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16601670, 2003
MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF,UK
Department of Psychiatry, and
3
University Neurology Unit, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK
2
Keywords: Alzheimer's disease, frontotemporal dementia, human, semantic dementia, perirhinal cortex, perception
Abstract
It has been demonstrated that patients with dementia of the Alzheimer's type show particular difculties with a task that measures
memory for object locations [R. Swainson et al. (2001) Dement. Geriatr. Cogn. Disord. 12, 26580]. The present study followed on from
this report by asking whether the decits seen in dementia of the Alzheimer's type were specic to this condition, or whether they would
also be seen in another common neurodegenerative syndrome, frontotemporal dementia. To investigate this important issue, we
examined memory for objectlocation pairs and visual recognition memory for novel patterns using two tests, the Paired Associates
Learning and Matching to Sample tasks, from the Cambridge Neuropsychological Testing Automated Battery. The performance of a
subset of the patients with dementia of the Alzheimer's type described by Swainson et al., selected on the basis of age and education,
was compared with matched groups of frontal variant frontotemporal dementia, semantic dementia and control subjects. In contrast to
the patients with dementia of the Alzheimer's type, who showed signicant impairment on both memory tests, the two frontotemporal
dementia groups did not perform signicantly poorer compared with control subjects on nearly all memory measures, other than
`memory score' from the paired associates learning task. These ndings conrm that tests of episodic memory, especially for the
location of objects in space, may be useful in the early diagnosis and differentiation of dementia of the Alzheimer's type.
Introduction
A recent study revealed that a visuo-spatial paired associates learning
task (PAL), in which subjects have to remember the location of objects,
accurately distinguished patients with dementia of the Alzheimer's
type (DAT) from depressed and control subjects (Swainson et al.,
2001). Furthermore, the task successfully identied a subgroup of
patients with questionable dementia who showed a similar prole to
DAT patients, a nding that suggests that these cases were already in
the early stages of Alzheimer's disease (see also Fowler et al., 1997).
Although this experiment revealed an exciting new paradigm for the
early detection of DAT, it is currently unclear whether a similar
impairment would be evident in patients with other forms of dementia,
such as frontotemporal dementia (FTD).
FTD is the second most prevalent cause of dementia in younger
populations (Hodges & Miller, 2001a,b; Ratnavalli et al., 2002), and
there are two clinically distinct forms: temporal variant FTD (or
semantic dementia, SD) and frontal variant FTD (fvFTD). In SD,
patients show a progressive, cross-modal, loss of semantic knowledge
in the context of focal atrophy to anterior and inferior temporal
lobe regions (Hodges et al., 1992). However, contrary to theories
that episodic memory is dependent upon intact semantic knowledge
(Tulving, 1995, 2001), SD patients typically demonstrate good pictorial associative and recognition memory, even for stimuli for which the
1661
Methods
Subjects
Four different subject groups participated in this study, including 11
SD patients, 12 fvFTD patients, 10 probable DAT patients (original
data from a subset of patients assessed by Swainson et al., 2001) and 18
age-matched healthy control subjects (18 were assessed on MTS and
16 on PAL). The two FTD groups were selected to match the DAT
patients on the basis of MMSE scores (DAT range 1824), age and
years of education. None of the subjects had any previous experience
of the experimental tasks. Owing to behavioural difculties during
testing, the data from one fvFTD patient were not included in the
statistical analyses of the data (reducing the number of cases to 11).
The patients were either tested at their own home or at the Early
Dementia Clinic at Addenbrooke's Hospital, Cambridge, UK. The two
tests that were used were taken from the CANTAB (Cambridge
Cognition plc, Cambridge, UK). The CANTAB is a series of computerized tests that were developed from classical neuropsychological
tasks designed to assess memory and cognitive function. In the present
study, a portable Databrick 486 computer (Datalux, Winchester, VA,
USA) tted with a touch-sensitive colour monitor was used to run the
CANTAB. Subjects were seated in front of the computer so that they
could comfortably touch the monitor during the tasks and were given
an opportunity to familiarize themselves with the screen prior to the
start of testing.
