Psychopharmacology (1993) t 10: 395-401
Psychopharmacology
© Springer-Verlag 1993
Further analysis of the cognitive effects of
tetrahydroaminoacridine (THA) in Alzheimer's disease:
assessment of attentional and mnemonic function
using CANTAB
Barbara J. Sahakian 1, Adrian M. Owen 1, Nicola J. Morant 2, Sarah A. Eagger 2, Stephen Boddington 2,
Lissa Crayton 2, Helena A. Crockford 2, Maureen Crooks 2, Katie Hill 1, and Raymond Levy 2
1Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK
2Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
Received June 1, 1992 / Final version September 23, 1992
Abstract. Results of a placebo controlled cross-over trial
(N = 89) of the anticholinesterase drug THA as a treatment for dementia of the Alzheimer's type (DAT) are
reported, with reference to previous trials of the drug and
the cholinergic hypothesis of aging and dementia. Using
computerised tests sensitive to specific aspects of memory
and attention, evidence is found for improvements in
attentional function rather than memory, in patients with
mild to moderate DAT. Although these improvements
were significant, they were small and restricted to certain
tests of attentional function. Nevertheless, they add to the
growing body of evidence that the chotinergic system is
involved in the control of attentional processes. The
results will be relevant to future investigations into the
therapeutic effects of enhancement of the cholinergic
system in DAT sufferers.
Key words: Tetrahydroaminoacridine (THA) - Dementia
of the Alzheimer type (DAT) - Attention Memory
CANTAB
The cholinergic hypothesis of aging and dementia attributes cognitive impairments to reduced central cholinergic function (Drachman and Sahakian 1979). Critical
evidence for this hypothesis is that the degree of cognitive
impairment in patients with DAT is positively correlated
with the decrease in choline acetyltransferase activity and a
reduction in acetylcholine synthesis in brain tissue measured in post mortem and biopsy studies, respectively
(Perry et al. 1978; Francis et al. 1985). Subsequently, there
has been great interest in the possibility of a therapeutic
strategy involving correction of the impairment in
memory and cognitive function of DAT patients by
enhancement of central cholinergic function. One way of
making more acetylcholine available at central synapses is
the inhibition of the breakdown of acetylcholine. This is
one of the many actions of the drug tetrahydroaminoacridine (THA). Its other actions include monoamine oxidase
inhibition (Kaul 1962), potassium channel blockade
Correspondence to." B.J Sahakian
(Drukarch et al. 1987) and interaction with subtypes of
muscarinic and nicotinic receptors (Perry et al. 1988).
There is a strong suggestion from the combined results
of a number of experimental studies that parts of the
central cholinergic system are involved in the control of
attentional processes (see Dunnett et al. 1991 and
Sahakian 1988 for reviews). Recent studies of neurotoxic
lesions in rats causing extensive cholinergic cell loss indicate that cholinergic regulation of the neocortex may
influence specific aspects of discrimination performance
and visual attention (Dunnett et al. 1991). In addition,
Warburton and Brown's work with rats (1971, 1972),
using both the cholinergic antagonist scopolamine and
the indirect cholinergic agonist physostigmine, suggest
that cholinergic agents affect the processing of information input rather than learning and memory. Recent work
by Sahgal et al. (1990) finding no effects of three cholinergic drugs (nicotine, oxotremorine and THA) on memory
mechanisms in rats is consistent with this. Drachman et al.
(1980) demonstrate that the effects of 1 mg of scopolamine
given to young adults mirror the effects of aging in a
dichotic listening task requiring high levels of attention
and information processing. Sahakian et al. (1989) found
that nicotine (which mimics the action of acetylcholine
a t nicotinic receptor sites) improved performance of
Alzheimer patients on tasks involving attention and
information processing, but failed to improve performance in a task of short-term memory.
There are several reports of improved performance in
clinical trials of cholinergic drugs in patients with DAT
(e.g. Christie et al. 1981; Belier et al. 1985). The degree of
improvement is typically not large and is highly variable
between doses and patients, probably reflecting the
heterogeneity in the DAT population. Many of these
studies are beset with problems of small sample sizes and
poor design. Several clinical trials of THA have been
conducted recently (e.g. Summers et al. 1986; Chatellier
and Lacomblez 1990; Gauthier et al. 1990; Molloy et al.
