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d SmithKline
Key Words
Early detection W Alzheimers disease W Depression W
Neuropsychological assessment W Differential
diagnosis W Neural and pharmacotherapeutic
implications
Abstract
The development of novel treatments for Alzheimers
disease (AD), aimed at ameliorating symptoms and
modifying disease processes, increases the need for early diagnosis. Neuropsychological deficits such as poor
episodic memory are a consistent feature of early-in-thecourse AD, but they overlap with the cognitive impairments in other disorders such as depression, making differential diagnosis difficult. Computerised and traditional tests of memory, attention and executive function
were given to four subject groups: mild AD (n = 26); questionable dementia (QD; n = 43); major depression (n = 37)
and healthy controls (n = 39). A visuo-spatial associative
learning test accurately distinguished AD from depressed/control subjects and revealed an apparent subgroup of QD patients who performed like AD patients.
QD patients performance correlated with the degree of
subsequent global cognitive decline. Elements of contextual and cued recall may account for the tasks sensitivity and specificity for AD.
Introduction
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neuropsychological task focussing on the cognitive difficulties specific to AD may be able to provide a relatively
inexpensive and easily administered method of detection
(and may of course be given in combination with these
other methods to increase accuracy further).
A neuropsychological approach to detection would be
predicated on there being testable deficits in cognition
which are consistent across individuals with the same
neuropathology and distinct from deficits caused by other
neurological or psychiatric conditions. AD pathology, being restricted in the early stages to parts of the medial temporal lobe, may well provide the potential for the development of such neuropsychological tests. The earliest neuropathological changes are seen in the transentorhinal cortex, with the accumulation of neurofibrillary tangles and
neuropil threads [10]. Symptoms are probably not clinically detectable at this stage and indeed may not be
noticed by the patients or their family. When the neuropathology involves the hippocampus and entorhinal cortex,
cognitive impairments become clinically detectable and
at first (probably before the neocortex itself becomes
affected) appear to affect only memory [11, 12]. Patients
at this stage have been referred to as having mild cognitive impairment [13], questionable dementia (QD) [14,
15] or minimal AD [16, 17] and many will qualify for the
probable AD diagnosis (NINCDS-ADRDA) [18] within
a few years, the conversion rate being roughly 1012% per
year compared with 1% per year in the general population
[13]. The capability to diagnose AD at the memoryimpaired stage would potentially be of significant benefit
to these patients. Testing the functioning of the hippocampus and entorhinal cortex may well form the basis of
such a diagnostic strategy, and indeed episodic memory
(memory for unique events which the individual has
experienced, in which the hippocampus is believed to
play a crucial role) is known to be particularly vulnerable
in AD [1924]. It is also important that patients without
AD are not falsely detected by such a test. One of the
most difficult disorders to differentially diagnose from
AD is depression, and contributing to this is the fact that
some episodic memory tests which are very sensitive to
AD particularly effortful tasks such as free recall are
also vulnerable in depression [25, 26]. A range of cognitive functions other than episodic memory, including
semantic memory (knowledge- or fact-based memory),
attention and executive function (high-level control processes), is significantly impaired in the mild stages of AD
[16, 27, 28], and indeed, tests of many different cognitive
capacities have been shown to be predictive of future AD
diagnosis among memory-impaired subjects [13, 29]. It
266
may be that a test of one, or a combination, of these functions would be sufficiently sensitive to the particular neuropathology in AD, as well as being suitably specific (with
regard to excluding conditions such as depression which
are difficult to differentiate clinically from early AD) to be
of diagnostic value. This is the issue which the present
study has sought to address.
