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Cholinergic-dependent cognitive deficits in Parkinson's disease.

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Cholinergic-Dependent
Cognitive Deficits in Padanson’s Disease
Bruno Dubois, MD, Francois Danze, MD, Bernard Pillon, PhD, Guliana Cusimano, MD,
FranSois Lhermitte, MD, and Yves Agid, MD, PhD
In a double-blind cross-over study, the effects of a subthreshold dose of scopolamine (0.25 mg) on memory were
compared in 32 control subjects and 32 parkinsonian patients who were without any sign of intellectual and mneniic
impairment. Although the scores of the controls in the memory test battery showed no deterioration after the administration of scopolamine, the same dose resulted in significantly reduced memory performance in parkinsonian patients
in two tests which involved the recognition of meaningless drawings. The selective vulnerability of parkinsonian
subjects without cognitive impairment to a subthreshold dose of scopolamine suggests the existence of an underlying
alteration of central cholinergic transmission. The neuropsychological findings in our study agree with postmortem
biochemical data, which showed decreased cortical choline acetyltransferase activity in all parkinsonian patients,
suggesting the existence of neuronal compensation in parkinsonian patients who are without cognitive impairment.
Dubois B, Dame F, Pillon B, Cusimano G, Lhermitte IF, Agid Y: Cholinergic-dependent
cognitive deficits in Parkinson’s disease. Ann Neurol 22:26-30, 1987
The cause of intellectual impairment in Parkinson’s
disease is unclear [20). Degeneration of cortical neurons, as suggested by the presence of Alzheimer-like
changes [157, may contribute to intellectual deterioration in some patients [3]. However, these cortical lesions are not considered to be responsible for the
more specific features of cognitive impairment in parkinsonian patients that are related to retrieval processes [6),perceptual motor dysfunction [32), and
frontal lobe-like symptoms [22). These disorders,
usually referred to as subcortical dementia [2], have
been postulated to result from neuronal loss in deep
gray matter structures [241. Symptoms reminiscent of
frontal lobe dysfunction may arise from selective degeneration of the dopaminergic nigrostriatal pathway,
as demonstrated in patients with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism [3 1). Lesions of ascending noradrenergic and
dopaminergic neuronal systems have also been implicated in cognitive dysfunction 116, 28). The most
severe cognitive impairment, however, is caused by
degeneration of ascending cholinergic neurons originating in the basal forebrain. This is suggested by the
profound disturbances in learning behavior described
after lesioning of the nucleus basalis magnocellularis of
the rat 113, 17) and reports of marked degeneration of
the ascending cholinergic system in patients with Alz-
heimer’s disease 123). fi role for the cholinergic subcorticocortical lesion in the genesis of cognitive impairment in Parkinson’s dislease is suggested by: (1) the
50% decrease in choline acetyltransferase activity in
the cerebral cortex of parkinsonian patients who show
intellectual deterioration 112, 14, 25); (2) the deleterious effect of anticholinergic drugs on memory in parkinsonian patients [26}; and (3) the frequent occurrence of confusional states in patients who are being
treated with anticholinergic drugs 17).
Interestingly, partial destruction of the ascending
cholinergic system can allso be suspected in parkinsonian patients who are nor: intellectually impaired, since
choline acetyltransferase activity has been found to be
significantly decreased in the cortex of nondemented
parkinsonian subjects wh.0 are not discovered to have
Alzheimer-type pathological lesions [12, 14, 2 11.
The absence of cognitive impairment in these patients
might be explained by the fact that up to a certain
degree of cholinergic denervation, normal intellectual
function is maintained, perhaps because of hyperactivity of the remaining cholinergic neurons 11) and hypersensitivity of muscarinic receptors [12). T o test
this hypothesis of a clinically compensated cholinergic
deficiency in nondemented parkinsonian patients, we
compared the effects on memory of a low dose of
scopolamine and placebo in control subjects and par-
From the Clinique de Neurologie et Newopsychologie and INSERM U289, HBpital de la Pitik-SalpCtriPre, 97 Bd de I’HBpital,
75013 Paris, France.
Address correspondence to Dr Dubois, Clinique de Neurologie et
Neuropsychologie, HBpital de la SalpCrriere, 47, Bd de I’HBpital,
75651 Paris Cedex 13, France.
Received July 24, 1986, and in revised form Nov 6. Accepted for
publication Nov 30, 1986.
26
Table I . Neuropsychological Characteristics of the Four Subgroups of Subjectsa
No. of
Patients
Age (yr)
Educational
Level (yr)
PM47
Wechsler
Memory
Scale
Deterioration
Index
~
Sequence 1
Control subjects (C1)
Parkinsonian patients (PI)
Sequence 2
Control subjects (C2)
Parkinsonian patients (P2)
16
16
56.5
62.8
16
16
58.1 5 2.1
60.9 2 3.0
5
?
