Pentagon drawing and neuropsychological

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cognitive performance on the MMSE and CAMCOG scales. Results Patients with DLB were found to draw significantly worse pentagons than those with AD or ...
INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int J Geriatr Psychiatry 2004; 19: 371–377. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/gps.1094

Pentagon drawing and neuropsychological performance in Dementia with Lewy Bodies, Alzheimer’s disease, Parkinson’s disease and Parkinson’s disease with dementia Francesca Cormack1,2, Dag Aarsland3, Clive Ballard2 and Martin J. Tove´e1* 1 Psychology Department, The Henry Wellcome Building For Neuroecology, Framlington Place, Newcastle University, Newcastle Upon Tyne, UK 2 Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle Upon Tyne, UK 3 Section of Geriatric Psychiatry, Psychiatric Hospital of Rogaland, Stavanger, Norway

SUMMARY Objectives Early and accurate diagnosis of Dementia with Lewy Bodies (DLB) to allow the appropriate clinical treatment is a priority, given reports of severe neuroleptic sensitivity and a preferential response to cholinesterase inhibitors in these patients. There have been suggestions that constructional apraxia is prevalent in DLB, and may provide a sensitive marker of the disease. Methods This study examined the pentagon drawings of 100 DLB patients, 50 Alzheimer’s disease (AD) patients, 81 Parkinson’s disease (PD) patients of whom 36 suffered from dementia (PDD). Performance on this task was correlated with cognitive performance on the MMSE and CAMCOG scales. Results Patients with DLB were found to draw significantly worse pentagons than those with AD or PD, but not those with PDD. Drawing scores were significantly correlated with MMSE scores for the AD and PDD groups but not those with DLB. More detailed analysis of the neuropsychological correlates of constructional performance for patients with AD and DLB, revealed that those with AD showed a broad cognitive basis to their impairment, in DLB drawing was linked only to perception and praxis. Conclusions This study has suggests that DLB subjects show an impairment of pentagon copying that is dissociable from more global cognitive impairments, whereas PD patients are relatively unimpaired on pentagon copying and AD and PDD patients show a linkage of their impairment in copying with more global cognitive deficits. Copyright # 2004 John Wiley & Sons, Ltd. key words — Dementia with Lewy Bodies; Alzheimer’s disease; Clock drawing; Pentagon drawing; constructional apraxia

INTRODUCTION Dementia with Lewy Bodies (DLB) accounts for 10–25% of dementia cases in clinical populations (Campbell et al., 2001), and is characterized by the presence of cognitive, psychiatric and motor symptoms. However, it is often difficult to accurately diag-

*Correspondence to: Dr M. J. Tove´e, Psychology Department, The Henry Wellcome Building For Neuroecology, Framlington Place, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK. Tel: 0191 222 8616. Fax: 0191 222 5622. E-mail: [email protected] Contract/grant sponsor: Research into Ageing; contract/grant number: 171s. Copyright # 2004 John Wiley & Sons, Ltd.

nose these patients, particularly at initial presentation. The need for early and accurate diagnosis of DLB to enable the appropriate clinical treatment has been emphasized by reports of severe neuroleptic sensitivity (McKeith et al., 1992) and preferential response to cholinesterase inhibitors in these patients (McKeith et al., 2000). Currently, a diagnosis of DLB is excluded if the motor features of Parkinson’s disease precede dementia by more than a year, and such cases are instead classified as Parkinson’s disease with dementia (PDD) (McKeith et al., 1996). This distinction is not clearly related to the underlying pathology, however, and recent research has pointed to considerable overlap in the clinical features of the two illnesses (Aarsland et al., 2001). Received 24 June 2003 Accepted 11 December 2003

