicate in the same assay. The intra-assay coefficient of variation for internal standards was in each case consistently less
than 5%.
Data from the postmortem human brain study have been expressed as mean i- SEM values. Levels of CCK-LI and VIP-LI in control tissue and the
two groups of HD cases (Table) were assessed using two-way
analysis of variance (ANOVA) by group and by area, followed by post hoc two-tailed t tests where appropriate. Cortical levels of CCK-LI, NPY-LI, VIP-LI, SRIF-LI, and SP-LI
were compared in control and HD tissue using two-way
ANOVA by group and by area, with post hoc analysis by
two-tailed t tests.
STATISTICAL ANALYSIS.
Animal Studies
SURGICAL PROCEDURES. Sixteen male Sprague-Dawley
rats (Charles-River, Qubbec) were involved in these experiments. They were housed in group cages, with free access to
food and water, on a 12-h daylnight light cycle. Eight of the
animals served as controls, while the remaining 8 received
unilateral excitotoxic lesions of the striatum. The rats were
225 to 250 gm at the time of surgery. Each was anesthetized
with sodium pentobarbital and placed in a Kopf small animal stereotaxic apparatus (David Kopf, Tujunga, CA). After
the skull was exposed and burr holes were drilled, injections
were made into the right striatum at the following stereotaxic
coordinates [15]: A/P 0.7; MIL 2.5; D/V 5.5 (from skull). A
10-pI Hamilton syringe with a 30-gauge, blunt-tipped needle (Hamilton Company, Reno, NV), mounted on an electrode carrier, was used to deliver the drug solution. The needle was lowered to the proper coordinate, left in place for 1
minute, and then 1.0 pl of either 0.9% saline (CONT) or
240 nm/kl quinolinic acid (QUIN; Sigma, St Louis, MO)
was injected over the course of 1 minute. After the injection
was complete, the needle was left in place for an additional 2
minutes, to minimize upward diffusion of the solution, then
removed. The scalp incision was closed with animal wound
clips and the animal returned to its home cage.
Twelve months following the intrastriatal injections, the animals were killed by
TISSUE PREPARATION AND ANALYSIS.
Mazurek et al: Peptides in Huntington Cortex
541
decapitation. The brains were removed and sectioned into
2-mm-thick coronal sections using a rat brain matrix (Harvard Apparatus, South Natick, MA). All slices were photographed for subsequent analysis of striatal area. The following brain areas were then dissected and processed for peptide
extraction, as described for the human tissue: frontal pole,
dorsolateral prefrontal cortex, anterior motor cortex, anterior
somatosensory cortex, posterior motor cortex, posterior somatosensory cortex, entorhinal cortex, striate cortex, and striatum. All areas were measured by radioimmunoassay for
CCK-LI, NPY-LI, VIP-LI, and SRIF-LI, as described above.
Statistical comparisons of tissue from control and lesioned
animals were made using two-way ANOVA by group and by
area, followed by post hoc two-tailed t tests where appropriate.
Results
The Table presents the concentrations of CCK-LI and
VIP-LI in 13 regions of cerebral cortex from control
brains and from HD brains showing mild-to-moderate
(grades 1 and 2) or severe (grades 3 and 4)striatal atrophy. In control samples, the levels of CCK-LI and
VIP-LI were fairly uniform across the various regions
of cortex that we studied, with a less than threefold
difference in concentration between the lowest (in primary visual cortex, Brodmann area 17) and the highest
(in orbitofrontal cortex, Brodmann area 12) levels measured. CCK-LI was elevated in both HD groups in virtually all of the cortical regions studied; it is interesting
that there was no significant difference in any region
between the levels of CCK-LI in the I 1 cases with
mild-to-moderate striatal atrophy and those in the 13
cases with severe striatal degeneration. VIP-LI was increased significantly in both H D groups in 9 of the 13
areas (while the post hoc tests showed significance in
area A4, the ANOVA did not reach significance). As
with CCK-LI, there was no significant difference in
levels of VIP-LI in the grades 1 and 2 cases, compared
with the grades 3 and 4 cases, for any of the cortical
areas that we studied.