1991). The many methodological problems of these trials
have been discussed elsewhere (Eagger et al. 1991a, 1992).
Nevertheless, it has been possible to find significant improvements on clinical rating scales (Eagger et al. 1991a,
396
b). H o w e v e r , of p r i m e c o n c e r n is t h a t specific effects o n
m e m o r y o r a t t e n t i o n m a y r e m a i n u n d e t e c t e d in tasks
w h i c h fail to s e p a r a t e t h e m o d a l i t i e s . I n the p r e s e n t s t u d y
c o m p u t e r i s e d tests d e s i g n e d to test v e r y specific a s p e c t s o f
m e m o r y a n d a t t e n t i o n are used. T h e s e h a v e b e e n s h o w n
to be p a r t i c u l a r l y sensitive to t h e e a r l y stages o f n e u r o d e g e n e r a t i v e diseases s u c h as D A T ( S a h a k i a n et al. 1988)
a n d also to the c h o l i n e r g i c a n t a g o n i s t , s c o p o l a m i n e
( R u s t e d a n d W a r b u r t o n 1988). T h e y h a v e the f u r t h e r
a d v a n t a g e of b e i n g c o m p a t i b l e w i t h m a n y o f the p a r a d i g m s u s e d in a n i m a l r e s e a r c h (see D u n n e t t et al. 1991).
Materials and methods
Subjects
Patients were selected from men and women of any age or race who
met N I N C D S - A D R D A criteria for a diagnosis of probable
Alzheimer's disease (McKhann et al. 1985). All subjects had a MiniMental State Examination (MMSE; Folstein et al. 1975) score in the
range of 8 28 and a Clinical Dementia Rating (Hughes et al. 1982) of
either I (mild dementia) or II (moderate dementia). Subjects were
excluded if there was: (1) any evidence of concurrent illness (e.g.
cerebral infarction, significant hepatic disease, clinical depression or
any other significant psychiatric symptoms); (2) any concurrent
medication likely to interfere with or confuse the interpretation of
the expected action of THA; (3) no reliable caregiver who could
ensure compliance with the protocol.
Of the 89 patients who entered the study, 65 completed it. Most
withdrawals were due to side-effects while on the active treatment.
The commonest reason for withdrawal was an elevation of liver
enzymes occurring in 12 patients (see Eagger et al. 1991a for further
details). Those who withdrew from the study were not significantly
different from those who completed it on any of the demographic of
baseline measures. Statistical analyses are on the data from the 65
patients who completed the study.
Des@n
This was a randomised, double-blind placebo controlled cross-over
study. Baseline assessments were followed by two 13-week treatment
periods (period 1 and period 2) separated by a 4-week washout.
Subjects were randomly assigned to either group A, (receiving active
THA and active lecithin followed by placebo THA and placebo
lecithin) or group B (receiving the treatments in reverse order). THA
dosage was gradually increased over 4 weeks from 50 to 150 rag/day
(up to a maximum tolerated dose). Neuropsychological and psychiatric assessments were made at the beginning, midpoint and end of
each treatment period. Liver function and choline levels were also
monitored carefully.
Neuropsychological tests
Initial assessment included the C A M C O G (Roth et al. 1986), to
assess overall cognitive profile; the National Adult Reading Test
(NART; Nelson 1982) as an estimate of premorbid IQ; and the
shortened version of the WAIS (Wechsler 1955) as a measure of
current IQ. Details of these are presented in Table 1.
The data discussed in the present paper were obtained using the
Cambridge
Neuropsychological
Test
Automated
Battery
(CANTAB) tests of visual memory and attention. They use nonverbal stimuli and record responses using a touch sensitive screen
linked to a BBC microcomputer. Subjects are familiarised with
testing procedure by way of a "motor screening task" in which they
are trained to point accurately at the screen.