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Drawing and copying performance is increasingly being used in the identification of cognitive impairment in the elderly, as it is quick and easy to administer, sensitive to degeneration early in the disease process (Ericsson et al., 1996), and correlates well with global cognitive functioning. Bourke et al. (1995) found that pentagon copying, measured on an ordinal six point scale, was highly correlated with both MMSE and total CAMCOG score in their sample of 77 AD patients. It was also significantly correlated with clock drawing performance, which the authors suggest is more appropriate as a screening instrument. The pentagon copying task has been significantly correlated with measures of memory, attention and naming (Tierney et al., 1997). A small, but significant correlation was observed between this and another constructional measure, the visual reproduction test (Tierney et al., 1997). The authors concluded that this pattern of correlations indicates that the intersecting pentagons task is not a specific measure of constructional performance. It also suggests that pentagon drawing is highly sensitive to the presence of cognitive impairment across a range of domains. The neuropsychological profile of DLB has been recently reviewed by Simard et al. (2000), and consists of attentional, executive and constructional deficits, in excess of those seen in AD. It has been suggested that the constructional deficit may be a sensitive indicator of DLB, and may, in future, have a role to play in the differential diagnosis of these dementias (Gnanlingham et al., 1997; Ala et al., 2001). A recent study has examined the performance of patients with DLB on the pentagon copying task. Ala et al. (2001) compared the performance of patients with pathologically confirmed DLB and AD. Drawings were analysed on a correct/incorrect basis. It was found that patients with DLB were more likely than those with AD to draw an incorrect pentagon, and they found that this technique had a sensitivity of 88% and a specificity of 59% in identifying DLB. However, Connor et al. (1998) reported no significant difference in the performance of subjects with DLB on the pentagon copying task. It is also unclear whether the neuropsychological basis of impaired pentagon copying in DLB is similar to that of AD. It is likely, given the specific profile of neuropsychological performance in AD and DLB that this is not the case. In addition, there has been no study comparing the performance of subjects with DLB to those with PD and PDD. This is of particular interest given the growing evidence of clinical and neuropsychological overlap between PDD and DLB. Copyright # 2004 John Wiley & Sons, Ltd.

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Specifically, it was impossible to discriminate DLB from PDD using measures of attentional functioning, which have previously proved to be sensitive in distinguishing DLB from AD (Ballard et al., 2002). On the basis of previous research we would predict that subjects with DLB would be both quantitatively more impaired than those with AD, and have a different pattern of neuropsychological predictors for their performance. We would expect, however, a much more similar pattern of impairments in DLB and PDD, sharing as they do many markers of cortical and subcortical pathology. METHODS Patients DLB and AD patients were recruited as part of a prospective dementia study. Patients were included in the study if they met the appropriate diagnostic criteria, gave informed consent, had a MMSE over 8 (i.e. were mildly to moderately impaired) at baseline, and had a reliable informant. Patients met the Consensus Criteria for the clinical diagnosis of DLB (McKeith et al., 1996), or the National Institute for Neurologic and Communicative Disorders and StrokeAlzheimer’s disease and Related Disorders Association (NINCDS-ADRDA) criteria for the diagnosis of AD. Only subjects with onset of EPS after one year or more of the onset of dementia were included. Patients with PD and PDD (Parkinson’s disease with dementia) from the county of Rogland, Norway were also included. These patients were drawn from an epidemiological study of 245 PD patients carried out in 1992 and 1993 (Tandberg et al., 1995), followed up in 1996–97. Full details of their recruitment and assessment can be seen in Aarsland et al. (2001), and are summarized below. Diagnosis was based on the clinical evaluation at baseline, response to levodopa, and disease development. All patients had a diagnosis of probable or definite PD (Larsen, 1991). Definite PD required unilateral onset and development, good or excellent response to dopaminergic therapy, the presence of resting tremor and two of the cardinal signs: akinesia, rigidity or postural abnormalities. For probable PD, two cardinal signs had to be present, but resting tremor was not required. Only one of the following atypical features was allowed: (1) autonomic failure at disease onset; (2) only a moderate response to levodopa and (3) symmetrical presentation of symptoms. Patients were excluded if they had mild dementia at Int J Geriatr Psychiatry 2004; 19: 371–377.