Figure 1 shows the comparative changes in HD cortex of levels of immunoreactive CCK-LI, NPY-LI,
VIP-LI, SRIF-LI, and SP-LI, each measured in the
same extracted sample. These results represent the
Levels of Immunoreactive CCK-LI and VIP-LI in Control and HD Postmortem Cerebral Cortex
CCK-LI
VIP-LI
HD Grades
l f 2
H D Grades
Controls
3 + 4
Controls
1 + 2
HD Grades
3 + 4
34.8 t 5.6 (9)
60.4 t 5.0" (10)
72.7 2 10.Ob (12)
24.1 t 2.1 (11)
36.1 t 3.5' (10)
34.7 C 3.4'(11)
42.1 -t 4.3 (10)
83.8 t 7.9d (10)
85.6 t- 8.6d (12)
31.7 t 2.9 (12)
46.8 t 4.8' (10)
44.4 t 4.3' (11)
38.7 2 5.7 (10)
64.8 t 7.4' (10)
60.2 f 5.6' (13)
28.3 t 3.5 (11)
43.9 It 5.7'(10)
45.2 -t 4.4' (13)
27.3 2 3.2 (11)
47.6 t 5.6' (10) 44.6 t 5.4' (12)
30.7 t 2.9 (12)
37.9 t 3.8 (9)
42.1 C 4.7 (13)
20.8 i 2.1 (11)
28.9 t 3.6 (11)
36.1 2 4.6' (12)
20.2 i 1.1 (9)
27.7 t 2.9 (10)
27.5 t 3.0 (13)
Premotor cortex
21.6 2 3.2 (7)
55.9 C 5.9d (11) 48.8 t 4.5d (12)
14.2 t 1.4 (9)
38.4 t- 3.4d (11)
30.9 t 3.4d (11)
Frontal eye field
(A81
Frontal cortex
21.1 2 1.8 (9)
57.3 t- 7.2d (11)
50.0 t 4.1" (13)
18.2 2 2.7 (12)
31.8 t 1.6" (11)
27.3 5 2.0' (12)
20.9 2 1.4 (8)
46.5 -t 4.6' (11) 50.4 t 4.6d (12)
18.6 -f 1.9 (11)
34.5 .f 2.2d (10)
32.6 2 3.8b (12)
23.6 ? 3.5 (10)
54.2 ? 8.2b (11) 43.6 ? 4.2b (13)
20.8 t- 2.0 (11)
32.1 t 2.Sb (10)
30.0 t- 3.7' (13)
16.2 2 2.3 (10)
29.4 t- 3.9'(11)
30.4 2 3.8'(13)
12.6 2 2.1 (11)
15.3 t 2.0 (11)
17.2 2 1.9 (12)
5.7'(11)
45.3 t 4.5' (13)
18.4 2 1.9 (8)
21.4 t 2.1 (11)
21.5 2 2.3 (11)
51.2 t- 6.4'(10)
52.3 t 5.4b (13)
25.4 t 1.7 (8)
36.1 t 3.0b (11)
32.7 t 2.5' (13)
40.0 2 5.5' (10)
38.8 ? 4.9" (13)
23.4 t 2.1 (9)
33.9 t 3.2' (11)
33.5 t 2.gb (12)
Orbitofrontal
(A1 1)
Orbitofrontal
('412)
Orbitofrontal
H D Grades
(A451
Orbitofrontal
(A471
Precentral gyrus
(A41
(A91
Frontal pole
(A10)'
Occipital cortex
(A-17)
Inferior temporal 24.9 t 3.7 (7)
gyrus (A20)
Middle temporal 31.1 t 2.3 (8)
gyrus (A21)
Superior temporal 21.4 ? 1.8 (8)
&us
43.8
?
(A2i)
Values represent mean t SEM peptide levels (pg/mg of tissue) from controls and cases of Huntington's disease with mild-to-moderate
(HD grades 1 2) or severe ( H D grades 3 4) striatal atrophy. Numbers of samples in each group are in parentheses.
+
+
"p < 0,001; " p < 0.01; ' p < 0.05; "p < 0.0001.
CCK-LI = cholecysrokinin-like immunoreactivity; VIP-LI = vasoactive intestinal polypeptide-like immunoreactivity; H D = Huntington's disease.