The CANTAB Visual Memory Battery comprises four tests (see
Sahakian et al. 1988 for full details):
1. Pattern recognition. Subjects are presented with a series of coloured visual patterns. They are then required to indicate which of
two simultaneously presented patterns they have seen before.
2. Spatial recognition. Subjects are presented with a series of five
open white squares located in different positions on the screen. They
are then required to indicate which position of two simultaneously
presented boxes they have seen before.
3. Delayed matching-to-sample. After a delay of 0, 4, 8 or 16 s,
subjects are required to pick the relevant matching stimulus from
four possible choices comprising shape and colour distracters. A
simultaneous matching condition is also run to control for perceptual deficits.
4. Conditional associative learning task. Six boxes around the screen
open up one by one to reveal the location of different patterns. Each
pattern then appears singly and subjects are required to indicate the
appropriate location. If they fail to respond correctly, the pattern
locations are shown again for up to ten trials. The task begins with
only one stimulus pattern and progresses to two, three, six and
finally eight patterns.
The CANTAB attentional battery comprises four tests (see
Downes et al. 1989 for full details of tests 1, 2 and 4) :
1. Following a simple rule and its reversal. Subjects are presented
with a large and a small dot and required to point as quickly as
possible to first the smaller dot for 20 trials and then the larger dot
for the following 20 trials. The number of correct responses is
recorded.
2. Attentional shift task. This has a similar rationale to the Wisconsin Card Sort Test (Berg 1948), in that it compares the capacity to
make attentional shifts within the same stimulus dimension (intradimensional shift) with shifts to the currently non-attended dimension (extra-dimensional shift). Subjects are required to learn a series
Table 1. Features at entry to trial (Patients completing study
N = 65)
Measure
Age (yrs)
Sex male}
female}
Memory impairment
duration (yrs)
Family yes}
History no}
Hughes CDR I}
CDR II}
CAMCOG
MMSE
AMTS
ADL
Full scale IQ"
Verbal IQ"
Performance IQ a
Premorbid IQ b
Premorbid verbal IQ b
Premorbid perf IQ b
Mean
(range)
66.7
30
35
(52-84)
4.6
26
39
40
25
64.3
17.3
5.7
34.7
99.2
108.5
86.8
111.2
110.7
110.7
(1-10)
Max possible score
lII
(31-96)
(8-28)
(2 9)
(22-47)
(61 150)
(46 157)
(48-140)
(88-128)
(85-129)
(92 124)
107
30
10
47
a Using shortened form of the Wechsler Adult Intelligence Scale
(Wechsler 1955)
b Predicted using the National Adult Reading Test (Nelson 1982)
397
of discrimination tasks in which one of two stimuli is correct, on the
basis of feedback provided by the computer following each choice.
There are nine levels, presented in ascending difficulty and the level
successfully attained is recorded.
3. Simple and choice reaction time test. There are five ascending
levels of difficulty in this test, the first four of which act as training
exercises to prepare subjects for the final level. At the first stage
subjects simply have to touch the screen when a yellow dot appears
in the centre, neither being too early nor too late. The choice
reaction task is introduced at the second stage, with the dot now
appearing in one of five locations. Subjects are introduced to the use of
a touch pad at the third level. They are required to lift lheir hand from
a touch pad as quickly as possible after a dot has appeared in a
single location on the screen. This requirement to release the pad is
combined with the requirement to touch the screen at the fourth
level. Subjects are required to hold down the touch pad until a single
dot appears in the centre of the screen and then to touch position of
the dot as quickly as possible (see Fig. la). Subjects are now considered to be adequately trained for the fifth and final level, a five
choice reaction time task. They are required to hold down the touch
pad until the dot appears at one of five locations on the screen, and
then point to the position on the screen where the dot was presented
(see Fig. lb). At the first three stages, subjects are required to reach a
criterion of 5/6 correct within 18 trials to go on to the next stage. At
the fourth stage, subjects continue until a criterion 5/6 is reached or
until 18 trials have been completed. At the fifth stage, subjects are
given 40 trials to reach a criterion of 5/6 correct. Both accuracy
(defined as the proportion correct at each stage) and speed of
response are recorded for this test. For stages 4 (simple reaction
time) and 5 (choice reaction time), the latter measure is divided into
reaction time (latency to release touch pad) and movement time
(from release of touch pad to touch of screen). In this study,
comparisons were made between performance at stage 4, (single dot,
release and touch) and stage 5, (5 locations, release and touch).