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deficits in drawing tasks disease onset, other neurological diagnoses, clinically significant changes in CT or MRI, and current or previous use of neuroleptic drugs. The identification of patients as suffering from PDD was based on guidelines in the DSM-III-R (American Psychiatric Association, 1987) and performance on the Dementia Rating Scale (Mattis, 1976) and MMSE. Subjects with dementia at had scores of less than 24 for the MMSE and 123 for the DRS. Patients who developed dementia more than one year after the onset of parkinsonism were included. In order to exclude DLB from this group, patients with dementia, repeated falls, or hallucinations at disease onset, or dementia at the primary evaluation, were not included. Of the 245 patients of the original 1993 sample, 88 died, seven have been given alternative diagnoses and 11 refused to participate. This left a study group of 131 PD patients, who were re-assessed during 1996–97, when the current data were obtained. Only those with a diagnosis of definite or probable PD at re-evaluation on this second occasion were included. Of these, pentagon copying was available for 117 patients 36 of whom were PDD and 81 of whom were PD. Patient characteristics Patient characteristics (age, gender and MMSE) are presented in Table 1. A one-way ANOVA identified significant differences between diagnostic groups for MMSE (F ¼ 110.070; p < 0.0001) and age (F ¼ 10.09 p < 0.0001). Tukey’s HSD post-hoc tests showed that PD group without dementia had a significantly higher MMSE score than the dementia groups ( p < 0.0001), but that the dementia patients were not significantly different from each other. The PD patients without initial dementia were also significantly younger than the all the other groups ( p < 0.0005), except the DLB group. The dementia groups (AD, DLB and PDD) were, however, matched for both age and cognitive impairment.

Cognitive assessment Cognitive assessment of the Newcastle cohort was carried out using the CAMCOG schedule, taken from the Cambridge Mental Disorders in the Elderly Examination (CAMDEX) (Roth et al., 1986). The CAMCOG comprises the assessment of functioning across ten subscales: orientation, language comprehension, language expression, praxis, attention and calculation, recent memory, remote memory, visual memory, perception, and abstract thinking. This scale contains items from the MMSE (Folstein et al., 1975), and a score on this scale can be calculated. Drawing and copying tasks are carried out as part of the Praxis sub-scale of the CAMCOG schedule. The drawing tasks used are clock drawing, copying intersecting pentagons, copying a spiral and a copying a three dimensional house. The Norwegian patients were administered the MMSE. Pentagon scoring Pentagon drawings were photocopied onto separate sheets so that they could be rated individually. Scoring was carried out while blind to diagnosis and MMSE score. The scoring system used was a sixpoint hierarchical scale (see Table 2) developed by Bourke et al. (1995), where 6 represented a perfect attempt, and 1 the worst. Statistical analysis Pentagon drawing was measured on an ordinal scale, so non-parametric statistics were used. Kruskal– Wallis is the non-parametric equivalent of one-way ANOVA and was used to test the null hypothesis that there were no differences between the groups. For post-hoc multiple comparisons, Mann–Whitney tests were carried out for pair-wise comparisons between groups. To correct for the increased risk of Type I errors, a Bonferroni correction was carried out. The familywise alpha was set to 0.05, which resulted in

Table 1. Mean MMSE and ages for AD, DLB, PDD and nondemented PD groups

Table 2. Intersecting pentagons scoring system (Bourke et al., 1995)

Diagnostic group

6 5

AD DLB PDD PD

n

100 50 36 81

% male

39 44 50 49

MMSE

Age

Mean

SD

Mean

SD

18.03 17.13 19.36 28.81

4.67 5.74 4.88 1.79

80.27 78.08 78.94 72.70

6.48 6.89 6.29 9.23

Copyright # 2004 John Wiley & Sons, Ltd.

