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					                                                Drug Development Research 12271-278 (1988)




Cognitive Functions Affected by
Scopolamine in Alzheimer’s Disease
and Normal Aging
F. Jacob Huff, Susan F. Mickel, Suzanne Corkin, and John H. Growdon

Department o Brain and Cognitive Sciences and Clinical Research Center,
            f
                        f                                                   f
Massachusetts institute o Technology (F.J.H., S.F.M., S.C.), and Department o
Neurology, Harvard Medical School (F.J. H., S.F.M., J. H.G.), Cambridge;
             f                                          f
Departments o Psychiatry and Neurology, University o Pittsburgh (I? H.)
                                                                      J.

ABSTRACT
Huff, F.J., S.F. Mickel, S. Corkin, and J.H. Growdon: Cognitive functions affected by
scopolamine in Alzheimer’s disease and normal aging. Drug Dev. Res. 12:271-278, 1988.

We gave scopolamine to patients with Alzheimer’s disease (AD) and age-matched control
subjects in order to identify which cognitive functions are affected by blocking muscarinic
receptors for acetylcholine (ACh). Both subject groups showed dose-related impairments
in verbal learning, and patients with AD exhibited enhanced vulnerability to effects of
scopolamine on attentional vigilance. In the same dose range, scopolamine did not alter
retrieval from long-term lexical-semantic memory or performance on a test of visual
discrimination, suggesting that cholinergic neurotransmission is not critical for these cog-
nitive functions. The importance of cholinergic transmission in learning and attention is
confirmed by this study, and the results indicate that both these abilities should be
measured in investigations of potential cholinergic treatments for AD.

Key words: learning, memory, language, attention, acetylcholine

INTRODUCTION
       Pharmacological studies using the muscarinic cholinergic antagonist scopolamine indi-
cate that cholinergic neurotransmission is involved in human memory processes [Safer and
Allen, 1971; Drachman and Leavitt, 19741. High doses of scopolamine also impair attentional
vigilance in normal subjects [Safer and Allen, 1971; Traub et al., 19871, but whether other



Received final version October 26,1987: accepted October 27, 1987

Address reprint requests to Dr. F. Jacob Huff, Alzheimer’s Disease Research Center, Iroquois Building,
Suite 400, 3600 Forbes Avenue, University of Pittsburgh, Pittsburgh, PA 15213.

0 1988 Alan R. Liss, Inc.
272       Huff et al.

cognitive functions are mediated cholinergically has not been definitely established. For
example, although Drachman and Leavitt [Drachman and Leavitt, 19741 observed decrements
on a verbal fluency test of retrieval from semantic categories, they observed that subjects
tended to shift categories during the test, suggesting that the decrement in retrieval may have
resulted from impairment of attention by scopolamine.
       A deficiency of brain acetylcholine (ACh) has been found in Alzheimer’s disease (AD),
but postsynaptic muscarinic receptors are preserved [Davies and Verth, 1978; Mash et al.,
19851. It has been suggested that cholinergic deficiency may account for some of the cognitive
impairments in AD [Corlun, 1981; Bartus et al., 19821. This hypothesis implies that patients
with AD would be more sensitive than healthy, nondernented subjects to an acute challenge
with a cholinergic antagonist. In order to test this prediction, we administered several doses of
scopolamine and a placebo to AD patients and control subjects, and measured drug effects on
cognitive test performance, including measures of learning and recent memory, attention,
lexical-semantic language, and visuospatial abilities. It was postulated that cognitive processes
dependent upon ACh would be impaired by scopolamine in a dose-dependent fashion in both
groups, and that the dose-response effect would be more pronounced in the AD group.

METHODS
       The subjects included ten patients with a clinical diagnosis of AD [McKhann et al.,
1984; Khachaturian, 19851 and six age-matched healthy control subjects. All subjects gave
informed consent before participating in the study. The AD and control groups were closely
matched for age, education, and body weight (Table 1). The mean body weight did not differ
significantly between the groups ( t = 0.62, P = .55),even though the proportion of men and
women was not the same in both groups. Two patients were receiving treatment for mild
hypertension, one with hydrochlorothiazide and a potassium supplement, the other with
labetalol. One patient and one control subject used topical corticosteroids, in a skin cream and
ophthdlmohgic solution, respectively. Two patients used aspirin or acetaminophen, and one
took a multiple vitamin preparation. No psychoactive drugs other than scopolamine were given
during the study. AD cases with dementia of mild to moderate severity were selected; their
mean score (sum of all subscales) on the Blessed Dementia Scale [Blessed et al., 19681 was
16.2.
       On successive days, subjects were given intramuscular injections of saline and subse-
quentially higher doses of scopolamine, as tolerated, from 0.1 mg up to 0.5 mg. The gradually
increasing fixed dosage schedule was used to minimize uncomfortable or dangerous side
effects of scopolamine. This procedure was chosen out of concern for subjects’ safety, with
knowledge that any practice effects that occurred on neuropsychological testing would be
confounded with increasing dose of scopolamine. Because previous research has consistently

