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European Journal of Neuroscience, Vol. 18, pp.

1660±1670, 2003

ß Federation of European Neuroscience Societies

Associative and recognition memory for novel objects in
dementia: implications for diagnosis
Andy C. H. Lee,1 Shibley Rahman,2 John R. Hodges,1,3 Barbara J. Sahakian2 and Kim S. Graham1
1

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 dif®culties with a task that measures
memory for object locations [R. Swainson et al. (2001) Dement. Geriatr. Cogn. Disord. 12, 265±80]. The present study followed on from
this report by asking whether the de®cits seen in dementia of the Alzheimer's type were speci®c 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 object±location 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 signi®cant impairment on both memory tests, the two frontotemporal
dementia groups did not perform signi®cantly poorer compared with control subjects on nearly all memory measures, other than
`memory score' from the paired associates learning task. These ®ndings con®rm 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 identi®ed a subgroup of
patients with questionable dementia who showed a similar pro®le 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

Correspondence: Dr A. Lee, as above.
E-mail: andy.lee@mrc-cbu.cam.ac.uk
Received 2 April 2003, revised 27 June 2003, accepted 1 July 2003
doi:10.1046/j.1460-9568.2003.02883.x

patients have lost semantic knowledge (Graham et al., 1997, 2000;
Simons et al., 2001, 2002).
In fvFTD, frontal pathology predominantly affects the orbitomedial
cortex causing changes in behaviour and personality, such as apathy,
loss of empathy, impulsivity, disinhibition, ritualistic behaviours and
increased risk-taking (Miller et al., 1995; Rahman et al., 1999; Bozeat
et al., 2000). With respect to episodic memory, Simons et al. (2002)
found that whereas a group of fvFTD patients possessed intact
recognition memory, they were profoundly impaired at recollecting
the time at which the studied stimuli had been presented (temporal
source monitoring). Spatial source monitoring (recollecting the spatial
location of visual stimuli) such as that assessed by the PAL has not
been examined in fvFTD, although, to our knowledge, frontal lobe
damage has not been previously associated with an impairment in
associative spatial memory.
In terms of contrasting DAT with FTD, Perry & Hodges (2000; also
Hodges et al., 1999) found that on episodic memory tests, such as
recall of a story and recognition memory for unfamiliar faces, the DAT
group showed a severe de®cit, with weaker impairments evident in
fvFTD and an even milder de®cit in SD. Studies in FTD suggest
therefore that although patients rarely show the profound amnesic
de®cits seen early in DAT, there can be signi®cant impairment
particularly in fvFTD patients in terms of encoding and/or retrieving
aspects of contextual information.
The ®rst aim of the present study was to determine whether the
de®cits seen in DAT patients on the PAL task from the Cambridge
Neuropsychological Test Automated Battery (CANTAB) could be
generalized to cases with FTD. Although the PAL task was the most