4. Complex visual search test. Subjects must match a stimulus
presented in the centre of the screen with an exact equivalent
presented simultaneously around the screen. Task difficulty is varied
with the number of matching stimuli presented (1, 2, 4 or 8). There
are 40 trials in total (10 at each level of complexity) and at each level,
the total number of correct responses are recorded.
Several standard paper-and-pencil tests of cognitive functioning
were also administered: the Object Learning Test (KOLT) and Digit
Copying Test (KDCT) from the Kendrick Cognitive Tests for the
Elderly (Kendrick 1985); Digit Span (DS) and Digit Symbol Substitution (DSST) tasks from the Wechsler Adult Intelligence Scale
(Wechster 1955); the Logical Memory subtest from the Wechsler
Memory Scale - immediate and 30 min delay (Wechsler and Stone
1973); and the Benton Visual Retention Test - Administration A
(Benton 1974).
The three main clinical outcome measures were the Mini-Mental
State Examination (MMSE, Folstein et al. 1975), the Abbreviated
Mental Test Score (AMTS, Hodkinson 1972) and a carer's rating of
activities of daily living (ADL, Lawton and Brody 1969). The Blessed
Dementia Rating Scale (Blessed et al. 1968) and the Rosen
Alzheimer's Disease Assessment Scale: non-cognitive sub-scale
(Rosen et al. 1984) were also administered.
Statistical m e t h o d o l o g y
Analysis followed a two stage procedure for the analysis of cross
over trials proposed by Hills and Armitage (1979). Each parameter
was tested initially for differential carry-over effects of the first
treatment across the washout period into the second treatment..This
was done using a 2 x 2 analysis of variance (ANOVA) on the two
treatment groups by the change in score over the treatment periods
(ie endpoint minus baseline scores). If no carry-over effects were
detected the treatment effect was tested using analysis of variance on
all the data. However, if significant carry-over effects were detected,
the treatment effect was tested using a one-way ANOVA on the
change during treatment period 1. The test is thus reduced to an
()
Fig. la, b. The simple (a) and choice (b) reaction time tasks. Subjects are required to touch the circle in which the dot appears
independent groups design. In either case, all data were analysed as
change scores; that is, the change in score in the THA condition (end
of treatment score - baseline score) versus the change in score in the
placebo condition (end of treatment score - baseline score).
A significance level of P _< 0.10 was used for the analysis of carryover effects. This was done because it was considered very important
to detect even relatively small carry-over effects, and because the test
is based on between subject differences and is therefore less powerful
than the treatment effect test based on within subject differences.
All analyses were performed using the SPSS-PC + package.
Results
T H A h a d n o significant effects o n the c o m p u t e r i s e d tests
of p a t t e r n a n d spatial r e c o g n i t i o n , d e l a y e d m a t c h i n g to
s a m p l e or p a i r e d associates c o n d i t i o n a l learning. In o r d e r
to illustrate these n e g a t i v e data, the results f r o m the test of
s i m u l t a n e o u s a n d d e l a y e d m a t c h i n g to s a m p l e are presented in Fig. 2. T h e r e was n o difference b e t w e e n the T H A
c o n d i t i o n a n d the p l a c e b o c o n d i t i o n a l t h o u g h in b o t h
g r o u p s t h e r e was a significant d e l a y - d e p e n d e n t deficit
[F(3,183) = 19.25, P < 0.0001]. By c o m p a r i s o n w i t h the
n o r m a l c o n t r o l subjects assessed by S a h a k i a n e t a l .