                TABLE 1. Descriotion of Control and AD Subiects
                                                     Control             AD
                                                      Group             Group
                                                     (N = 6)           (N = 10)

                Age
                  Mean (yr)                           63.8              62.5
                  Range                               54-72             55-70
                Education (mean No. of yr)            14.5              13.7
                Sex (males/fcmales)                   412               4!6
                Mean weight (kg)
                  Males                               82.0              80.5
                  Females                             63.2              62.9
                  Totdl                               75.7              71.7
                                                Scopolamine in Alzheimer’s Disease            273

shown only decremental effects of scopolamine on cognition, however, any improvement
observed across test sessions in the present study was assumed to result from practice effects
and not drug effects. The peripherally active cholinergic antagonist methscopolamine was
given (0.5 mg p.0) with the saline injection, and placebo pills were given with scopolamine
injections, in order to keep subjects blind to the scopolamine dosage schedule.
       Testing of cognitive function began a half-hour after the scopolamine injection, and
lasted about 90 min. The following tests were selected to measure cognitive processes that are
commonly impaired in AD. The tests were given in the same sequence to each subject and in
each drug condition.
Word-List Learning
      In this variant of a standard auditory verbal learning test [Rey, 19641, subjects were
given six learning trials with a list of 10 unrelated words. The total number of correct responses
across trials (0-60) was scored for analysis.
Continuous Performance Test [Rosvold et al., 19561
       This test measured sustained attention. Subjects were instructed to press a key in
response to each occurrence of a specified letter in a random series of letters. Letters were
presented at the rate of one per second on a video screen attached to a microcomputer. Six
blocks of 70 letters werc presented, each block containing seven instances of thc target letter.
With rest breaks between blocks, the test lasted about 10 min. The total number of target
letters correctly detected (0-42) was scored.
Category Fluency [Newcombe, 1969; Huff et al., 1986al
      This test measured retrieval from semantic memory. Subjects were given 1 min to list
members of each of four semantic categories (vegetables, vehicles, tools, and clothing). The
score was the total number of correct responses across al categories.
                                                        l
Naming to Definition
       This test also measured lexical-semantic retrieval, but placed less demand upon atten-
tional processes than did Category Fluency. Subjects completed definitions, for example, “A
tool used to pound nails is called a . . .” The number of correct responses (0-24) was scored.
Visual Form Discrimination[Huff et al., 1986a]
       Subjects indicated whether pairs of 12-sided polygons were identical or different. The
total number of correct responses (0-24) was scored.


RESULTS
       All subjects received 0.1-mg and 0.2-mg doses of scopolamine. The symptoms reported
at those doses were thirst (n = 6 ) , lightheadedness or vertigo (n = 4), gait ataxia (n = 2),
headache, nausea, dysarthria, and drowsiness (all n = 1). All subjects except one control
subject received the 0.3-mg dose, but several were unable to complete testing because of side
effects. Additional side effects not observed at lower doses were a drop in heart rate and blood
pressure ( n = 2 ) and visual hallucinations and blurred vision (both n = 1). Two control and
six AD subjects received 0.4 mg. One AD subject developed delirium and urinary retention
after testing had been completed; thirst, vertigo, and ataxia were observed in most subjects.
Only one subject proceeded to the 0.5-mg dose level.
       Test results (Table 2) were analyzed using repeated measures analysis of variance,
examining main effects of subject group and scopolamine dose (0, 0.1, and 0.2 mg), and the
interaction between them. A main effect ( P < .05) of subject group (the AD group being
impaired in relation to the control group) was evident for all tests except the Continuous
274        Huff et al.

TABLE 2. Test Performance in AD and Control groups
                               Scopolamine          Group scores: Mean (SD)             Results
                                  dose                                                    of
Test
-_                                 (mg)            Control            AD             ANOVA”
Word list learning                  0.0           43.0 (6.0)      21.5 (6.9)       g**, d*
                                    0.1           39.0 (8.4)      21.4 (6.1)
                                    0.2           37.3 (3.9)      17.1 (7.2)
Continuous performance              0.0           41.4 (1.3)      35.2 (7.3)       g+, d + , i*
                                    0.1           41.8 (0.4)      35.4 (8.6)
                                    0.2           41.8 (0.4)      31.6 (10.5)
Category fluency                    0.0           50.0 (6.5)      25.5 (14.0)      g**, d**
                                    0.1           54.8 (6.9)      26.3 (14.3)
                                    0.2           57.5 (8.2)      28.2 (13.6)
Naming to definition                0.0           21.3 (2.0)      16.8 (3.7)       g**, d**
                                    0.1           22.5 (1.0)      16.2 (4.4)
                                    0.2           23.2 (0.7)      17.7 (3.8)
Form discrimination                 0.0           22.4 (0.9)      20.6 (3.2)       g*
                                    0.1           23.0 (0.7)      20.7 (1.9)
                                    0.2           22.7 (1.6)      21.3 (1.6)
“Group effect: g + = P < .lo; g* = P < .05; g** = P < .01.
Dose effect: d + = P < .lo; d* = P < .05; d** = P < .01.
Group x dose interaction: i* = P < .05.