542
Annals of Neurology
Vol 41
No 4
April 1997
%
:
::
j2o
5 0O :
200
i
C
150
T
R
0
L
100
50
n
All
A
300
A12
A45
A47
1
C
150
T
R
0
L
100
50
n
A17
A20
A21
A22
B
300
250
%
:
200
C
150
T
R
0
L
100
50
"
n
C
A4
A6
A8
A9
A10
Fig 1. Comparative levels of neuropeptide irnmunoreactiviy in
various Brodmann areas of Huntington j disease (HD) postmortem cerebral cortex. (Top) Orbitofrontal cortex. (Middle)
Other areas offiontal cortex. (Bottom) Occipital and temporal
cortex. Levels of immttnoreactive cholecystokinin (CCK), neuropeptide Y (NPI.3, vasoactive intestinal polypeptide (VIP),
somatostatin (SRIF), and substance P (SP) from HD samples
are in each case represented as a percentage of control values.
The error bars represent the standard errors of the mean.
Data were analyzed by two-way analysis of variance by group
and by area, followed by two-tailed student t tests. Post hoc
signijcance levels are denoted as fallows: 9 < 0.01, *p <
0.001,
**p<
0.0001.
combined HD group of 24 cases, with data expressed
as a percentage of control values and the criterion for
significance set at p < 0.01.
In all 4 areas of orbitofrontal cortex that we studied
(Fig 1, top graph) highly significant changes in levels
of CCK-LI were observed, with levels increased by 61
to 101% in H D brains compared with controls. Concentrations of NPY-LI and VIP-LI were also elevated
in the HD samples, with NPY-LI increased by 52 to
64% in 3 of the 4 brain areas and VIP-LI by 31 to
58%; neither peptide was significantly changed in
Brodmann area 47. Neither SRIF-LI nor SP-LI was
significantly changed in HD orbitofrontal cortex, although there was a trend toward elevated SRIF-LI in
several areas.
In other regions of frontal cortex (Fig 1, middle
graph), the changes in concentrations of CCK-LI were
again dramatic, with HD brains showing levels approximately double those of controls in most areas examined. Levels of NPY-LI and VIP-LI were markedly elevated by 56 to 129% in premotor cortex (Ab), frontal
eye field (A8), and prefrontal cortex (A9), with lesser
changes in VIP-LI observed in the frontal pole (A10)
and precentral gyrus (A4). SRIF-LI was significantly
increased by 47% in area A10, and slight elevations of
SP-LI were detected in Brodmann areas A6, A8, and
A9.
In temporal and occipital cortex (Fig 1, bottom
graph), levels of CCK-LI were consistently increased by
67 to 85% in HD brains. NPY-LI was not significantly
altered in any of the regions studied, although there
was a trend toward increased values in temporal cortex.
Concentrations of VIP-LI showed 35 to 44% increases
in the superior and middle temporal gyri and a 29%
increase in the primary visual cortex. Neither SRIF-LI
nor SP-LI was changed in any of the regions of temporal or occipital cortex that we studied.
The animals with chronic sttiatal lesions had a 61%
depletion of striatal levels of SP-LI compared with control animals ( p < 0.01; data not shown), reflecting the
loss of striatal output neurons. The area of the lesioned
striatum was, on average, 65% smaller than that of the
unlesioned striatum or the striata of control animals
( p < 0.01; Fig 2 ) . There was no loss of SP-LI in the
nucleus accumbens, indicating sparing of this structure.
Despite the long-standing striatal degeneration in the
lesioned group, there was no significant difference between lesioned and control animals in levels of CCKLI, NPY-LI, VIP-LI, or SRIF-LI in any of the 8 cortical regions that were studied (Fig 3).
Discussion
Although cognitive impairment is a recognized clinical
feature of H D , it remains unclear whether this is attributable to basal ganglia deterioration (so-called subcortical dementia [16, 17]),or to cortical dysfunction,
Mazurek et al: Peptides in Huntington Cortex
543
200
150
~
0
F
g
100
ti
T
R
0
L
60
0
Frontal POI.