(1988; see Fig. 2) it is clear t h a t whilst this test is n o t
sensitive to the effects of T H A in D A T , it is c e r t a i n l y
sensitive to the disease itself. T h i s lack of effect is clearly
n o t d u e to a f l o o r effect as the m e a n v a l u e s w e r e well
a b o v e c h a n c e level (25%).
In the m o r e t r a d i t i o n a l p a p e r a n d pencil tests a s s u m e d
to m e a s u r e m e m o r y capacity, s h o r t t e r m m e m o r y a n d
learning, t h e r e w e r e also n o significant effects of the drug.
398
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Fig. 2. The mean percentage correct scores in the simultaneous
(SIM) and delayed (0 16 s) matching to sample task. Whilst this
memory task is clearly not sensitive to the effects of THA, significant
deficits are evident in patients with DAT when compared to normal
controls (Sahakian et al. 1988b) (- O ) Controls; ( • ) THA; ( [ ] - )
placebo
In contrast, there were a number of significant differences between the drug and placebo conditions on certain
of the computerised tests of attentional abilities. Specifically, in the test of simple and choice reaction time there
were differences between the two tasks in terms of both
speed and accuracy of responding.
In terms of simple reaction time accuracy, there was no
significant interaction between treatment (THA or
placebo) and time (baseline to end of treatment) [F(1,59)
= 0.06, P > 0.05]. In contrast, in the choice reaction time
condition, there was a significant difference across the two
treatment conditions [F(1,57) = 5.26, P < 0.05]. In Fig. 3,
the mean change in the overall proportion of correct
responses in the T H A and placebo conditions are presented. The mean change in the T H A condition was, in
fact, significantly positive, overall, 50% of patients deteriorated in this condition compared to 68% in the placebo
condition. Among the patients who became quicker on
THA, average improvement was approximately 16%
(mean scores = 0.68-0.85 correct).
In terms of simple reaction time latency, there was
again, no significant interaction between treatment and
time [F(1,37)= 0, P > 0.05]. In contrast, in the choice
reaction time condition, differences emerged in terms of
both reaction time and movement time. In Figs 4 and 5,
mean changes in reaction time (Fig. 4) and movement time
(Fig. 5) in the T H A and placebo conditions are presented.
For the reaction time measure, there was a significant
interaction between treatment and time [F(1,33)= 9.23,
P < 0.005]. The overall mean change was positive in the
Placebo
Condition
Fig. 3. The mean change in the overall proportion of correct
responses whilst in the THA and placebo conditions
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Fig. 4. The mean change in choice reaction time in the THA and
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Fig. 5. The mean change in choice movement time in the THA and
placebo conditions
T H A condition with no significant change in the placebo
condition (see Fig. 4). Importantly, only 18% of patients
became slower during the THA condition whilst 67%
became slower during the placebo condition. Among the
patients who actually became quicker on THA, average
improvement was approximately 17% (from 0.64 to
0.53 s).
Similarly for the movement time measure, there was a
significant interaction between treatment and time
[-F(1,33) = 5.97, P < 0.05]. The overall mean change was
positive in the T H A condition with no significant change
in the placebo condition (see Fig. 5). Again, only 6% of
patients became slower in the T H A condition compared
to 67% on placebo. Among those patients who actually
improved on THA, average improvement was approximately 13% (from 0.84 to 0.73 s).
When reaction time and movement time were combined into one overall measure of response latency, there
was a highly significant interaction between treatment
condition and time [F(1,33) = 14.6, P < 0.001]. Thus, in
terms of speed of responding, T H A had a significant
beneficial effect in measures of both movement time and
reaction time in the choice condition, but had no effect on
simple reaction time.
In the test designed to assess the patients' ability to
follow a simple rule and to reverse that rule, there was a
significant interaction between condition and time
IF(l,15) = 9.62, P < 0.01]. In the T H A condition, only
16% of patients deteriorated on this task compared to
26% in the placebo condition. Among those that became
more accurate on THA, average improvement was 8%
(from 33.6 correct dots to 36.28 correct dots). However,
T H A did not improve all forms of attentional dysfunction.