Table 1. Mean (with standard error in parentheses) background neuropsychological data for the four subject groups
Group
Age
(years)
Education
(years)
MMSE
(30)
Category
fluency (total
score from
8 categories)
SD
fvFTD
DAT
Control 1y
Control 2
Control 3
61.64 2.11
62.50 2.75
62.50 2.75
60.25 1.45
60.39 1.29
69.67 1.60
12.10 1.02
11.57 0.78
11.50 0.60
12.31 2.60
12.28 2.47
10.78 0.46
23.18 1.68
25.70 2.33
20.60 0.75
N/A
N/A
29.17 0.21
28.55 7.50
81.00 9.15
54.10 2.62
N/A
N/A
113.71 3.96
Naming
(% correct
of 48 or 64)
0.41 0.20
0.96 0.01
0.90 0.03
N/A
N/A
0.930.02
Recognition
memory (% correct)
Words
Pictures
Words
Faces
0.73 0.05
0.96 0.02
N/A
N/A
N/A
N/A
0.78 0.04
0.97 0.009
N/A
N/A
N/A
0.98 0.02
0.76 0.05
0.83 0.05
0.70 0.03
N/A
N/A
0.94 0.01
0.77 0.05
0.76 0.03
0.77 0.03
N/A
N/A
0.88 0.01
Control subjects tested on PAL. Control subjects tested on MTS. Control subjects for background neuropsychological tasks (from Hodges & Patterson, 1995).
Significantly impaired at a corrected level compared with control group (P 0.001). Significantly impaired at a corrected level compared with fvFTD and
control groups (P 0.0001). Significantly impaired at a corrected level compared with fvFTD, DAT and control groups (P 0.0001).
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
Fig. 2. Screen-shots of the MTS simultaneous condition during (a) stimulus presentation, (b) the response stage and (c) the response feedback stage.
Fig. 1. Selected screen-shots from the PAL task during the encoding (a and b)
and retrieval (c and d) stages of the task.
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
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Results
Background neuropsychology
General characteristics
One-way ANOVAs revealed no signicant differences between all
groups assessed on the PAL and MTS tasks in terms of age
(F4,65 0.269, P > 0.9) or years of education (F4,58 0.238,
P > 0.9). There was also no signicant difference between the three
patient groups in terms of MMSE (F2,31 2.142, P > 0.1). Thus, any
signicant group effects in task performance were unlikely to be a
result of differences in age, education or the degree of disease severity
of the three patient groups.
Semantic memory function
As expected, the SD patient group exhibited impaired performance on
general tasks of semantic memory function compared with control data
taken from Hodges & Patterson (1995). One-way ANOVAs revealed a
signicant group effect for category uency (F3,55 44.43,
P < 0.001), picture naming (F3,55 30.80, P < 0.001) and the picture
version of the pyramid and palm trees test (PPT) (F2,44 41.44,
P < 0.001). Post-hoc tests showed that the SD group was signicantly
impaired in comparison with fvFTD and control groups on all these
tests (all P < 0.0001). Similarly, the SD group was found to perform
signicantly worse compared with the DAT group on picture naming
(P 0.0001), although there was only a trend towards a signicant
difference on category uency (P 0.046) at a corrected level.
Episodic memory function
On the recognition memory test (RMT) words version, there was a
signicant group effect (F3,51 12.37, P < 0.001). Whereas post-hoc
analyses revealed only a trend towards a signicant difference between
the fvFTD patients and the control group (P 0.034), both SD and
DAT patient groups were signicantly impaired compared with controls (both P < 0.001). On the RMT face version, there was also a
signicant group effect (F3,51 6.14, P 0.001), with all three patient
groups performing similarly. However, although there was a signicant
group effect, post-hoc analyses revealed that at a corrected level, there
were only trends towards a signicant difference between each of the
patient groups and the control group (SD, P 0.01; fvFTD, P 0.02;
DAT, P 0.02).
PAL
From Fig. 3, it can be seen that whereas all DAT patients failed to pass
the 6-object stage of the PAL task, all control subjects managed to pass
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
Fig. 3. Percentage of subjects passing each stage of the PAL task. Stage 12, 1
object; Stage 34, 2 objects; Stage 56, 3 objects; Stage 7, 6 objects; Stage 8, 8
objects.
Fig. 4. (a) Mean memory score and stages completed for the four subject
groups ( standard error). (b) Mean memory score for the subject groups at each
stage of the PAL task ( standard error).
Fig. 5. Mean number of errors on the 6-object stage for the individuals of each
subject group (`F' indicates that subject failed to reach this stage).
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
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2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
Fig. 7. The proportion correct (arcsin transformed) at (a) the simultaneous condition, (b) the 0 s condition, (c) the 4 s condition and (d) the 12 s condition for the
individuals of each subject group. The dotted line represents the control mean and the dashed line indicates two standard deviations below this.
threshold (all P > 0.04). Figure 8 shows, however, that all three patient
groups were taking longer to respond than the neurological healthy
subjects.
Correlation with semantic function
Given recent suggestions that the perirhinal cortex may subserve
semantic memory processes in humans (Murray & Bussey, 1999),
the relationship between semantic function and performance on the
PAL and MTS tasks was examined. Multiple correlation analyses
between the SD patients' performance on tests of semantic function
and their level of impairment on the different measures of performance
on the PAL revealed only one signicant correlation between the
category uency score for living items and the PAL total memory score
(P 0.004, corrected for multiple comparisons). There were no signicant correlations between the semantic test scores and the SD
patients' performance on the different conditions of the MTS task.