In this study, a group of memory-impaired subjects are
being tracked over 2 years with neuropsychological testing
at 8-monthly intervals, the intention ultimately being to
determine whether their clinical outcome could have been
predicted at an earlier time from the results of neuropsychological testing. Three other groups of subjects are also
undergoing repeated testing; these groups will show how
subjects who fall clearly into the categories of mild probable AD, major depression and healthy elderly can be
expected to perform on the same tests over time. This first
report from the study shows how all four groups performed on a wide range of traditional and computerised
tasks when first tested (baseline performance). It also
shows the degree of accuracy with which scores on the various tests are able to classify subjects into diagnostic
groups and how well test performance at baseline predicted the degree of global cognitive decline over the subsequent 8 months. A wide range of tests is being used in
the study, including measures of episodic and semantic
memory, attention and executive function. Many of the
tests included e.g. Mini-Mental State Examination
(MMSE) [30], Alzheimers Disease Assessment Scale
(cognitive subscale) [31], Warringtons Short Recognition
Memory Tests [32] and the Wechsler Memory Scale logical memory recall [33] are used in standard clinical
practice, to assess levels of global, and more specific, cognitive ability. Also included are a range of computerised
tests, mainly taken from the CANTAB (Cambridge Neuropsychological Test Automated Battery; CeNeS Pharmaceuticals PLC; fig. 1) [20, 34]. Many of the CANTAB tests
were developed from the kinds of tests used in lesion and
drug studies with animals, allowing the potential to be
able to relate the deficits of patients to the neuronal and
neurochemical abnormalities produced by the disease
process. Two CANTAB tests paired associates learning
(PAL) and delayed matching to sample (DMTS) have
been used previously in a longitudinal study by Fowler et
al. [14, 15]. That study showed that both tasks were more
sensitive to decline among QD patients than were traditional measures such as the WAIS-R and WMS-R, and
that an error score from PAL, tracked over 6 or 12
months, divided the QD patients into apparently distinct
sub-groups. The performance of approximately half of the
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
displayed one at a time in the available boxes (6 boxes in all but the 8-pattern stage).
Each pattern is then displayed centrally, and the subject has to touch the box in which
the pattern was previously seen. If all responses are correct, the test moves on to the
next stage; otherwise all patterns are redisplayed in their original locations, followed
by another recall phase. Ten presentations and recall phases may be given, following
which, if all patterns have not been placed correctly, the task terminates.
Early Detection of AD
control groups
AD
n
Age
NART
MMSE
GDS
Ham-D
QD
26
43
68.6 (8.3)
65.0 (9.1)
108.4 (10.1) 118.4 (7.2)
21.0 (3.0)
28.0 (2.4)
7.6 (4.7)
8.9 (5.2)
N/A
N/A
Dep
37
60.8 (8.6)
111.7 (9.5)
28.1 (1.6)
21.9 (5.8)
21.4 (6.2)
Con
39
64.6 (8.5)
119.2 (7.7)
29.4 (0.7)
4.1 (2.7)
N/A
267
Measures analysed
37
30
63
31
Predicted verbal IQ
Total score 030 (! 24 indicates
dementia)
Depressive responses/30
Total errors 070
32
20
20
65
CANTAB DMTS
20
20
33
66
67
Category fluency
68
69
70
71, 72
Letter fluency
73
74
75
Percentage correct
Percentage correct
Total correct (max. = 24)
Total correct at 12 s delay
(max. = 10)
The score allocated to subjects who failed prior to the 6-pattern stage of PAL was arbitrary, and its precise value is therefore not recorded here. The actual score
allocated was chosen simply on the basis that it was higher than any error score actually achieved by any subject attempting the stage and thereby signified poorer
performance on the task. This is not equivalent to the adjustment used by Fowler et al. [14, 15].
268
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
Statistical Analyses
Data were analysed using the SPSS for Windows 9.0.0 package
for the PC [39]. Three forms of analysis were carried out on the baseline data: group comparisons, individual patient classification analyses and assessments of predictive validity.
Differences between group mean (or median) performance were
tested using one-way ANOVA or non-parametric Kruskal-Wallis
ANOVA. Planned orthogonal contrasts (which require no reduction
in the significance level applied) were carried out to address the specific hypotheses of the study: firstly, whether the tests were sensitive
to AD in comparison with all other groups (AD vs. QD/depression/
controls); secondly, whether the tests were sensitive to QD when
assessed against a combined control group of depressed and healthy
control subjects (QD vs. depression/controls), and thirdly, whether
the tests were sensitive to depression when compared with healthy
controls (depression vs. controls). Because the AD group were on
average slightly older and of lower estimated IQ than the QD, depression and control groups, the scores of an older, less intelligent group
of controls are provided in the results tables. These data are taken
from groups of healthy control subjects between the ages of 70 and 79
and of estimated IQ 100109, and are available for most of the
CANTAB tests (CeNeS Pharmaceuticals PLC).