60  0.90  0. The diagnosis of probable DAT was based on inclusion and exclusion criteria (McKahnn et al. age and years of education. phonology.01 0. can impair a monkey's ability to process conjunctions of visual features (Buckley et al. social withdrawal.75 N/A N/A 29. 1992). Cambridge. restlessness.. SD patients may be impaired on the MTS task. None of the subjects had any previous experience of the experimental tasks. 1995). Owing to behavioural dif®culties during testing.28  2.60 12.70  2. Cambridge. USA) ®tted with a touch-sensitive colour monitor was used to run the CANTAB. All the FTD patients recruited for the study ful®lled the Lund±Manchester consensus criteria for frontotemporal lobar degeneration (Neary et al. 2001. However. UK). the second aim of this study was to assess whether the CANTAB MTS task may also be a useful tool in the early diagnosis and differentiation of neurodegenerative diseases. In the present study.78  0. 2001. the data from one fvFTD patient were not included in the statistical analyses of the data (reducing the number of cases to 11).21 28. although the use of complex novel stimuli could affect MTS task performance.. 1984) developed by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA). 1984).64  2.05 0.88  0. The MTS task is also interesting because it assesses recognition memory using novel stimuli (items. (2001) that signi®cantly correlated with global cognitive function.50  2.31  2.04 0.60 12.60 12. The patients were either tested at their own home or at the Early Dementia Clinic at Addenbrooke's Hospital. 2002) and.50  0.41  0. and have been longitudinally assessed on an extensive neuropsychological battery..20 0.02 0. in this case coloured rectangles. §Control subjects tested on MTS.0001). it was dif®cult to make clear predictions about the FTD patients. Table 1 provides the mean scores for each subject group on these tests. for comparison. but not in depressed patients. 1996). reduced empathy.29 69.00  9.50  2.78 11. Considering the existing literature.76  0. There is accumulating evidence to suggest that there is signi®cant perirhinal cortex atrophy in SD (Chan et al. a portable Databrick 486 computer (Datalux.55  7. verbal and non-verbal comprehension and recognition memory. Recent studies have used novel visual items to demonstrate that lesions to the perirhinal cortex. 2001) and 18 age-matched healthy control subjects (18 were assessed on MTS and 16 on PAL). Davies et al.75 62. reduced verbal output and verbal stereotypes (Gregory & Hodges. impulsiveness. 18.57  0. 12 fvFTD patients. Patients diagnosed with the SD subtype were characterized by a de®cit in semantic knowledge.50 81.78  0. poor planning. 10 probable DAT patients (original data from a subset of patients assessed by Swainson et al. apathy. (2001). poor self-care.. Bussey et al.17  0.. The two FTD groups were selected to match the DAT patients on the basis of MMSE scores (DAT range 18±24). combined with relative preservation of syntax.05 0.96 Naming (% correct of 48 or 64) 0.62 N/A N/A 113.96  0. The CANTAB is a series of computerized tests that were developed from classical neuropsychological tasks designed to assess memory and cognitive function. which is situated in the lateral bank of the collateral sulcus. The control subjects were not assessed on these tasks and thus. UK..46 23. 1660±1670 .96  0. Cambridge.47 10. 2002). By contrast.71  3. 2001. 1661 Table 1 provides a summary of the mean age and years of education of the subject groups. there is little evidence for frontal lobe involvement in spatial associative memory. normative data for these tests have been taken from a previous study (Hodges & Patterson. This study received ethical approval from the Cambridge Health Authority Local Research Ethics Committee and informed consent from all participants.76  0.03 0. perceptual and visuospatial abilities. All the patients tested in this study presented through the Memory Disorders Clinic at Addenbrooke's Hospital.0001). The semantic and episodic memory abilities of the patients were quanti®ed with a series of tests assessing word production.  ß 2003 Federation of European Neuroscience Societies.98  0.67  1.009 N/A N/A N/A 0. The SD patients were likely to show good performance on both tasks.01 y Control subjects tested on PAL.77  0.68 25.. Significantly impaired at a corrected level compared with fvFTD and control groups (P ˆ 0. that are not familiar from everyday life). the Pyramid and Palm Trees Test (Howard & Patterson. patients diagnosed with fvFTD presented with a history of progressive change in personality and behaviour with a number of possible de®ning features including disinhibition. UK. Furthermore.45 60. thus. which requires the discrimination of novel complex stimuli on the basis of both pattern and colour.39  1. 1998). picture naming. Winchester.73  0.03 N/A N/A 0. Procedure Methods Subjects Four different subject groups participated in this study.03 N/A N/A 0. as assessed by the Mini Mental State Examination (MMSE).70  0.25  1.11 62. 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.01 0. the fvFTD patients were likely to demonstrate good recognition memory on the MTS task.18  1. an additional task from the CANTAB battery ± matching to sample (MTS) after a delay for visual stimuli ± was also impaired in both DAT and a subgroup of patients with questionable dementia. (2002) observed dif®culties with contextual recall in fvFTD.02 11. 1995). DAT and control groups (P ˆ 0.33 20.77  0. 1992).02 N/A N/A N/A N/A 0.10  2. Given that both FTD groups demonstrate relatively preserved episodic recognition memory. ôControl subjects for background neuropsychological tasks (from Hodges & Patterson.02 Pyramids & Palm Trees (% correct) Recognition memory (% correct) Words Pictures Words Faces 0.930. These included category ¯uency. performance on the MTS and PAL tasks were the only mnemonic measures utilized by Swainson et al. non-verbal problem solving and aspects of episodic memory (Hodges et al. VA. including 11 SD patients.05 0.05 0. The two tests that were used were taken from the CANTAB (Cambridge Cognition plc.83  0. Table 1. Significantly impaired at a corrected level compared with control group (P ˆ 0. Significantly impaired at a corrected level compared with fvFTD.15 54.001). Galton et al. European Journal of Neuroscience.. 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 3ô 61. and the Recognition Memory Test (Warrington.75 60.10  1..03 N/A N/A 0.97  0.Memory in frontotemporal dementia sensitive measure reported by Swainson et al. It was uncertain whether the fvFTD group would be impaired on the PAL: although Simons et al.94  0.

1660±1670 . (b) the response stage and (c) the response feedback stage. European Journal of Neuroscience. H. 1. Lee et al.1662 A. 18. Screen-shots of the MTS simultaneous condition during (a) stimulus presentation. ß 2003 Federation of European Neuroscience Societies. Selected screen-shots from the PAL task during the encoding (a and b) and retrieval (c and d) stages of the task. C. 2. Fig. Fig.