4 3 2 1

Copied correctly Two figures intersecting with one a pentagon, or additional lines joining two pentagons together Two figures drawn and intersecting Two figures not intersecting One closure figure drawn Lines drawn not making closure figure, drawn inside figure, or no attempt

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Table 3. Mean and standard deviation of pentagon drawing scale for the four diagnostic groups Diagnostic group

Mean

Standard deviation

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Table 4. To determine how good the pentagon drawing scale was at distinguishing DLB from each of other three pathologies, we calculated sensitivities at a series of cut points, which are shown here Cut point

AD DLB PDD PD

3.87 2.84 3.08 5.20

1.82 1.69 1.87 1.32

a significance level of 0.008 being assumed for each test. The association between pentagon copying and other cognitive assessments was quantified using Spearman’s correlation coefficients, and ordinal regression analysis (Polytomous Universal Models (PLUMS)) from SPSS. RESULTS The mean and standard deviation of the pentagon copying scores for AD, DLB, PD and PDD patients are shown in Table 3. Comparison of the groups using the Kruskal– Wallis test showed a main effect of group on pentagon copying (2 ¼ 53.16; df ¼ 3; p < 0.0001). Post-hoc analysis indicated that AD, DLB and PDD were all significantly different from PD patients without dementia. AD and PD were significantly different from DLB, but PDD was not (Figure 1). Sensitivity and specificity of pentagon copying The results suggest that DLB patients perform worse than AD and PD patients on pentagon copying, and

1 2 3 4 5

Sensitivity

0.22 0.60 0.70 0.74 0.90

Specificity PD

AD

PDD

0.96 0.93 0.88 0.84 0.61

0.89 0.66 0.57 0.48 0.25

0.66 0.58 0.39 0.19 0.14

that all patients with dementia perform worse than non-demented PD patients. In order to attempt to use these results to distinguish DLB from other pathologies, various cut off points for this scale were calculated and used to discriminate DLB from the other three groups and are presented in Table 4. It can be seen that the specificity varies greatly between groups, with the best being obtained for PD and the worst being obtained with PDD. Pentagon copying and MMSE A correlation with MMSE of 0.563 ( p < 0.001) was obtained when all patients were pooled. However, when the different diagnostic groups were analysed separately, it emerged that only AD and PDD had significant correlations of copying and MMSE (AD r ¼ 0.533, p < 0.001; PDD r ¼ 0.606, p < 0.001). DLB and PD patients did not show any significant correlation with MMSE score (DLB r ¼ 0.152, p ¼ 0.309; PD r ¼ 0.209, p ¼ 0.103). CAMCOG cognitive profile and pentagon copying in DLB and AD

Figure 1. Mean and SD pentagon score for AD, DLB, PDD and PD patients *significantly different from the PD group ( p < 0.001) *significantly different from DLB ( p < 0.001). Copyright # 2004 John Wiley & Sons, Ltd.

In order to investigate the hypothesis that DLB patients have different neuropsychological basis to their drawing impairment to the other dementia groups pentagon copying score was correlated with global cognitive performance, measured by the MMSE score, and CAMCOG subscale scores. Unfortunately this data was only available for DLB and AD groups. As can be seen in Table 5, pentagon copying scores are significantly correlated with MMSE and all CAMCOG subscales except visual and recent memory in AD. In contrast, DLB patients’ scores are significantly correlated only with Praxis and Perception. This pattern of correlations was analysed further using ordinal regression analysis. A separate ordinal regression was carried out for the pentagon score of Int J Geriatr Psychiatry 2004; 19: 371–377.

deficits in drawing tasks Table 5. Correlation of pentagon drawing with measures of global cognitive functioning and CAMCOG subscales in AD and DLB CAMCOG subscale

Correlation coefficient (r) AD

MMSE CAMCOG Orientation Comprehension Expression Praxis Recent memory Visual memory Remote memory Attention Perception Abstract

0.539*** 0.482*** 0.273* 0.359*** 0.297** 0.463*** 0.088 0.175 0.298** 0.509*** 0.298** 0.367***

DLB 0.118 0.296 0.140 0.134 0.138 0.445** 0.058 0.021 0.167 0.176 0.416* 0.248

*significant at p < 0.05 level; **significant at p < 0.005 level; ***significant at p < 0.0001 level.