Performance Test, for which a trend (P < .lo) toward a group effect was observed. A
significant (P < .05) negative dose effect was observed only for the Word-list Learning Test,
both groups showing worse performance at higher doses. A trend (P < .lo) toward a negative
dose effect was observed for the Continuous Performance Test. Positive dose effects were
observed for the Category Fluency and Naming to Definition Tests, and probably represented
practice effects owing to repeated exposure to the same test materials. The group by dose
interaction was significant (P < .05) for the Continuous Performance Test, but nonsignificant
for all other tests.
       For the tests on which a negative dose effect or group by dose interaction was observed,
post hoc comparisons between scores at baseline and the 0.2-mg dose were made in each
subject group independently using paired t-tests. These comparisons revealed dose effects in
both the control (t = 2.49, P = .05) and AD ( t = 2.64, P = .03)groups for Word-list
Learning, and a dose effect in the AD (t = 3.02, P = .02) but not the control ( t = 1.00, P =
.37) group for the Continuous Performance Test.
       Performance at the 0.4-mg dose level was examined in the two control and six AD
subjects who received that dose. The group by dose interaction on the Continuous Performance
Test that was demonstrated at lower doses (Table 2) was also evident after the 0.4-mg dose, a
further decline occurring in AD patients’ scores (mean 26.0, SD 16.6), but not in those of the
control subjects (mean 41.5, SD 0.7). A decrement (compare with Table 2) in Category
Fluency performance was observed after the 0.4-mg dose in the AD group (mean 21.2, SD
10.2), but not the control group (mean 58.0, SD 5.7). No decrement was found in performance
on the Naming to Definition Test for either the AD (mean 17.7, SD 4.4) or control (mean 23.0,
SD 1.4) group.

DISCUSSION
      The results of this investigation confirm previous studies indicating the importance of
cholinergic neurotransmission in learning, memory, and attentional processes. The failure to
find dose-dependent decrements in lexical retrieval and form discrimination with scopolamine
                                                Scopolamine in Alzheimer’s Disease            275

 implies that these other processes are less dependent upon cholinergic transmission. It is
possible, however, that these negative findings reflect insensitivity of the tests used to measure
the cognitive processes in question. Control subjects performed close to the maximal score on
 some tests, possibly reducing the sensitivity of the tests to drug effects in those subjects. The
 fact that group differences were detected with the tests nevertheless indicates that their
 sensitivity was sufficient to detect drug effects comparable in magnitude to the symptoms
 of AD.
        No deterioration in retrieval from long-term lexical-semantic memory was observed in
 this study at doses of scopolamine that interfered significantly with Word-list Learning. This
 result suggests that retrieval from semantic memory is less dependcnt upon cholinergic
transmission than is registration of new information into episodic memory. Similar results have
been reported by others [Davis et al., 1983; Beatty et al., 19861. Higher doses of scopolamine
 may be required to disrupt performance on fluency tests and other measures of retrieval from
semantic memory. Several studies of healthy subjects have shown this effect [Drachman and
Leavitt, 1974; Caine et al., 19811, and Sunderland et a]. [1985] reported that AD patients
 receiving 0.25 mg scopolamine showed such disruption, whereas control subjects did not.
 Similarly, among subjects in our study who received 0.4 mg of scopolamine, Category Fluency
scores deteriorated in AD patients but not in control subjects, whereas Naming to Definition
scores did not deteriorate in either group.
        Fluency tests place demands upon attention and ability to suppress habitual responses
 [Perret, 19741 as well as upon semantic memory, whereas Naming to Definition is a more
specific test of retrieval from lexical-semantic memory. Both fluency and attention were more
sensitive to disruption by scopolamine in AD patients than control subjects in the present study,
and our results are therefore consistent with the hypothesis that decrements on fluency tests
with scopolamine are due to impaired attention. The conclusion that retrieval from semantic
memory is unaffected by scopolamine must be viewed cautiously, however, because the
practice effect on Naming to Definition may have masked a small drug effect. With the
knowledge from the present study that scopolamine had no effect on visual discrimination, it
will be possible in future investigations to measure lexical-semantic retrieval with tests of
visual object naming, for which multiple equivalent forms are available that could be used to
minimize practice effects [Huff et al., 1986bl. Alternatively, because the present study suggests
that scopolamine at doses of 0.2 mg or lower can be administered safely to AD patients and
elderly control subjects, practice effects may be controlled statistically by counterbalancing the
sequence of drug doses and placebo across subjects.
        The group by dose interaction observed on the Continuous Performance Test indicates
                                                                          n
that attentional vigilance is more vulnerable to muscarinic blockade i patients with AD than
in healthy individuals. This interaction effect suggests the possibility that cholinergic agonists
may produce greater enhancement of attentional processes in patients with AD than in control
subjects. The enhanced sensitivity of attentional performance to scopolamine in AD may be
mediated by cholinergic neurons in the basal forebrain projecting directly to neocortex, or by
pedunculopontine neurons projecting to intralaminar neurons in the thalamus, which project to
neocortex [Mesulam, 19851. Decreased cholinergic activity in neocortex has been documented
in AD [Bowen et al., 1976; Davies and Maloney, 1976; Perry et al., 19771, and has been
attributed to a loss of neurons in the forebrain nucleus basalis whitehouse et al., 19821. Loss
of cholinergic neurons is more pronounced in the basal forebrain than in the pedunculopontine
[Zweig et al., 19871 and thalamic regions [Davies, 1979; Rossor et al., 19821, suggesting that
the nucleus basalis lesion is more likely to account for the attentional deficit produced by
cholincrgic blockade.
        The effects of scopolamine on learning and recent memory are also probably mediated
by cholinergic neurons in the ventral forebrain, particularly those arising from the medial
septa1 nuclei or the diagonal band of Broca and projecting to the hippocampus [Mesulam et
al., 1983; Van Hoesen, 19851, although nucleus basalis neurons projecting to the neocortex
276        Huff et al.