In order more rigorously to examine the potential diagnostic value of a test, it was necessary to assess how well it could categorise
individual patients into different groups. This was done firstly by
calculating the degree of overlap between the ranges in the AD and
combined depression/control groups (i.e. the number of individual
scores from either group within the overlapping region as a percentage of the total number of scores). In addition, logistic regression
analysis was carried out using a forward stepwise (likelihood ratio)
method for entry of variables [40]. The variable contributing most
significantly to classification was entered first; any variables which,
when also entered, improved this classification would also be incorporated into the final model. (QD patients, belonging at this point in
the study in neither classification group, were excluded from the classification analyses).
At the time of writing, V2 (8-month follow-up) data were available for the entire QD group, but not for all subjects in the other
groups. (This was due to the fact that recruitment of the QD patients
was complete before recruitment of the other groups; follow-up data
on all tests for the QD group and the other groups will be analysed in
future publications from this study.) MMSE scores at follow-up were
therefore available for the QD patients and provide a useful measure
of global ability 8 months subsequent to initially completing the neuropsychological tests. The change in performance on the MMSE over
8 months was calculated for the QD group and used as an interim
measure of cognitive decline. This decline score was used to corre-
Early Detection of AD
Neuropsychological Testing
Baseline Visit 1 (V1)
Where possible, subjects were tested at their own home over 2
sessions, although in some cases a third session was needed in order
to complete all of the tests. These sessions were completed within 3
weeks of each other. Duration of these sessions was usually about 2 h,
but could be longer if the subject wished to continue; a substantial
break was usually given about half way through each session to minimise fatigue. To minimise differential practice effects, tests were
given with counterbalanced forward:reverse ordering in each group.
Tests given are described in table 2.
Follow-Up Visits 24 (V2, V3, V4)
At 8, 16 and 24 months (B 4 weeks) after the baseline visit, all
subjects are being tested again on the complete battery of tests (with
the exception of the NART which is only given at V1 and V4;
table 2), given in the same order as for the same subject at V1. These
visits are still in progress.
269
Task
AD
QD
22.38 (1.11)
11.14 (0.91)
9.32 (0.64)
6.67 (0.38)
Recognition
Warrington SRMT words
Warrington SRMT faces
Pattern recognition
Spatial recognition
Doors recognition
DMTS (correct 12 s delay)
17.31 (0.55)
19.31 (0.54)
58.17 (1.99)
60.96 (2.73)
9.46 (0.48)
4.56 (0.30)
22.33 (0.54)
22.00 (0.51)
80.04 (2.11)
75.47 (1.86)
14.98 (0.57)
6.14 (0.29)
23.08 (0.48)
22.57 (0.51)
83.11 (1.74)
77.30 (1.56)
16.03 (0.62)
6.69 (0.31)
24.21 (0.21)
23.64 (0.22)
86.86 (1.53)
81.28 (1.63)
17.03 (0.47)
7.28 (0.29)
n/a
n/a
75.0 (1.63)