Pratrontal
Motor 1
Somatosensory 1
Somatosensory 2
Striate
Entorhinal
A
20(
~
15(
0
F
g
10(
N
T
R
0
L
Fig 2. Representative histological section from each of 8 rats
that underwent unilateral lesioning of the striatum 12 months
earlier. The mean striatal area was decreased by 65% on the
lesioned side (p < 0.01). The lesioned side is represented on
the right.
or to some combination of the two. Data obtained using positron emission tomography showed that reduced
glucose metabolism in the cerebral cortex was the best
measure of cognitive impairment in HD patients, emphasizing the potential importance of cortical pathology in the illness [2].
The present findings indicate widespread alterations
in several neuropeptide systems in HD cerebral cortex.
The most consistent and dramatic changes were those
of CCK-LI, which was increased in the prefrontal, premotor, temporal, and occipital cortex of HD postmortem brain. VIP-LI was also consistently elevated in H D
cortex, although the changes were not so pronounced
as those observed for CCK-LI. T o the best of our
knowledge, these findings represent the first documentation of CCK-LI and VIP-LI changes in HD postmortem cerebral cortex. Emson and colleagues [18, 131
measured CCK-LI and VIP-LI in a single area of HD
prefrontal cortex and found no significant change.
Among the other peptides that we studied, NPY-LI
was increased in 5 of the 7 areas of prefrontal cortex
that we examined but was not significantly altered in
other areas of HD brain. As we have previously reported [5, 61, SRIF-LI and SP-LI were generally un-
544 Annals of Neurology
Vol 41
No 4
April 1997
5(
(
Motor 2
B
Fig 3. Comparative levels of peptide immunoreactivity in the
cerebral cortex of rats with long-standing ( I 2 months) lesions
of the striatum. Concentrations of immunoreactive cholecystokinin (CCK), neuropeptide Y (NPY), vasoactive intestinal
polypeptide (VIP), and somatostatin (SRIF) fiom lesioned animals are in each case represented as a percentage of control
values. The error bars represent the standard errors of the
mean. There were no significant differences between lesioned
animals and controls in any of the 8 cortical areas we examined.
changed, significant elevations being limited to a few
areas of frontal cortex.
W e considered the possibility that our findings
might be artifactual. One concern was that many of
the HD patients were taking psychoactive medications,
particularly neuroleptics, which are frequently used to
treat the choreoathetotic movement disorder associated
with HD. The use of neuroleprics is unlikely, however,
to offer an adequate explanation for the peptide
changes that we observed. W e have found that concentrations of each of the peptides measured in this study
are unchanged in the cortex of rats treated for 8 weeks
with neuroleptics (Mazurek MF, Garside S, Beal MF,
unpublished data), in contrast to the widespread
changes found in the H D brains. The cause of death is
also unlikely ro be a factor, according to a study by
Perry and associates [20] who showed that agonal status had no significant effect on neuropeptide levels.
Another possibility is that we might simply have used
an unusual cohort of controls for this study; challenging this notion is that when these same control specimens were compared with samples from Alzheimer’s
disease (AD) brain, the levels of CCK-LI, which were
increased in H D , were normal or decreased in AD cortex [ 141. These findings, taken together, would indicate that the differential neuropeptide changes that we
observed in HD cortex may be directly related to the
illness itself.
The neuropeptide-containing neuronal systems in
cerebral cortex are fundamentally similar. In contrast to
the cholinergic, noradrenergic, and serotonergic systems, which project to the cortex from subcortical cell
bodies, most of the neuropeprides present in the cerebral cortex of both human and nonhuman primates are
found in locally projecting intrinsic neurons with small
(8-10 Fm) diameter perikarya concentrated in layers
11, 111, and VI and in the subjacent white matter [21,
221. These peptidergic neurons give rise to complex axonal arborizations in layers I1 to VI and horizontally
oriented axons in layer I [22]. Populations of cortical
interneurons immunoreactive for somatostatin, NPY,
CCK, SP, and VIP each account for 1.4 to 2.5% of
the total neuronal population in cortex with good correspondence between studies of human and nonhuman
primates [21, 221. Somatostatin and NPY appear to be
colocalized in most cases. The great majority of these
somatostatin-NPY cells also contain y-aminobutyric
acid (GABA), as do virtually all of the CCK-containing
neurons in cortex [2 I]. The somatostatin-NPY cells
are found predominantly in the infragranular layers of
the cortex and in the subjacent white matter [22] and
generally terminate on small peripheral dendrites.