01.51 ˆ 12.9). P > 0.034). P > 0. If these were exceeded without success. the SD group was found to perform signi®cantly worse compared with the DAT group on picture naming (P ˆ 0.14.9) or years of education (F4.269. Post-hoc tests showed that the SD group was signi®cantly impaired in comparison with fvFTD and control groups on all these tests (all P < 0.43. On the RMT face version. The accuracy and response latency data for the simultaneous condition and the three delay conditions of the MTS task were analysed separately. DAT. then the task automatically terminated and the subject was considered to have failed the task at that particular stage. The other two choice stimuli were partial distractors. one 6pattern problem (Stage 7) and. (2001). Performance was assessed according to three measures. In the simultaneous condition. as well as aurally.5 s and was instructed to study this stimulus as a recognition trial would follow immediately (see Fig.02. the SD patient group exhibited impaired performance on general tasks of semantic memory function compared with control data taken from Hodges & Patterson (1995). P < 0. In order to discourage the subject from completing the task by simply learning the colour and shape of a single quadrant. each of the choice stimuli possessed one quadrant that was taken from the target stimulus.008 (corrected for multiple comparisons) was used.58 ˆ 0. with the second being the most accurate at distinguishing DAT from depressed/control subjects and identifying a subgroup of patients with questionable dementia who performed similarly to the DAT group. although there was a signi®cant group effect. after which the four choice 1663 stimuli appeared and the subject was required to make a response. One-way ANOVAs revealed a signi®cant group effect for category ¯uency (F3. Episodic memory function On the recognition memory test (RMT) words version. fvFTD. there was a signi®cant group effect (F3. which was the sum of the number correct across all stages after the ®rst presentation of the stimuli only (maximum score 26). two of which (2 and 3) were designed to take into account the fact that the subjects were allowed up to ten attempts to produce a correct answer: (1) number of stages passed. (2) total errors across all response attempts for Stage 7 only (6-object problem) and (3) memory score. The subject was ®rst presented with a single rectangular pattern comprising four quadrants of different colour and shape for 4.51 ˆ 6. Statistical analyses A series of parametric tests (analyses of variance.1). in which at least one pattern was misplaced. 2).001) and the picture version of the pyramid and palm trees test (PPT) (F2.046) at a corrected level. 3. a statistical threshold of P < 0.05) by the number of possible comparisons between the four subject groups (6). ANOVA) were used to contrast the different subject groups' performance on the PAL and MTS tasks.001). with all three patient groups performing similarly. Only one of the four choice stimuli matched the target stimulus exactly. education or the degree of disease severity of the three patient groups.44 ˆ 41.0001). 4 s or 12 s. The subject was then given another attempt to locate successively all the patterns and in total was allowed nine further attempts following the ®rst attempt.001). On the ®rst trial.142. a statistical threshold of P < 0. The ®rst two measures were previously adopted by Swainson et al. The task gradually progressed in dif®culty.05 (uncorrected for multiple comparisons) was adopted.001). for which eight white boxes were presented. If an incorrect response was given. the target stimulus remained on the screen while four choice stimuli appeared directly below and the subject was required to touch the stimulus that was exactly identical to the target stimulus. PAL From Fig. Whereas post-hoc analyses revealed only a trend towards a signi®cant difference between the fvFTD patients and the control group (P ˆ 0. P ˆ 0. in the form of a green tick or red cross and the word `correct' or `incorrect'.31 ˆ 2. via a high or low computergenerated tone.44. P < 0. However.238. starting with two 1-pattern problems (Stages 1 and 2). it can be seen that whereas all DAT patients failed to pass the 6-object stage of the PAL task. Results Background neuropsychology General characteristics One-way ANOVAs revealed no signi®cant differences between all groups assessed on the PAL and MTS tasks in terms of age (F4. Feedback was provided visually. 1660±1670 . although there was only a trend towards a signi®cant difference on category ¯uency (P ˆ 0. P > 0.55 ˆ 44. Simultaneous and delayed matching to sample (MTS) This test assessed the ability to perceive and learn abstract visual stimuli.5 s presentation period. there were only trends towards a signi®cant difference between each of the patient groups and the control group (SD. two 3-pattern problems (Stages 5 and 6). ®nally. Similarly. For post-hoc analyses.55 ˆ 30.80. P < 0. all the boxes were re-opened in a randomized order to remind the subject of the locations of the patterns. both SD and DAT patient groups were signi®cantly impaired compared with controls (both P < 0.001). The subject was initially presented with six white boxes in a circular con®guration and these then opened one at a time for 3 s each in a randomized order. all control subjects managed to pass ß 2003 Federation of European Neuroscience Societies. There was then a delay of 0 s. any signi®cant group effects in task performance were unlikely to be a result of differences in age.001). Performance was assessed according to the proportion correct and the average response time for each condition.02). If the subject made the correct response then the phrase `All correct' appeared in the middle of the screen and the task progressed to the next problem. One of four possible conditions then ensued: a simultaneous condition or one of three delay conditions. If an incorrect response was given. Thus.0001). post-hoc analyses revealed that at a corrected level. This stimulus was then presented in the centre of the screen and the subject was required to touch the box that contained this pattern. This threshold was derived by dividing the uncorrected threshold (P ˆ 0. followed by two 2-pattern problems (Stages 3 and 4).37. P ˆ 0. the subject had to continue responding until the correct stimulus was selected. For planned comparisons. one 8-pattern problem (Stage 8). There was also no signi®cant difference between the three patient groups in terms of MMSE (F2. Semantic memory function As expected. The delay conditions were identical to the simultaneous condition except that the target stimulus disappeared after the initial 4.65 ˆ 0. there was also a signi®cant group effect (F3. picture naming (F3. P ˆ 0. P < 0. 1).Memory in frontotemporal dementia Paired associates learning (PAL) This test assessed the ability to learn the spatial positions of up to eight abstract visual patterns (see Fig. with one possessing the same colour as the target stimulus but a different shape and the other possessing the same shape as the target stimulus but a different colour. P ˆ 0. one of these boxes contained a pattern and the subject was required to remember the pattern and its spatial location. One of the other choice stimuli was a completely novel distractor in that it differed in terms of both colour and shape. European Journal of Neuroscience. 18.