72.2 (1.91)
n/a
5.98 (0.30)
Cued/free recall
Logical memory (30 min recall)
PAL (stages passed)
PAL (6-pattern errors)1
1.96 (0.67)
4.84 (0.29)
42.81 (2.84)
12.42 (1.44)
7.30 (0.17)
12.80 (2.38)
16.14 (1.15)
7.74 (0.09)
9.37 (1.39)
19.87 (1.02)
7.85 (0.08)
7.79 (1.09)
n/a
7.00 (0.08)
n/a
Semantic naming/fluency
Graded naming test
Semantic naming
Category fluency
14.2 (1.3)
57.3 (1.0)
28.5 (1.8)
23.3 (0.7)
62.0 (0.3)
48.6 (2.0)
22.4 (0.7)
63.0 (0.2)
50.4 (2.0)
24.1 (0.7)
62.7 (0.3)
61.1 (2.1)
n/a
n/a
n/a
24.65 (0.10)
24.70 (0.13)
24.72 (0.10)
n/a
Divided attention
5-choice reaction time (accuracy) 23.48 (0.52)
5-choice reaction time
(latency), ms
492 (30)
Sustained attention
RVIP 1-sequence (A)
RVIP 1-sequence (latency), ms
Executive function
Stroop interference
Letter fluency
ID/ED (stages completed)
One-touch Tower (selections to
solution, 5 moves)
415 (12)
Dep
412 (17)
Con
390 (14)
Elderly Con
n/a
n/a
0.918 (0.017)
0.978 (0.004)
0.963 (0.005)
0.988 (0.003)
570 (34 )
482 (23)
461 (12)
417 (11)
n/a
n/a
10.6 (1.7)
26.3 (2.4)
5.52 (0.65 )
4.1 (1.4)
44.5 (2.4)
8.49 (0.13)
7.4 (1.5)
36.2 (2.6)
7.54 (0.34)
4.6 (1.4)
49.8 (2.2)
8.51 (0.17)
n/a
n/a
7.00 (0.36)
3.35 (0.31)
1.98 (0.13)
2.07 (0.13)
1.72 (0.09)
n/a
Means (SEM). n/a = Not assessed; Dep = depression group; Con = control group.
In order to indicate the actual number of errors made, only subjects attempting the stage contributed to the mean
(SEM) score presented here.
1
270
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
Fig. 2. Scores of individual subjects on PAL, ADAS-cog, pattern recognition and logical memory recall (i.e. the four
tests best able to classify AD and depression/control subjects). PAL and ADAS-cog are scored in terms of errors, so a
high score indicates poor performance, whereas pattern recognition and logical memory recall are scored in terms of
items correct, so a low score indicates poor performance. F indicates that the subjects failed to reach the 6-pattern
stage.
Early Detection of AD
Results
271
Task
Contrast
Overlap
AD vs. Dep/Con, %
AD vs. QD/Dep/Con
QD vs. Dep/Con
***
U = 131
p ! 0.001
**
U = 1,090
p = 0.002
***
U = 404.0
p = 0.001
21
Recognition
Warrington SRMT words
***
n.s.
Pattern recognition
***
Spatial recognition
***
Doors recognition
***
DMTS
(correct 12 s delay)
***
U = 557
p = 0.06
U = 0.62
p = 0.27
t = 1.4
p = 0.15
t = 1.53
p = 0.13
t = 1.29
p = 0.20
t = 1.43
p = 0.16
99
***
U = 1,315
p = 0.06
U = 1,324
p = 0.08
t = 2.28
p = 0.02
t = 1.76
p = 0.08
t = 2.41
p = 0.02
t = 2.45
p = 0.015
n.s.
U = 295
p ! 0.001
U = 495
p ! 0.001
t = 10.24
p ! 0.001
t = 6.92
p ! 0.001
t = 8.99
p ! 0.001
t = 5.41
p ! 0.001
U = 132
p ! 0.001
t = 9.75
p ! 0.001
U = 228
p ! 0.001
U = 1,282
p = 0.016
t = 2.01
p = 0.056
U = 1,053
p = 0.002
n.s.
U = 603
p = 0.18
t = 0.64
p = 0.53
U = 474
p = 0.015
23
t = 8.82
p ! 0.001
U = 462
p ! 0.001
t = 9.36
p ! 0.001
n.s.
t = 0.10
p = 0.92
U = 1,201
p = 0.012
t = 3.03
p = 0.003
n.s.
t = 1.62
p = 0.11
U = 677
p = 0.62
t = 3.79
p ! 0.001
89
t = 4.26
p ! 0.001
t = 4.06
p ! 0.001
n.s.
t = 0.75
p = 0.46
t = 1.18
p = 0.24
n.s.
t = 0.24
p = 0.81
t = 0.97
p = 0.34
97
U = 644
p ! 0.001
t = 4.53
p ! 0.001
n.s.