Results summary
As predicted, the DAT group was signicantly impaired compared with
the control group on all three performance measures of the PAL task
(stages passed, memory score and errors at the 6-object stage). By
contrast, the SD groups was only signicantly impaired on the memory
score measure, whereas the fvFTD group was not signicantly impaired
at a corrected level on any measure, although there was a trend towards
a signicant difference on the memory score (see Table 2).
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
SD
fvFTD
DAT
PAL
Stages completed
Memory score
Errors at 6-object stage
Unimpaired
Impaired
Unimpaired
Unimpaired
Unimpaired
Unimpaired
Impaired
Impaired
Impaired
MTS simultaneous
Accuracy
Latency
Unimpaired
Unimpaired
Unimpaired
Unimpaired
Unimpaired
Unimpaired
MTS delay
Accuracy
Latency
Unimpaired
Unimpaired
Unimpaired
Unimpaired
Impaired
Unimpaired
On the simultaneous and delay conditions of the MTS task, all three
patient groups were numerically worse in terms of accuracy and
response latency in comparison with the control group. Only the
DAT group, however, was signicantly impaired at a corrected statistical threshold (P < 0.008) in terms of accuracy on the delay
conditions (see Table 2).
Discussion
Our experimental study was aimed at addressing issues about episodic
memory, in particular cross-modal association learning (PAL) and
recognition memory (MTS), in patients with neurodegenerative disease.
Paired associates learning in FTD
The rst question asked whether the decits previously documented in
DAT by Swainson et al. (2001) using the PAL task would generalize to
patients with FTD. Consistent with previous studies (Fowler et al.,
1997; Swainson et al., 2001), the PAL was found to be particularly
sensitive to DAT, with patients showing decits on all three performance measures (number of stages passed, number of errors at the 6pattern stage and memory score) compared with all other tested groups
(controls and FTD patients). By contrast, both groups of FTD patients
showed relatively good performance on the PAL task, although notably
the SD group was signicantly impaired on the `memory score'
measure (with a trend towards a signicant decit for the fvFTD
group) when the number of items correct at all stages after the rst
presentation of the stimuli was summed. Although this decit was
much milder than that seen in DAT (there was no signicant difference
between the two FTD groups and the control group on the memory
score up to the rst 2-object stage) this nding is important.
Although the majority of FTD patients were capable of performing
the PAL task at least in terms of accurately learning the association
between object and location the number of patients passing the
difcult 6- and 8-item stages was less than controls (see Fig. 3),
thereby reducing the total memory score obtained by these groups
compared with controls. This nding suggests poorer memory in some
patients with FTD, compared with age- and education-matched
healthy subjects, especially when larger sets of items are to be
remembered, and provides an interesting issue for further study.
At a clinical level, the most important nding was that at the critical
6-object stage, the majority of FTD patients performed well on the
PAL tasks, a result suggesting that PAL is indeed useful in the early
diagnosis of DAT. As noted by Swainson et al. (2001), not only does it
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2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
Summary
Patients with fvFTD and SD showed better episodic memory, as
measured by a paired associate learning task requiring retrieval of
objectlocation information, than a matched group of DAT patients.
Moreover, the two FTD groups performed better than the DAT group
on a delayed-matching-to-sample task comprising novel stimuli with
different patterns and colours, although this numerical difference did
not reach statistical signicance. These ndings support the accruing
2003 Federation of European Neuroscience Societies, European Journal of Neuroscience, 18, 16601670
Acknowledgements
We would like to thank all participating subjects, Andrew Blackwell and Robyn
Vessey (Department of Psychiatry, University of Cambridge, UK), Rachel
Swainson (School of Psychology, University of Nottingham, UK), Adrian
Owen (MRC-CBU, Cambridge, UK) and Eleanor Toye and Prisha Shah
(Cambridge Cognition plc, Cambridge, UK) for their assistance with the current
project. This work was funded by the MRC, UK and Alzheimer's Research
Trust, UK, and partly completed within an MRC Centre for Clinical and
Behavioural Neuroscience.
Abbreviations
CANTAB, Cambridge Neuropsychological Test Automated Battery; DAT,
dementia of the Alzheimer's Type; FTD, frontotemporal dementia; fvFTD,
frontal variant frontotemporal dementia; MMSE, Mini Mental State Examination; MTL, medial temporal lobe; MTS, Matching to Sample task; PAL, Paired
Associates Learning task; SD, semantic dementia.
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