3. an additional one-way ANOVA was conducted to examine the memory score up to and including the ®rst 2-object stage (stage 3 on Fig. there was no signi®cant difference between the FTD groups and the control group (both P > 0. P < 0. it is at the later stages of the task that the FTD patients were making more errors than the controls.1). 1 object. This revealed a signi®cant effect of group (F3. 18.47 ˆ 42.47 ˆ 15. Thus. 2 objects. by all subjects. the DAT group was signi®cantly impaired compared with the SD. 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). but not necessarily passed.1664 A. the higher mean memory score demonstrated by the control group is likely. As seen in Fig. ß 2003 Federation of European Neuroscience Societies. 4b. Of the FTD groups. (b) Mean memory score for the subject groups at each stage of the PAL task ( standard error). To account for this. European Journal of Neuroscience. 4. fvFTD and control groups (P < 0. It is important to highlight that the memory score (sum of the number correct across all stages after the ®rst presentation of the stimuli only) is con¯ated with the number of stages passed. 3). whereas a number of the patients. Stage 1±2. C.47 ˆ 40. 3 objects.60.001).80. Fig. H. P < 0. failed to reach the later stages of the task. 9% of fvFTD and 36% of SD cases failed at the critical 6-object stage whereas 27% and 45% failed at the most dif®cult 8-object stage. see Fig. 1660±1670 . This ®nding implies that although overall the FTD patients were able to solve the PAL task and complete virtually all stages. and there was a trend towards the fvFTD group's memory score being signi®cantly lower than that of the controls (P ˆ 0.001) at this early stage of the PAL. in part. 8 objects.38. P > 0. Stage 3±4. Whereas the SD and fvFTD groups showed a similar level of performance to controls on the `number of stages completed' (both. 6 objects. in particular in the DAT group.001) and the memory score (F3. Stage 7. the highest stage that was reached. 5. Stage 8. Fig.0001) and post-hoc analyses showed that although the DAT group performed signi®cantly poorer than the control group and the two FTD groups (all P 0. P < 0.001). the SD group's `memory score' was signi®cantly lower than that obtained by the controls (P ˆ 0. they made more errors than the controls after the ®rst presentation of the stimuli items. Figure 4a illustrates a signi®cant effect of group on the number of stages passed (F3. to re¯ect the ®nding that all the control subjects reached the 8object stage of the PAL.001). all stages. 4b). (a) Mean memory score and stages completed for the four subject groups ( standard error).8. Fig. Stage 5±6. Percentage of subjects passing each stage of the PAL task. Post-hoc analyses revealed that on both these measures.01). Lee et al.