3.5
2.7
9.8
?
9.5
2
0.8
0.6
28.6
27.8
_t
-t-
1.2
1.6
41.7 % 1.6
43.6 -c 2.5
3.4 -t- 1.8
1.6 c 2.1
9.5 2 0.6
9.3 0.7
30.4
28.1
2
2
1
1.4
43.8 ? 2.3
42.8 -c 2.9
1.9 2 1.7
4.7 _c 1.6
*
"Values are +- SEM
PM47 = Raven 47 progressive matrices.
kinsonian patients who were without any signs of
mnemic and intellectual impairment.
Testing Pmcedures
Methods
Subjects
Test batteries given on the first and second days were similar,
but the actual data to be memorized were different to minimize any possible retest effect. The battery consisted of five
memory tests:
Sixty-four subjects (32 with Parkinson's disease and 32 controls) were tested. All gave informed consent. To ensure that
all subjects were free of intellectual impairment, they underwent neuropsychological study with tests selected for their
sensitivity to intellectual and mnemic impairment: three
Wechsler Adult Intelligence Scale (WAIS) verbal tests (digit
span, similarities, arithmetic), a visuospatial task (Raven 47
progressive matrices IPM47J), and the Wechsler Memory
Scale. The subjects were allowed unlimited time to do the
tests. The corresponding verbal, visuospatial, and memory
IQs were used to determine a deterioration index for each
patient, taking into account age, education, and professional
level C22).
The 32 parkinsonian and 32 control subjects were distributed randomly into two subgroups of 16 patients each. The
four subgroups (P1 and P2, parkinsonian patients; C1 and
C2, control subjects) were matched for age, years of education, scores on verbal tests, PM47, Wechsler Memory Scale,
and index of intellectual deterioration (Table 1). Parkinsonian patients in Subgroup P1 and Subgroup P2 showed no
significant differences in age of onset, basal disability score,
and Hoehn and Yahr score.
1. Digit span of the Wechsler Memory Scale.
2. Immediate recall test (9.picture location test [18}). Nine
meaningful images in a definite order were shown for 2
minutes on a board with nine subdivisions. The subjects
had to learn the location of each picture. The pictures
were then removed and reshown one by one. The subject
had to restore each one to its original position.
3. Recognition test without order (10 figures). Ten meaningless drawings were presented for 5 seconds each. Subjects
were then asked to recognize each of the 10 drawings
among a matrix of 25 different drawings. Subjects had
to give 10 responses. Three successive trials were performed.
4. Recognition test with order (6 figures). Six meaningless
drawings were presented for 5 seconds each. Subjects not
only had to recognize the 6 figures among a matrix of
twenty others but also to give them in their original order.
5. Delayed recall test (9-picture location test). At the end of
the session, 30 minutes after initial presentation, subjects
were again asked to put each of the nine pictures back in
the correct position.
Schedule of Drug Administration
Statistical Analysis
From a pilot study carried out on control subjects, a fixed
dose of 0.25 mg of scopolamine was selected as an appropriate subthreshold dose that produced no evidence of central
effects. Peripheral effects such as nausea or dry mouth were
observed at this dose in some patients. Saline solution was
used as placebo. In a double-blind cross-over design, scopolamine and placebo were administered to all parkinsonian
patients (PI and P2) and control subjects (C1 and C2).
In sequence 1, subjects in Subgroups C1 and P I received
a subcutaneous injection of placebo on day 1 and scopolamine on day 2. In sequence 2, subjects in Subgroups C2
and P2 received the subcutaneous injection of scopolamine on
day 1 then the placebo on day 2. In both experiments, performance on a memory test battery after scopolamine
injection was compared to that after placebo. The tests were
given 90 minutes after each injection and lasted approximately half an hour.
Results
Digit Span, Immediate Recall Test,
and Dehyed Recall Test
None of the control and parkinsonian subgroups
scored significantly worse on the three tests after administration of scopolamine. According to analysis of
variance, scopolamine was ineffective in both groups
of patients (Table 2). There was a tendency for an
improved digit-span performance on day 2 in all subgroups, although the difference was significant only in
Subgroup C1. This was due to a retest effect, as shown
by analysis of variance ( p < 0.01 in the control population; results not shown).
In this cross-over design, statistical analysis was performed
using the paired Student's t test and analysis of variance.
Dubois et al: Cholinergic-Dependent Cognitive Deficits in Parkinsonism 27
Table 2. Performances on Memory Tests of Control Subjects and Parkinsonian Patients after Iiijection of Placebo and Scopolamine?