AD and DLB, with sub-scale scores and MMSE used as predictive variables. In this analysis, all predictors are entered simultaneously into the model. For AD pentagon copying a significant model was constructed (2 ¼ 48.357, df ¼ 11, p < 0.001), with MMSE as the only significant covariate. For DLB, the overall model failed to reach significance, (2 ¼ 17.771, df ¼ 11, p ¼ 0.087), as did all of the individual predictors. DISCUSSION The pentagon copying assessment scale (Bourke et al., 1995) was used to score 267 pentagons drawn by individuals with AD, DLB, PD and PDD. Significant differences were found between the groups, such that unimpaired PD patients performed better than all other groups, and DLB performed significantly worse than AD and PD groups, but could not be separated from PDD. Similarities have been observed between DLB and PDD patients on other measures such as psychiatric symptoms (Aarsland et al., 2001), severity of EPS (Gnanalingham et al., 1997), and features of their cognitive impairment, such as prominent executive dysfunction (Dubois and Pillon, 1997; Connor et al., 1998), and attentional performance (Ballard et al., 2002). This is consistent with the view that these two disorders are extremely closely linked, sharing as they do many pathological features (Perl et al., 1998). Before going on to discuss the results obtained, some of the limitations of the current study need to be addressed. Firstly, there is the issue of recruitment from different study populations. Newcastle is a Copyright # 2004 John Wiley & Sons, Ltd.

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tertiary centre which receives referrals, and may, therefore see cases with more severe illness, whereas the Rogland sample came from a population-based study which would see cases with more variable severity. Related to this issue is the possibility of overlap between the DLB and PD groups. This is a concern given the documented overlap between the diseases, and may have been made more likely given that diagnosis was carried out at different centres with different areas of expertise. However, the inclusion and exclusion criteria employed attempted to minimize this confound. Subjects with PD were excluded if they had cognitive impairment from the onset of the disease, or bilateral onset of EPS, both of which have been found to be important factors in differentiating PD from DLB (Litvan et al., 1998). The exclusion from the DLB group of subjects with onset of EPS within a year of the onset of cognitive impairment, and the exclusion of those with onset of cognitive impairment within a year of the onset of EPS limited the overlap between the two groups, and eliminated the possibility that cases with PDD may have received a diagnosis of DLB had they been assessed in Newcastle. However, given the pathological overlap between the illnesses, and the fundamentally arbitrary nature of the ‘one year’ cut-off points, there is the possibility that some cases may be misclassified. This an issue which can only be resolved by further research into the neuropathology and aetiology of the two dementias. Another possible confound is that the neuropsychological protocol was different in the two populations, with the CAMCOG not being administered to the cases in Norway. For this reason analysis was limited to the MMSE and pentagon copying. It is possible that differences between the two populations, e.g. their educational attainments, may have resulted in one population performing worse than the other on both MMSE and pentagon copying. This explanation alone cannot, however, explain the dissociations we observe. Further, the large samples recruited from both centres and the broad sampling of the community which both groups represent, are likely to have reduced the impact of this source of error. In addition, the dementia groups are matched for age, gender and cognitive impairment. All these issues should be borne in mind when considering the results presented here, but so too should the fact that prospectively acquired data obtained from large samples at different centres, such as that presented here, allows for greater sensitivity, and can go on to inform further investigations. In AD and PDD patients there was a strong correlation of pentagon copying score with MMSE. In Int J Geriatr Psychiatry 2004; 19: 371–377.