may also be involved [Kesner, 19851. The fact that no dose by group interaction was found for
Word-list Learning indicates that patients with AD and healthy control subjects have similar
dose-response functions, and implies that they may show similar improvements in verbal
learning with cholinergic agonists. The absence of a dose by group interaction suggests,
however, that patients with AD will not have an enhanced response to such agents relative to
healthy subjects. Studies of drugs that increase cholinergic neurotransmission have demon-
strated improved learning in some AD patients, but the gains have generally been modest
 [Peters and Levin, 1979; Mohs et al., 1985; Thal et al., 1983; Summers et al., 19861.
       The fact that a large group difference was found on Word-list Learning, whereas the
dose-response function was no greater in the AD than in the control group, suggests that a
substantial component of the memory deficit in AD is not cholinergically mediated. Deficien-
cies in other neurotramsitters, in particular glutamate [Hyman et al., 1986; Maragos et al.,
 19871 and vasopressin [Mazurek et al., 19861 have been associated with the hippocampal
pathology of AD, and are probably in part responsible for the memory impairment. Reductions
in other neuropeptide [Beal and Martin, 19861 or monoamine [Rossor et al., 1984; Francis et
al., 1985; Arnsten and Goldman-Rakic, 19851 neurotransmitters may also contribute to the
memory deficit in AD.
       Because attention as well as verbal learning was impaired by scopolamine in AD patients
in our study, we cannot exclude the possibility that the attentional impairment caused the
learning impairment in those subjects. However, the fact that control subjects showed similar
learning impairments without attentional impairment at the same doses of scopolamine argues
against that explanation. Drachman [I9771 and Caine et al. [1981] also report evidence in
healthy subjects that the effect of scopolamine on memory is independent of its attentional
effects.
       Our results raise the possibility that cholinergic agonists may improve attentional pro-
cesses in AD, and indicate that attention as well as learning and memory should be measured
in studies of cholinergic drugs proposed as treatments of AD. Simultaneous improvements in
attention and learning abilities in patients with AD would be expected to result in better
performance in activities of daily living, and thus would be clinically important. Although the
cholinergic deficit is not the only neurotransmitter abnormality in AD, an effective cholinergic
therapy may prove to be an important palliative treatment for patients suffering with that
disease.


ACKNOWLEDGMENTS
       This research was supported by NIA grants AG00232, AG05133, and AG05134. The
authors thank the staff of the MIT Clinical Research Center for providing patient care; Marie
Wiminger and Kathleen Swift Banks for testing subjects; Lisa Mack for data entry, Steven
Belle, Ph.D., for statistical analyses; and Kathleen Preksta for manuscript preparation. These
results were presented at the Fourth Meeting of the International Study Group on the Pharma-
cology of Memory Disorders Associated with Aging, Zurich, Switzerland, January 16-18,
1987.


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