I~n the visual discrimination learning task designed to
assess set-shifting ability there was no difference in the
mean scores for stage reached in the T H A condition I-weT H A s t a g e - - 4 . 3 2 (0.37), post-THA stage = 4.61 (0.38)]
and the placebo condition [pre-placebo stage ='4.37 (0.4),
post placebo stage = 4.59 (0.4)]. Similarly, in the complex
visual search test, the mean total correct score (maximum
= 40) did not differ in the THA condition [-pre-THA
score = 38.08 (1.2), post-THA score = 39.34 (1.23)] and
the placebo condition [we-placebo score = 37.57 (1.25),
post-placebo score = 37.63 (1.4)].
In summary, significant effects of THA were only
found for the computerised tests of choice reaction time
and simple rule learning, with no other results approaching significance.
For comparison with the effects found with computerised testing, analysis of the three main clinical outcome measures showed statistically significant effects of
the drug on the M M S E [-F(1,64) = 28.77, P < 0.0001] and
AMTS [F(1,64)= 16.61, P = 0.0001], but not the ADL
[F(1,64) = 0.09, P = 0.764]. The relative lack of effect on
the ADL score did not appear to reflect the known
insensitivity of this instrument in mild and moderate DAT
since no significant change was observed even when only
those patients with MMS scores of 15 or less were included in the analysis [F(1,35) = 0.756, P = 0.39]. None
of the other psychiatric measures showed significant improvements under THA. These clinical outcome measures
have been described in great detail by Eagger et al.
(1991a).
In order to identify features which might predict a
good response to THA on the computerised tests of
attention, Pearson product moment correlation coefficients were calculated between the change scores (on T H A
and placebo) for these tests and changes on the M M S E
and AMTS clinical outcome measures. No significant
correlations were observed. In addition, no other patient
characteristics, including age, age of onset, duration of
illness, initial IQ or disease severity correlated with response on these tasks.
Discussion
Analysis of the specific tests of memory and attention
reported here show that the statistically significant effects
of T H A in DAT patients occurred on attentional tasks.
Thus, the cognitive effects of this acetylcholinesterase
inhibitor are most evident on some aspects of information
processing and attentional function, rather than mnemonic performance. This supports other evidence,
(Sahakian et al. 1989; Dunnett et al. 1991), that activity in
the cortical cholinergic system helps to control attentional
processes. Not only do these results enhance our understanding of the mechanisms involved, but they are also
consistent with the report of an advantage of T H A over
placebo on the psychiatric rating scales M M S E and
AMTS.
The effect of T H A on performance on the choice
reaction time task was small but significant, both for
400
latency and accuracy indices of performance. In terms of
accuracy 50% of patients improved with THA compared
to 32% for placebo. However, there were insufficient
numbers of particular types of errors to allow a detailed
analysis of whether the drug was exerting its significant
improvement by reducing errors of commission or omission or preventing premature responses. Latency scores
improved in 82% and 94% of cases under THA compared
to 33% and 38% in controls for reaction time and movement time, respectively. This improvement in both speed
and accuracy means that patients treated with THA were
not simply trading speed for accuracy. The effects on the
five choice reaction time task were paralleled by a significant improvement on following a simple rule and its
reversal task. Evidently the drug improved performance in
the ability to follow an explicit rule, suggesting that it was
improving attention to the task requirements.
However, THA failed to improve all forms of
attentional function. Thus the capacity to deduce rules on
the basis of reinforcing feedback and to use them to solve
simple discrimination tasks including shifting across
stimulus dimensions was not improved by THA. In contrast to the other attentional tasks, this test does have a
small working memory component. The ability to perform a visual search task in which subjects were required
to match complex visual stimuli was also unimproved by
THA. Finally, THA was unable to improve any of the
measures of visual recognition memory and learning.
Therefore, it is evident that the therapeutic efficacy of
THA on cognition as measured by objective neuropsychological tests is somewhat limited.