~~~~~~
~~~
Digit span
Control subjects
Parkinsonianpatients
Immediate recall test
Control subjects
Parkinsonianpatients
Delayed recall test
Control subjects
Parkinsonian patients
~
Day 2
(Placebo)b
Scopolamine
Effect'
C2: 6.7 ? 0.4
P2: 6.4 2 0.4
7.1 5 0.3
6.6 t 0.4
NS
NS
8.9 2 0.1
8.8 2 0.2
C2: 8.9 ? 0.1
P2: 9.0 t 0.0
9.0
0.0
9.0 +- 0.0
NS
NS
8.6
C2: 8.9 ? 0.1
P2: 8.9 2 0.1
8.9 +- 0.1
8.9 ? 0.1
NS
NS
Day 1
(Placebo)
Day 2
(Scopolamine)b
C1:
P1:
6.0 t 0.3
7.0 ? 0.4
6.6
7.6
i 0.4
C1:
PI:
9.0 +_ 0.0
8.7 t 0.2
Day 1
(Scopolamine)
~
?
0.3d
5 0.2
8.7 2 0.2
C1: 8.7 ? 0.2
P1: 9.0 t 0.0
"Correct responses were expressed as the mean
'Paired Student's f test.
?
?
SEM.
'Analysis of variance.
dp < 0.05.
NS = not significant.
Recognition Test without Order (10 Figures)
Performance of control subjects (Subgroups C1 and
C2) significantly improved on day 2 (Table 3). Analysis
of variance showed that these results were explained
by a retest effect ( p < 0.001). In parkinsonian patients
(Subgroup P1) the score did not improve during retest
(day 2), suggesting that the retest effect was counteracted by the deleterious effect of scopolamine. In
Subgroup P2, scores after scopolamine administration
(day 1) were lower than those after placebo (day 2), for
both the total score and the scores obtained at each of
the three trials. The difference was due to scopolamine
administration, not a retest effect, as demonstrated by
analysis of variance ( p < 0.001).
Recognition Test with Order (6 Figures)
The performance of control subjects (Subgroups C1
and C 2 ) was not affected by scopolamine, but scores of
parkinsonian patients in both subgroups decreased after administration of scopolamine when compared to
results following placebo injection (see Table 3 ) . The
effect of scopolamine was significant in the parkinsonian population ( p < 0.001) for both the total scores
and the scores for each of the three trials, as shown by
analysis of variance.
Discussion
The dose of scopolamine administered (0.25 mg)
could be considered subthreshold because the performance of control subjects showed no deterioration
on any of the five neuropsychological tests following
its administration. A previous study in human volunteers demonstrated that this dose induced no modification in categorized serial learning 1291, a process
known to be sensitive to psychoactive drugs. In contrast, learning has been shown to be significantly impaired with 0.50 mg [29} or 1 mg 111) of this drug.
Nevertheless, after the same subthreshold dose of
28 Annals of Neurology Vol 22
No 1 July 1987
scopolamine, performa.nce was significantly reduced in
parkinsonian subjects for the two tests using meaningless drawings. Interprecation of the disorders following
injection of scopolamine merits discussion. A subtle
memory deficit induced by a low dose of scopolamine
cannot be ruled out. However, there was no apparent
direct effect on memory because the performance of
parkinsonian subjects 'was not altered either in immediate recall tests (digit span, immediate recall test)
or in the delayed recall test. Thus, under these experimental conditions, the ability to encode, store, and
recall information remained unimpaired. The absence
of any effect of scopolamine o n the immediate recall
test (%picture location test) also eliminated any major
primary disorder in spatial organization 118) or perceptive integration. These results were surprising, for
scopolamine is known to impair maze learning in animals 18) and memory storage in humans 15, 11). However, this effect is dose-dependent in humans [27}, and
the small dose used in the present study might not
have been sufficient to interfere with basic memory
processes.
O n the other hand, memory difficulties found in
parkinsonian patients are observed when tests are
timed or require an active organization of response
1341. In our study, the use of meaningless drawings
made the information more difficult to integrate: to
identify the correct drawings out of 25 required much
selective attention; the serial recognition test also required sequential organization. Thus, defective performance seems to result fro~ma slowing of the cognitive
processes or impaired selective attention, integration,
or sequential programming rather than an information
storage disorder-all disturbances that could reflect
frontal lobe dysfunction { 19}.
The specificity of the action of scopolamine is debatable. Parkinsonian patients, like all brain-damaged patients, might be more sensitive to any psychoactive
Table 3. Performances on Recognition Memory Tests of Control Subjects
and Parkinsonian Patients afer Injection of Placebo and Scopolaminh
Memory Test
Trial
Day 1
(Placebo)
Day 2
(Scopolamine)b
Day 1
Day 2
(Scopolamine) (Placebo)b
Scopolamine
Effect'
RECOGNITIONTEST (10 figures)
c1
1
Control subjects
1
2
3
Total
6.9
8.4
9.0
24.3
c2
7.9 5 0.4d
8.8 2 0.3
2 0.3
9.4 0.2
2 1.1 26.1 ? 0.8d
?