CCK- and VIP-immunoreactive neurons are found
predominantly in the supragranular layers and synapse
on the somata and proximal dendrites of pyramidal
neurons. In the rat, an additional pool of CCK-LI appears to be contained in a subpopulation of corticalstriatal projection neurons [23, 241. Cortical neurons
staining intensely for SP appear to be colocalized with
somatostatin-NPY in a subpopulation of intrinsic neurons in layer VI and the subjacent white matter, with
an additional population of weakly immunoreactive SP
neurons found predominantly in the middle layers
[=I.
It is not clear why the various peptidergic systems in
cerebral cortex should be differentially affected in HD.
Of particular interest is the finding that NPY-LI is increased in most areas of H D prefrontal cortex, while
SRIF-LI, with which it is colocalized about 90% of the
time in cortical neurons, shows much less impressive
changes. A similar dissociation of cortical levels of
NPY-LI and SRIF-LI has been observed in AD, in
which concentrations of SRIF-LI are markedly depleted, while NPY-LI is relatively preserved [25, 261.
These findings from AD and HD postmortem brain
suggest that the production and/or release of somatostatin and NPY can be differentially regulated within
individual cortical neurons. There is evidence that the
differential regulation of colocalized neuropeptides occurs elsewhere in the brain, an example being the parvocellular neurons of the hypothalamic paraventricular
nucleus, in which the peptides vasopressin and
corticotropin-releasing factor are differentially regulated
by circulating glucocorricoids [27].
The cognitive impairment associated with HD is often referred to as a subcortical dementia [16, 171, the
implication being that the disturbed mental function is
a reflection of abnormal input to the cerebral cortex
from subcortical nuclei. We have previously shown
that striatal lesions can produce behavioral impairments similar to those associated with frontal cortex
dysfunction [28, 291. Since the neuropathological hallmark of HD is degeneration of the neostriatum, we
were interested in whether the observed changes in cortical neuropeptide systems might reflect abnormal input to cerebral cortex from the diseased basal ganglia
feedback circuit. O n the assumption that this feedback
would tend to be increasingly disrupted as the striatal
degeneration progressed, we divided the H D samples
into those with mild-to-moderate striatal atrophy and
those with severe atrophic changes. It is somewhat surprising that there was no relationship between the degree of striatal atrophy and the levels of CCK-LI or
VIP-LI in cerebral cortex; for both of these peptide systems, the abnormalities found in mild-to-moderate
cases were fully comparable with those observed in severe cases. This is consistent with recent histopathology
studies that show that atrophy, neuronal loss, and neuritic changes in H D cortex do not correlate with the
degree of striatal atrophy [8, 10, 301. ‘The increased
concentrations of neuropeptide imniunoreactivity
would appear to represent a preservation, or upregulation, of peptide-containing neuronal elements at
a time when the surrounding tissue matrix in cortex is
undergoing atrophy and degeneration [8 -10, 12, 301.
Not all of the cortical peptide systems, however, nor all
regions of cortex, showed comparable degrees of upregulation; CCK-LI, NPY-LI, and VIP-LI were consistently increased in HD cortex, particularly dorsolateral
prefrontal areas, while levels of SRIF-LI and SP-LI in
the same samples were relatively normal.
Further evidence that the peptide changes in HD
cortex may occur independently of the striatal pathology comes from the animal study. In contrast to the
widespread cortical abnormalities found in all grades of
HD cases, animals with chronic striatal lesions showed
normal neuropeptide levels in all areas of cortex. This
suggests that the changes in HD cortex do not result
Mazurek et al: Peptides in Huntington Cortex
545
from disordered feedback from the degenerating striatum, but instead reflect an independent process in the
cortex itself.