Although it is difficult to equate tests, it is important to
note that the main effects in this study were limited to
simpler tests of attentional function. Compared, for example, to the test of delayed matching to sample (see
Fig. 2), where normal elderly controls generally score
between 80 and 90%, control performance on both the
choice reaction time task (96% correct) and the test
designed to test simple rule learning ability (97% correct)
is somewhat superior (Sahakian et al. unpublished observations). Performance on the more complex variants of
these tests or on the tests of mnemonic or learning ability
was not improved with THA.
In support of the pattern of results with CANTAB,
when the components of the Rosen Alzheimer's Disease
non-cognitive scale (Rosen et al. 1984) were-analysed,
the only subscore showing a significant advantage of
THA was "concentration/distractibility" [F(1,63) = 5.55),
P = 0.022]. This item measures how much the patient is
distracted by irrelevant stimuli and/or must be reoriented
to the ongoing task because of loss of train of thought.
Consistent with this is anecdotal evidence from carets,
many of whom noted that the effect of THA was to make
patients more alert. Although these findings are clearly
less precise than those obtained on the computerised
batteries, they are consistent with our hypothesis that the
effect of THA is primarily on attentional processes.
The results reported here demonstrate typically small
improvements on THA. Many previous studies investigating the possible therapeutic effects of THA in Alzheimer's
disease report negative findings (although more promising
results have recently been presented by Warner-Lambert
in the US [FDA Advisory Committee Meeting for Peripheral and Central Nervous System Drugs: March 15,
1991]). Molloy et al. (1991) suggest that one reason why
cholinergic based treatments in DAT are not as effective
as would be theoretically expected, is that the drug is
acting within the context of significant deficits in other
neurotransmitter systems. This may of course be true
especially in the more moderate or severe stages of the
disease, where significant neuropathological changes may
be evident.
As well as employing a sufficiently rigorous design,
and patients in the mild to moderate stages of the disease,
the present research is unique in that it employs highly
sensitive tests designed specifically to measure aspects of
memory and attention separately. Thus, in previous studies, the CANTAB battery has been shown to be sensitive
to the early effects of DAT and Parkinson's disease and
other disorders (Sahakian et al. 1988; Downes et al. 1989)
as well as to the effects of the muscarinic antagonist,
scopolamine (Rusted and Warburton 1988).
Part of the rationale for this battery is based on the
comparison with findings from the animal neuropsychological literature, which thus enhances our understanding
of the possible neuroanatomical and neurochemical
mechanisms involved. It is relevant that THA has recently
been found to have little effect on performance in a
delayed matching to position test (Sahgal et al. 1990). The
five choice reaction time task is analogous to a test used by
Robbins et al. (1989) in rats with lesions of the substantia
innominata which reduced cortical choline acetyltransferase activity by up to 50%. Deficits in both accuracy and
speed of response were found. Although these may not
have resulted from damage specifically to cholinergic cells,
recent findings have strongly suggested that there is an
important cholinergic component to the deficits, which
can be reversed by the anticholinesterase physostigmine
and by cholinergically enriched grafts (Muir et al. 1992).
These results are of special significance in view of the
previous resistance of cognitive decline in DAT to pharmacological treatment. This suggests that such an approach to treatment may still prove viable for cases in the
mild to moderate stages of the disease. It remains to be
seen whether other drugs of this class currently being
developed will be able to produce larger effects, possibly
including improvements in other areas of cognition.
In conclusion, the present study has found evidence of
improvements in certain aspects of attentional function
with THA in mild to moderate cases of DAT. The clinical
relevance of these improvements, given the possible side
effects, remains a matter for individual clinical judgement.
These data, obtained in a carefully controlled study of a
large number of DAT patients, will also clearly provide
important comparative data for future investigations of
putative cognitive enhancing drugs in DAT sufferers.
Acknowledgements. We wish to thank Parke Davis, Division of
Warner lambert Company for support and Prof. Brian J Everitt for
expert statistical advice. We also thank Dr. TW Robbins for his
helpful comments on the manuscript. The CANTAB tests were
developed with the assistance of a major award from the Weltcome
Trust to Drs. TW Robbins, Barry J Everitt and BJS. BJS thanks The
Eleanor Peel Foundation and The Wellcome Trust for support.
401
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