fvFTD. it was noticeable that every DAT patient was two standard deviations below the control mean regardless of which PAL measure was considered. 4 s and 12 s conditions of the MTS task for each subject group ( standard error). although as for the accuracy measure none of the post-hoc contrasts was signi®cant. no signi®cant difference at a corrected level between the DAT patients and both FTD groups (SD vs. fvFTD.63. in which a stimulus of the correct colour but incorrect shape was chosen. MTS Figure 6 illustrates the mean performance accuracy and corresponding standard errors of each subject group on the different conditions of the MTS task. P < 0. By contrast. 18. DAT.25.02).02). no signi®cant difference between the groups (all F3. P > 0. both SD and fvFTD groups made a signi®cantly greater proportion of colour and shape errors compared with controls (all P < 0. whereas three were impaired at the 4 s stage and two exceeded this criterion at 12 s. it was found that all subject groups generally committed a greater proportion of colour (SD. Numerically.72. on the simultaneous condition. control. P > 0. 1997). however. 7%. fvFTD. P < 0. Further analyses revealed that the group effect could be attributed to poorer scores in the DAT group compared with controls (P < 0.05) and delay (F2. DAT. Post-hoc analyses revealed that the DAT group committed a signi®cantly greater proportion of distractor errors compared with controls and SD patients (both P < 0.001). 0.94 ˆ 2. 25%.19. fvFTD. Given that performance was measured in terms of proportion correct. control. 3. there was no consistency in which patients were impaired on the different PAL measures. (2) shape errors.001) but there was no evidence of a delay-bygroup interaction (F6.23 < 2. At the delay conditions. 33%. 21% of delay errors) and shape errors (SD. To determine whether the different subject groups could be differentiated on the basis of the type of errors they made on the MTS task.001) and delay (F2. indicating that all four subject groups did not commit signi®cantly different proportions of the three different error types on the simultaneous condition. In the simultaneous condition.14). 67%.92 ˆ 0. control. A log10 transformation was applied to the response latency data prior to statistical analysis. P < 0.001). 7. There was. with a trend towards a signi®cant difference between the DAT group and the fvFTD group (P ˆ 0.17. however.04. Post-hoc analyses found no differences between the subject groups that were signi®cant at the corrected ß 2003 Federation of European Neuroscience Societies. Figure 8 suggests that all three patient groups were marginally slower at this task than controls. 54%. P < 0. DAT.145. P < 0. 78% of delay errors) were also more frequent than distractor errors (SD.001). in which a stimulus of incorrect colour and shape was chosen. there were no SD patients below this criterion at 0 s.Memory in frontotemporal dementia To analyse whether the total number of errors they made at the 6object problem alone differed between the groups. The proportion correct (arcsine transformed) on the simultaneous. 6. For the simultaneous condition. only 2±4 of the SD and fvFTD patients were impaired according to this criterion and. post-hoc analyses revealed that the DAT group performed signi®cantly worse on this component than the three other groups (P < 0. 63%. 0%. Although. DAT. DAT.001) but not a signi®cant group interaction (F6. it can be seen that there was a signi®cant effect of group (F3. the DAT group showed poorer performance than all three groups and there was a trend towards a signi®cant difference between the DAT patients and controls (P > 0.46 > 8. 11. P < 0. Only one SD patient.92 ˆ 12. 55%. 0 s. DAT. On the delay conditions. Figure 5 shows the scores of individual subjects on the PAL at the 6-pattern stage and. 71% of simultaneous errors) errors than distractor errors (SD. A multivariate ANOVA revealed. there was a signi®cant effect of group (F3. DAT. suggesting that the error pro®les of the four subject groups were different from one another on the delay conditions.05% of delay errors). P < 0.07). DAT. 28%. however. control.49 ˆ 3. DAT. whereas the DAT group was not signi®cantly different compared with the control group on colour errors (P > 0. only those patients who reached that stage were included (SD. Figure 8 illustrates the mean response latencies and corresponding standard errors of each subject group on the different conditions of the MTS task. By contrast. 7%. 18%. control. 38%. P > 0. MTS response latency Fig. fvFTD.06). however. Similar to the other PAL measures. control. 75%.06. however.46 ˆ 9.05).49 ˆ 4.02). P > 0. On the three delay conditions. an arcsine transformation (2  arcsine(Hx)) was applied to the data prior to statistical analysis (see Howell. 16). Only 1±2 of the fvFTD patients were impaired at each delay condition whereas 3±8 of the DAT patients were beyond two standard deviations below the control mean at each delay. 19%. in which a stimulus of the correct shape but incorrect colour was chosen and (3) distractor errors. control. colour (SD.06.0001). 1660±1670 . 0%. 38%.008).48 ˆ 3.02). multivariate ANOVAs were conducted on the proportion of error types that the three patient groups and the control group committed on the delay and simultaneous conditions.40 ˆ 16.8). European Journal of Neuroscience. 21%. There was. fvFTD vs. a signi®cant difference between groups on all three error types (all F3. posthoc analyses found no differences that were signi®cant at the corrected threshold. two fvFTD patients and three DAT patients performed greater than two standard deviations below the control mean at the simultaneous condition. 51%. As seen from Fig. a repeated measures ANOVA found a signi®cant effect of both group (F3. In terms of individual patients.002). 0% of simultaneous errors).41.92 ˆ 18. fvFTD. 29% of simultaneous errors) and shape (SD. and between the FTD groups and controls (both P > 0. 1665 Figure 7 illustrates the performance of individual subjects in each group on the different conditions of the MTS task. P < 0.01).6). P > 0. moreover. 11. from this. None of the other contrasts reached corrected statistical signi®cance. There were three types of error that were possible: (1) colour errors. the ANOVA analysis showed a signi®cant effect of group (F3. A repeated measures ANOVA based on the delay condition results found a signi®cant effect of group (F3. although there was a trend towards a signi®cant difference on shape errors (P ˆ 0. fvFTD. one of the fvFTD patients and the SD patient were only marginally below this criterion.