The significance of the elevated levels of CCK-LI,
VIP-LI, and NPY-LI in HD cortex is at this point a
matter for speculation. Of particular interest is the
finding that levels of CCK-LI and VIP-LI were increased even in the grade I cases, when striatal atrophy
was barely evident. This suggests that the observed
changes in HD cortex might play some role in the
pathogenesis of HD striatal degeneration. The loss of
spiny projection neurons in HD striatum is thought to
involve an excitotoxic process, which may occur as a
consequence of impaired energy production [31]. Recent evidence indicates that CCK-LI is present in a
subpopulation of cortical neurons that project to the
medial striatum (23, 241, and both CCK-LI and
VIP-LI are found in locally projecting cortical neurons
that synapse on the cell bodies and proximal dendrites
of pyramidal neurons [21, 321. CCK is reported to
have a depolarizing effect on pyramidal neurons [33]
and VIP promotes glycogenolysis in cerebral cortical
slices 1341. If the elevated levels of CCK-LI and VIP-LI
in HD cortex are indicative of increased peptidergic
activity, the result might be increased glutamate release
in the striatum, which could potentially initiate the excitotoxic process.
Supported by the Scottish Rite Foundation, the Natural Sciences
and Engineering Research Council of Canada, N I H grant NS
16367, and the Brain Tissue Resource Center (MNINS 31862). Dr
Mazurek is a Career Scientist of the Ontario Ministry of Health.
______
References
I . Folstein SE. Huntington’s disease. Baltimore: Johns Hopkins
University Press, 1989
2. Kuwcrr T,Lange H W , Langen KJ, et al. Cortical and subcortical glucose consumption measured by PET in patients with
Huntington’s disease. Brain 1990;113:1405-1423
3 . Hedreen JC, Peyser CE, Folstein SE, Rose CA. Neuronal loss
in layers V and VI of cerebral cortex in Huntington’s disease.
Neurosci Lett 1991;133:257-263
4. Ellison DW, Bedl MF, Mazurek MF, et al. Amino acid neurotransmitter abnormalities in Huntington’s disease and the
quinolinic acid animal model of Huntington’s disease. Brain
1987;1 10:1657-1673
5. Beal MF, Mazurek MF, Ellison DW, et al. Somatostatin and
neuropeptide Y concentrations in pathologically graded cases of
Huntington’s disease. Ann Neurol 1988;23:562-569
6. Beal MF, Ellison DW, Mazurek MF, et al. A derailed examination of substance P in pathologically graded cases of Huntington’s disease. J Neurol Sci 1988;84:5 1-61
7. Mazurek MF, Beal MF, Ellison DW, et al. Cholecystokinin immunoreactivity in Huntington’s disease: widespread increases in
postmortem cerebral cortex. In: Hughes J , Dockray G , Woodruff C , eds. The neuropeptide cholecystokinin. New York:
John Wiley, 1989:28-32
8. de la Monte SM, Vonsattel J-P, Richardson EP Jr. Morphometric demonstration of atrophic change in the cerebral cortex,
546
Annals of Neurology
Vol 41
No
4
April 1997
white matter, and neostriatum in Huntington’s disease. J Neuropathol Exp Neurol 1388;47:516-525
9. Cudkowicz M, Kowall N W . Degeneration of pyramidal projection neurons in Huntington’s disease cortex. Ann Neurol 1990;
27:200-204
10. Sotrel A, Paskevich PA, Kiely DK, et al. Morphometric analysis
of the prefrontal cortex in Huntington’s disease. Neurology
1991;41:1117-1123
11. Storey K, Kowall NW, Finn SF, et al. The cortical lesion of
Huntington’s disease: further neurochemical characterization,
and reproduction of some of the histological and neurochemical
features by N-methyl-D-aspartate lesions of rat cortex. Ann
Neurol 1992;32:526-534
12. Selemon LD, Rajkowska G, Goldman-Rakic P. Abnormally
high neuronal density in the schizophrenic cortex. h c h Gen
Psychiatry 1995;52:805- 8 18
13. Vonsattel J-P, Meyers RH, Stevens TJ, et al. Neuropathological
classification of Huntington’s disease. J Neuropathol Exp Neurol 1985;44:559-577
14. Mazurek MF, Beal MF. Cholecystokinin and somatostatin in
Alzheimer’s disease cerebral cortex. Neurology 1991;41:716719
15. Paxinos G, Watson C. The rat brain in stereotaxic coordinates.
New York: Academic Press, 1982
16. McHugh PR, Folstein MF. Psychiatric syndromes of Huntington’s chorea: a clinical and phenomenological study. In: Benson
DF, Blumer D, eds. Psychiatric aspects of neurological disease.