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patients with AD, correlations were present between all CAMCOG subscale scores, except recent and visual memory, and pentagon copying. However, a different pattern was observed in patients with DLB, with no correlation present between pentagon score and MMSE. In addition, the only CAMCOG subscales which were found to be related to the severity of pentagon copying impairment were perception and praxis. This suggests that in AD and PDD, constructional disability appears to develop proportionately to a global cognitive impairment (which is likely to reflect the severity on the underlying neuropathology), and so a correlation between global cognitive impairment and pentagon drawing can also be observed. This does not necessarily mean that the impairment is not caused by a dissociable constructional disability, but that in AD and PDD, the global cognitive impairment covaries with this constructional disability. However, in DLB there seems to be a dissociation of the constructional ability from global cognitive abilities. There is a selective impairment of constructional ability, above and beyond the global impairment, and a correlation between pentagon copying and a constructional disability can be demonstrated. It suggests that one way to distinguish DLB from the other three forms of dementia included in this study is on the basis of DLB subjects displaying a significant impairment on copying tasks not linked to more severe global cognitive impairments. Our findings are consistent with existing reports from AD and DLB subjects. Tierney et al. (1997) reported that pentagon copying was highly correlated with other measures of cognitive functioning in their sample of AD patients. Bourke et al. (1995) found that pentagon copying was correlated with MMSE score and clock drawing performance. A relationship between drawings performance from the CAMCOG scale and neuropathology in AD was also repaired (Forstl et al., 1993). In these patients, as in those reported above, performance on these tasks was linked to global cognitive impairment (MMSE and CAMCOG). Significant correlations were observed between drawing performance and both overall brain weight and neuron counts in the hippocampus and parahippocampal gyrus. No relationship was observed between drawing impairment and changes of the parietal lobes. This suggests that constructional apraxia was not related to the dysfunction of spatial mechanisms mediated by parietal areas. This has been recently confirmed by the results of a single photon emission computed tomography (SPECT) study. Ueda et al. (2002) found that clock drawing performance was significantly correlated with posterior Copyright # 2004 John Wiley & Sons, Ltd.

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temporal lobe SPECT activation in AD patients. Although this may be related to semantic aspects of clock drawing, these data are also congruent with the notion that, in AD, constructional performance is related to global cognitive, rather than specifically visuospatial impairment. In DLB, it is known that there is a disproportionate impairment of visuoperceptual and visuoconstructive ability but relatively spared memory function in DLB relative to AD subjects (Shimomura et al., 1998). It may be possible to link these perceptual impairments to the reported pattern of neuropathology. Changes in the occipital and temporal lobes of these patients have been observed in both imaging, neuropathological and neurochemical studies (Albin et al., 1996; Donnemiller et al., 1997; Ishii et al., 1998; Perry et al., 1998; Imamura et al., 1999; Higuchi et al., 2000). This has been linked to some perceptual impairments, such as the analysis of form (Mori et al., 2000). It is possible that in DLB, an impairment of perceptual analysis caused by a disruption of these occipitotemporal areas may underlie the drawing deficit which has been consistently seen in these patients. However, direct comparisons between resting metabolism, structural damage and drawing performance have not been carried out in either DLB or PDD. In conclusion, pentagon copying, which is part of the widely used MMSE scale, is significantly more impaired in DLB patients than in those with AD and PD. In addition, there is evidence to suggest that the underlying pattern of neuropsychological impairment is different in AD and DLB, with the latter subjects showing correlations with perceptual and constructional performance, and AD with global cognitive functioning. Although the level of impairment in the performance of the the pentagon copying task in PDD was similar to that seen in DLB, they did show a correlation of drawing with MMSE, suggesting that as in AD, constructional disability is not dissociated from a more global cognitive impairment. ACKNOWLEDGEMENTS This research was funded by Research into Ageing grant (171s) made to Dr M. J. Tove´e and Professor C. Ballard. We would like to thank the referees’ for their constructive and helpful comments. REFERENCES Aarsland D, Ballard C, Larsen JP, McKeith I. 2001. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J Geriatr Psychiatry 16: 528–536. Int J Geriatr Psychiatry 2004; 19: 371–377.

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