1666 A. 18. The dotted line represents the control mean and the dashed line indicates two standard deviations below this.004. There were no signi®cant correlations between the semantic test scores and the SD patients' performance on the different conditions of the MTS task. The proportion correct (arcsin transformed) at (a) the simultaneous condition. European Journal of Neuroscience. whereas the fvFTD group was not signi®cantly impaired at a corrected level on any measure. memory score and errors at the 6-object stage).04). The average latency of correct trials (log10 transformed) on the simultaneous. that all three patient groups were taking longer to respond than the neurological healthy subjects. 7. Fig. C. Lee et al. although there was a trend towards a signi®cant difference on the memory score (see Table 2). (b) the 0 s condition. Fig. corrected for multiple comparisons). Correlation with semantic function Given recent suggestions that the perirhinal cortex may subserve semantic memory processes in humans (Murray & Bussey. however. the relationship between semantic function and performance on the PAL and MTS tasks was examined. the SD groups was only signi®cantly impaired on the memory score measure. threshold (all P > 0. ß 2003 Federation of European Neuroscience Societies. 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 signi®cant correlation between the category ¯uency score for living items and the PAL total memory score (P ˆ 0. Results summary As predicted. 0 s. 8. (c) the 4 s condition and (d) the 12 s condition for the individuals of each subject group. By contrast. 4 s and 12 s conditions of the MTS for each subject group ( standard error). Figure 8 shows. 1660±1670 . H. 1999). the DAT group was signi®cantly impaired compared with the control group on all three performance measures of the PAL task (stages passed.

all three patient groups were numerically worse in terms of accuracy and response latency in comparison with the control group. all patients with FTD passed the stage. the majority of FTD patients performed well on the PAL tasks. showed the most ß 2003 Federation of European Neuroscience Societies. Further investigation into alternative performance measures (such as total errors adjusted for number of stages passed and response attempts made) and combinations of these scores also failed to identify a measure or combination of measures that would be able to distinguish between the different patient groups more effectively. (2001) using the PAL task would generalize to patients with FTD. 1998). By contrast.. especially when larger sets of items are to be remembered. Maguire et al. and extra trials at various stages of the task may provide more data at critical levels of dif®culty. showed a moderate memory de®cit..and education-matched healthy subjects. not only does it 1667 accurately identify patients with questionable dementia who will go on to develop full-blown DAT (Swainson et al. Schacter et al. On the simultaneous and delay conditions of the MTS task. (2002). 3). however. compared with age. in particular cross-modal association learning (PAL) and recognition memory (MTS). At a clinical level. 1999). the subject is required to recall the pairing of the object and its presented location). although notably the SD group was signi®cantly impaired on the `memory score' measure (with a trend towards a signi®cant de®cit for the fvFTD group) when the number of items correct at all stages after the ®rst presentation of the stimuli was summed. whereas Simons et al. rather than frontal lobe regions. suggests that whereas source monitoring tasks similar to that used by Simons et al.. Consequently the PAL task. was signi®cantly impaired at a corrected statistical threshold (P < 0. in which many patients showed normal performance on an associative task for door-sofa stimuli and a test requiring recollection of the set ownership of studied pictures. 1996. but it also. in many cases. Swainson et al. 18. Consistent with previous studies (Fowler et al.008) in terms of accuracy on the delay conditions (see Table 2).Memory in frontotemporal dementia Table 2. In support of this.008) compared with control group. to our knowledge. 