U = 1,597
p = 0.84
t = 1.75
p = 0.08
***
U = 391
p = 0.001
t = 2.04
p = 0.04
95
t = 2.76
p = 0.007
t = 5.38
p ! 0.001
U = 730
p ! 0.001
t = 5.83
p ! 0.001
n.s.
t = 0.91
p = 0.36
t = 0.52
p = 0.61
U = 1,466
p = 0.25
t = 0.57
p = 0.57
n.s.
t = 1.63
p = 0.11
t = 4.03
p ! 0.001
U = 511
p = 0.008
t = 1.99
p = 0.049
95
Cued/free recall
PAL
(stages passed)
PAL
(6-pattern errors)
Logical memory
(30 min recall)
***
***
***
Semantic naming/fluency
Graded naming test
***
Semantic naming
***
Category fluency
***
Divided attention
5-choice reaction time
(accuracy)
5-choice reaction time
(latency), ms
***
***
Sustained attention
RVIP 1-sequence (A))
***
RVIP 1-sequence
(latency), ms
***
Executive function
Stroop interference
**
Letter fluency
***
ID/ED
(stages completed)
One-touch Tower (selections
to solution, 5 moves)1
***
***
n.s.
*
n.s.
*
*
*
**
*
***
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
*
n.s.
***
n.s.
***
**
*
78
26
58
53
70
7
27
94
33
77
92
78
99
45
Dep = Depression group; Con = control group; U = Mann-Whitney U test; t = Students t test.
* p ! 0.05; ** p ! 0.01; *** p ! 0.001; n.s. p 1 0.05.
Only 10 AD patients were able to attempt the one-touch Tower task.
272
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
Early Detection of AD
273
Task
rs = 0.19
p = 0.12
n.s.
Mnemonic tasks
Warrington SRMT words
Warrington SRMT faces
Pattern recognition
Spatial recognition
Doors recognition
DMTS (correct 12 s delay)
PAL (stages passed)
PAL (6-pattern errors)
Logical memory (30 min recall)
Graded naming test
Semantic naming
Category fluency
rs = 0.13
rs = 0.23
rs = 0.15
rs = 0.03
rs = 0.19
rs = 0.29
rs = 0.39
rs = 0.33
rs = 0.24
rs = 0.03
rs = 0.09
rs = 0.20
p = 0.21
p = 0.07
p = 0.17
p = 0.42
p = 0.11
p = 0.03
p ! 0.01
p = 0.02
p = 0.06
p = 0.43
p = 0.28
p = 0.11
n.s.
n.s.
n.s.
n.s.
n.s.
*
**
*
n.s.
n.s.
n.s.
n.s.
rs = 0.21
rs = 0.32
rs = 0.01
rs = 0.24
rs = 0.01
rs = 0.25
rs = 0.01
p = 0.09
p = 0.02
p = 0.47
p = 0.06
p = 0.47
p = 0.06
p = 0.47
n.s.
*
n.s.
n.s.
n.s.
n.s.
n.s.
rs = 0.26
p = 0.05
274
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
Discussion
Early Detection of AD
275
276
Swainson/Hodges/Galton/Semple/Michael/
Dunn/Iddon/Robbins/Sahakian
Early Detection of AD
277
Acknowledgments
We would like thank Drs. Tom Dening, Deborah Girling and
Carol Gregory for referring patients; Claire Fisher, Melissa Jefferies,
Claire ONeill and Isabel Stow for testing patients; Carolyn Crane for
recruiting patients, and all of the patients and control subjects for
allowing us to test them. This project was funded by an MRC-LINK
grant to B.J.S., J.H.R., T.W.R. and J.S., and completed within the
MRC Co-operative Group in Brain, Behaviour and Neuropsychiatry. The CANTAB tests are available from CeNeS Pharmaceuticals
PLC [www.cenes.com].
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