0.5
* 0.4
*
*
P1
Parkinsonian patients
1
2
3
Total
RECOGNITION TEST WITH ORDER
7.8
8.9
9.3
25.9
7.1
0.3 8.4
0.3 8.8
1.0 24.3
?
?
?
*
0.4
0.4
0.4
1.1
7.1
8.2
8.8
24.0
* 0.5
2
4
?
4
?
0.2
0.8'
NS
NS
NS
NS
C
e
e
f
(6 figures)
~~~
Parkinsonian patients
0.4'
* 0.24
8.4 _t 0.3'
9.3 t 0.3'
9.6 % 0.2d
27.2 2 0.7'
0.5
0.5
1.4
~~
c1
Control subjects
-t-
P2
* 0.4
4
?
5
8.3
9.4
9.6
27.3
7.3 t 0.4
8.6 2 0.4
9.2 ? 0.3
25.1
1.0
1
2
3
Total
1
2
3
Total
2.5 2 0.4
3.9 0.5
5.0 2 0.4
11.4
1.1
*
*
3.4 2 0.4
4.8 2 0.4
5.5 & 0.2
13.6 t 0.8
c2
3.5 ? 0.5
4.3 4 0.6
4.4 2 0.6
12.3 t 1.5
3.1 2 0.3
4.0 r 0.4
5.3 2 0.4
12.8 t 0.9
P1
2.3
3.7
4.3
10.3
-14
5
?
drugs. In addition, a generalized cerebral dysfunction
following scopolamine injection in parkinsonian patients cannot be excluded. Nevertheless, in an earlier
study, Drachman 1101 showed that elementary learning was selectively reduced in control subjects after
administration of 1 mg of scopolamine, whereas Damphetamine (20 mg orally), a powerful catecholamine
agonist, was ineffective. Therefore, altered cognitive
function may be attributed to reduced central cholinergic transmission caused by blockade of the muscarinic
receptors {27).The selective vulnerability of parkinsonian subjects to a subthreshold dose of scopolamine
can be explained by an underlying alteration of central
cholinergic transmission, which is compensated for
in patients without intellectual deterioration. These
results agree with earlier biochemical studies, which
showed choline acetyltransferase activity to be significantly reduced in several neocortical structures in
parkinsonian subjects, with no signs of intellectual
deterioration or Alzheimer-type changes in the cortex
112, 14, 21).
Postmortem biochemical results, along with the
?
2
?
*
4
0.5
0.5
0.5
1.4
NS
NS
NS
NS
P2
2.6 2 0.4
3.6 2 0.5
4.2 2 0.4
1.1
10.4
0.5
O.Sd
0.4'
1.8'
"Correct responses of each of the three trials were expressed as the mean
bPaired Student's I test.
'Analysis of variance.
dp < 0.05; ' p < 0.01; 'p < 0.001
NS = not significant.
3.3
4.0
4.8
12.1
*
3.3 2 0.3
4.8 & 0.4d
5.4 2 0.2'
13.5 2 0.8'
Ll
e
f
f
SEM.
present neuropsychological data, could indicate that
the cholinergic neurons projecting to the cerebral cortex are partially destroyed or hypoactive in all parkinsonian subjects, even those who are not demented.
The absence of slight cognitive disorders in these patients (see Table l) suggests that neuronal compensation occurs, probably because of hyperactivity of the
remaining cholinergic neurons 111. In this hypothesis,
intellectual impairment in these patients most likely
becomes evident only when cortical cholinergic transmission is substantially reduced, i.e., beyond a certain
threshold of neuronal destruction. This hypothesis
presupposes that reduced cholinergic transmission
plays a part in the genesis of cognitive disorders, which
results from experimental studies in both animals {S,
13, 171 and humans [lo, 11) seem to indicate.
These conclusions have therapeutic consequences.
Cholinergir blocking agents used in the treatment of
Parkinson's disease may partially account for some of
the cognitive disorders observed in these patients [4,
26, 331. Anticholinergic drugs are also known to produce confusional states in parkinsonian patients, partic-
Dubois et al: Cholinergic-Dependent Cognitive Deficits in Parkinsonism
29
ularly when patients are old [30}, the daily dosage is
high [9},and above all, when intellectual deterioration
is already present 171. The use of anticholinergics may
be useful and harmless in early stages of Parkinson’s
disease in relatively young patients showing no intellectual disorders. On the other hand, these drugs are
contraindicated in the treatment of the disease in its
later stages or in older patients with intellectual deterioration.
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