1996. A group of fvFTD patients were instructed to learn pairs of words and pictures and then performed a cued-recall memory task. our fvFTD group performed well on the PAL. with patients showing de®cits on all three performance measures (number of stages passed. In particular. Paired associates learning in FTD The ®rst question asked whether the de®cits previously documented in DAT by Swainson et al. 1990). considered alongside our PAL ®ndings. Craik et al. Discussion Our experimental study was aimed at addressing issues about episodic memory. European Journal of Neuroscience. as it is presently designed. a 6-object±location trial. frontal damage has only very rarely been reported in the literature to cause associative spatial memory de®cits. and provides an interesting issue for further study. Johnsrude et al. We found that the DAT group. This result.and 6-item conditions. 1997. in the 3item condition. however. both groups of FTD patients showed relatively good performance on the PAL task. yet passed by all FTD cases (see Fig. a 4. 1660±1670 . Although this de®cit was much milder than that seen in DAT (there was no signi®cant 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. By contrast.. does not appear to be sensitive enough to differentiate these two diseases suf®ciently. a result suggesting that PAL is indeed useful in the early diagnosis of DAT. so did approximately 10±40% of fvFTD and SD cases. a result they attributed to the patients' prefrontal damage (see also ®ndings in normal subjects. Further support for the critical role of MTL areas in associative spatial tasks comes from neuroimaging studies that have demonstrated right parahippocampal/hippocampal region activity during tasks of object±place memory tests (Owen et al. The discrepancy in these ®ndings may be explained by considering a study by Dimitrov et al. the most important ®nding was that at the critical 6-object stage. and from studies in non-human primates that have found impairments in spatial scene learning following both perirhinal and hippocampal lesions (Murray et al. (2001).. associative memory tasks may require more input from regions in the temporal lobes. 2001). (2002) observed that ®ve patients with fvFTD had poor temporal source memory but good item detection. as reported by Swainson et al. Recognition memory for novel stimuli in DAT and FTD The second question addressed by our study was whether an MTS task based on novel stimuli would also serve as a sensitive tool for diagnosis and differentiation between DAT and FTD.. may be particularly dependent upon the prefrontal regions.and 8-item stages was less than controls (see Fig. As noted by Swainson et al. In the next condition. who had additional temporal lobe damage. as demonstrated by the sensitivity of the PAL to DAT but not fvFTD. that the test was not 100% accurate: there was no condition that was failed by all DAT patients. 2001).e.. This ®nding suggests poorer memory in some patients with FTD. For example. in patients with neurodegenerative disease. 1984. Only the DAT group. Although the majority of patients were unimpaired. respectively. (1999). 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 dif®cult 6.. whereas all DAT patients failed. number of errors at the 6pattern stage and memory score) compared with all other tested groups (controls and FTD patients). (2001). It is important to note. as did approximately 35% of DAT patients. a small subgroup of fvFTD patients. 3).and/or 5-item condition may bridge the gap between the current 3. spatial tasks such as PAL may be predominantly reliant upon medial temporal lobe (MTL).. despite this task also requiring recollective memory processes (i. The fact that the majority of SD cases showed good cross-modal associative learning is consistent with the results from Simons et al. Future designs should perhaps include additional problems to circumvent this particular methodological problem. differentiates patients with fvFTD and SD from those with established DAT. Summary of overall group performances on PAL and MTS tasks Patient group vs control group Task 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  Significantly impaired (at a corrected level P ˆ 0. the PAL was found to be particularly sensitive to DAT. For example. thereby reducing the total memory score obtained by these groups compared with controls.