New York: Grune and Stratton, 1975:267-286
17. Cummings JL, Benson DF. Subcortical dementia: review of an
emerging concept. Arch Neurol 1984;41:874-879
18. Emson PC, Rehfeld JF, Langevin H , Rossor M. Reduction in
cholecystokinin-like immunoreactivity i n the basal ganglia in
Huntington’s disease. Brain Res 1980; 198:497-500
19. Etnson PC, Fahrenkrug J, Spokes EGS. Vasoactive intestinal
polypeptide (VIP) distribution in normal human brain and in
Huntington’s disease. Brain Res 1979;173:174-178
20. Perry EK, Perry RH, Tomlinson E. The influence of agonal
status on some neurochemical activities of postmortem brain
tissue. Neurosci Lett 1982;23:303-307
21. Jones EG, Hendry SHC. The peptide containing neurons of
the primate cerebral cortex. In: Martin JB, Barchus J, eds. Implications of neuropeptides in neurological and psychiatric diseases. New York: Ravcn, 1986163-178
22. Hornung JP, De Tribolet N, Tork I. Morphology and distribution of neuropeptide-containing neurons in human cerebral
cortex. Neuroscience 1992;51:363-375
23. Morino P, Herrera-Marshitz M, Castel M N , et al. Cholecystokinin in cortico-striatal neurons in the rat: immunohistochemical studies at the light and electron microscopical level. Eur
J Neurosci 1394;6:681-692
24. Morino P, Mascagni F, McDonald A, Hokfelt ’I‘. Cholecystokinin corticostriatal pathway in the rat: evidence for bilateral
origin from medial prefrontal cortical areas. Neuroscience 1994;
59:939-952
25. Allen JM, Cross AJ, Crow TJ, et al. Dissociation of neuropeptide Y and somatostatin in Parkinson’s disease. Brain Res 1985;
337: 197-200
26. Mazurek MF, Beal MF, Martin JB. Neuropeptides in Alzheimer’s disease. Neurol Clin 1986;4:753-768
27. Sawchenko PE. Evidence for differential regulation of
corticotropin-releasing factor and vasopressin immunoreactivities in parvocellular neurosecretory and autonomic-related projections of the paraventricular nucleus. Brain Res 1987;437:
2 5 3-263
28. Furtado JCS, Mazurek MF. Behavioral characterization of
quinolinate-induced lesions of the medial striatum: relevance
for Huntington’s disease. Exp Neurol 1996; 138:158 -1 68
29. Garside S, Furtado JCS, Mazurek MF. Dopamine-glutamate interactions in the srriatum: behaviourally relevant modification
of excitotoxicity by dopamine-receptor mediated mechanisms.
Neuroscience 1996;75: 1065-1074
30. Jackson M, Gentlemen S, Lennox G, et al. The cortical neuritic
pathology of Huntington’s disease. Neuropathol Appl Neurobiol 1995;21: 18-26
31. Beal MF. Does impairmenr of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann
Neurol 1992;31:119-I30
32. Magistretti PJ. VIP neurons in the cerebral cortex. Trends
Pharmacol Sci 1990;11:250-254
33. Dodd J, Kelly JS. The actions of cholecystokinin and related
peptides on pyramidal neurons in the mammalian hippocampus. Brain Res 1981;205:337-350
34. Magistretti PJ, Morrison JH, Shoemaker WJ, et al. Vasoactive
intestinal peptide induces glycogenolysis in mouse cortical
slices: a possible regulatory mechanism for the local control of
energy metabolism. Proc Natl Acad Sci USA 1981;78:6535-
6539
Mazurek et al: Peptides in Huntington Cortex
547
Документ
Категория
Без категории
Просмотров
1
Размер файла
804 Кб
Теги
may, change, cortical, degeneration, disease, huntington, striata, independence, peptide
1/--страниц
Пожаловаться на содержимое документа