2000. Murray. Meunier et al. Further studies of aspects of memory function in SD. 1994. 1993. 7).. 1660±1670 . 1997b). 1995. 2000. It is possible therefore that a number of the SD patients included in our study did not have suf®cient damage.. Buckley & Gaffan. One suggested explanation for the discrepancy between the two literatures has been that patients with SD were not tested on novel stimuli. this damage is incomplete and a proportion of the perirhinal cortex remains intact. either to the perirhinal cortex or involving this structure bilaterally. the de®cit is typically milder than that seen in DAT and performance on standard tests of perceptual processing is usually good (Simons et al. it is possible that the lack of a signi®cant de®cit in the current study and previous studies of novel recognition memory in perirhinal lesion patients may be attributed to the use of stimuli of insuf®cient visual complexity (e. These ®ndings support the accruing ß 2003 Federation of European Neuroscience Societies. there has been little support from human studies. will need to combine volumetric measurements of regions within the MTL with concurrent performance on more cognitively clean neuropsychological measures of perirhinal cortex function.. 2002. So. including the perirhinal cortex. (1994) reported that rhinal cortex lesioned monkeys were impaired in both simultaneous and 0 s delay conditions of an MTS task. 1982. Chan et al. Future investigation into this measure of performance may determine its suitability in the discrimination of FTD and DAT. Simons et al. Davies et al. Eacott et al.. 2001. European Journal of Neuroscience. Buckley et al. (1998) and Holdstock et al.. It has also been documented that perirhinal lesioned monkeys were impaired on visual concurrent discrimination tasks when the stimulus set sizes were large (Buckley & Gaffan..g. 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. who were more likely to make colour or shape errors. 1994. 1998). to produce a signi®cant de®cit in recognition memory.1668 A.. colour and size (thought to be dependent upon TE regions). the FTD groups were more likely to retain at least one aspect of information correctly. than a matched group of DAT patients. suggest that these de®cits may be attributed to problems with higher order visual perception. with the latter committing a greater proportion of distractor errors compared with both FTD groups. Lastly. 2002). Lee et al. Buckley & Gaffan. 2001). More recently. 1997a) or used different orientations of the stimuli across trials (Buckley & Gaffan. there are a number of theoretical reasons to explain the absence of a signi®cant impairment in this study. which is situated in the banks of the collateral sulcus in man. 1997. Evidence for a critical role of the perirhinal cortex in object recognition memory comes largely from animal lesion studies that have demonstrated that rhinal but not hippocampal lesions produce severe stimulus recognition de®cits (Zola-Morgan et al. albeit asymmetrical. It is interesting to note. 18. although caudal inferotemporal cortical regions. SD patients typically show normal pictorial recognition memory early in the disease (Graham et al. are involved in the representation of simple stimulus features. Buffalo et al. Volumetric studies that have been carried out in SD have shown that patients with this disease show signi®cant. Buckley et al. Bachevalier. including higher visual areas V4 and TE/TEO. Relevant to this issue are the ®ndings of Stark & Squire (2000) who observed that patients with perirhinal damage were able to perform simple visual discriminations between stimuli of differing shape. 1999. it may not be particularly useful in discriminating between DAT and FTD.. 1999). 1993. as well as on more dif®cult discriminations between photographs of different three-dimensional objects in a range of orientations (demonstrated to be dependent upon perirhinal cortex in monkeys. 1989.. the fact that this volumetric analysis was carried out on structural MRI volumes not concurrent with the period during which testing was conducted for this study prevents any valid correlation analyses between test scores and volumetric measurements. 2002). Alvarez et al. Furthermore. It is possible that a lack of statistical power underlies this non-signi®cant result. 2001). although it is notable that Stark & Squire (2000) used only a relatively small set of stimuli. Investigating recognition memory for novel stimuli in SD is also of important theoretical interest because studies in non-human primates suggest that the perirhinal cortex (BA 35/36). Buckley & Gaffan. Murray & Bussey. contained a large number of distracting stimuli (Buckley & Gaffan. 1999. 1999. Moreover. shape and colour.. 2001. Thus. 2001). Buckley et al. From these data it has been proposed that the perirhinal cortex may form the ®nal stage of the ventral visual processing stream (Ungerleider & Mishkin. although this task may be sensitive to DAT... a subset of which were included in this study. profound de®cits on MTS whereas the SD and fvFTD groups were not signi®cantly impaired on any conditions of the MTS task (see Fig. Moreover. This suggests that whereas the DAT group failed to remember any colour or shape information on many of their error trials. 1997a). despite neither imposing a signi®cant memory demand. Buckley et al.. atrophy to nonhippocampal MTL regions including the perirhinal cortex (Galton et al. although this did not reach statistical signi®cance. although a subset of the SD patients from this study have been shown. Recent studies. affecting most often left temporal lobe regions (Chan et al. 1998. Eacott et al. particularly those that address perirhinal cortex function. even in the small number of patients who show de®cient recognition memory. Murray & Bussey. First. The scores of the FTD groups occupied an intermediate position and were not signi®cantly different to either controls or DAT. Murray & Mishkin. Firstly. 2002). via volumetric analysis. 1994.g.. 2001). 2002). store conjunctions of stimulus features. The present study provides tentative evidence in support of this in that the SD group performed numerically poorer than the control subjects on the MTS task. 2001.. to have disproportionate atrophy to the perirhinal cortex compared with DAT patients (Davies et al. (2002) demonstrated that a group of SD patients. This ®nding implies that the human perirhinal cortex may not subserve the same visual functions as those suggested from the non-human primate studies (e. 2000. H. (2001) found that perirhinal cortex ablations impair a monkey's ability to make visual discriminations on the basis of object perception but not their ability to discriminate on the basis of simple features such as size. C. 2000). Similarly. Galton et al. volumetric studies in SD patients reveal a pattern of atrophy that is typically asymmetrical. as measured by a paired associate learning task requiring retrieval of object±location information. (2000) reported normal performance on MTS in patients with focal lesions affecting the perirhinal cortex in both a simultaneous and 0-s delay condition. although this numerical difference did not reach statistical signi®cance. rostral regions.. Bussey & Saksida. 2001. Murray & Bussey. Suzuki et al. exhibited signi®cant disproportionate atrophy to the perirhinal and temporopolar cortices compared with a matched group of DAT patients. Second.. which are more typically adopted as test items in the nonhuman primate investigations. is critical for object recognition memory (Aggleton & Brown. In support of this. Summary Patients with fvFTD and SD showed better episodic memory. that the FTD and DAT groups showed different error pro®les on the delay conditions of the MTS task. Despite a number of non-human primate studies providing evidence for a role of the perirhinal cortex in visual processing. Bussey et al. Alternatively. Bachevalier & Mishkin. and that a larger sample of SD patients would push this difference towards signi®cance. however. however.

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