Reader Benefit: The quantitatively assessed cube-copying test may be useful in estimating cognitive and motor dysfunction in patients with Parkinson disease, and in monitoring disease progression.
CCT=cube-copying test; MoCA=Montreal Cognitive Assessment; PD=Parkinson disease; UPDRS=Unified Parkinson’s Disease Rating Scale.
Parkinson disease (PD) is a neurodegenerative disorder that manifests clinically with resting tremors, rigidity, bradykinesia, postural instability, and cognitive impairment (Haas et al, 2012). Approximately 24% to 31% of patients with PD have been diagnosed as suffering from dementia (Aarsland et al, 2005). Longitudinal studies suggest that up to 78% of patients with PD will develop dementia after exhibiting nearly 2 decades of motor symptoms (Aarsland et al, 2003).
The cube-copying test (CCT) is reported to be a more sensitive examination for detecting cognitive ability than are non-cube 2-dimensional figure-drawing tests (Ericsson et al, 1996; Griffiths et al, 1988). The CCT is a brief and convenient examination that can be easily performed and quantitatively assessed. Poor CCT performance has been identified as a risk factor for mild cognitive impairment in patients who later develop Alzheimer disease or another form of dementia (Maeshima et al, 2004). In PD, the CCT may also reflect the examinee’s cognitive function (Maeshima et al, 1997). However, until now patients with PD had not been evaluated for the relationship between the CCT and comprehensive clinical profiles of cognitive and motor ability, as well as disease progression.
In this study, we used the Montreal Cognitive Assessment (MoCA), a validated and sensitive measure of cognitive assessment in persons with PD (Hoops et al, 2009); the Unified Parkinson’s Disease Rating Scale (UPDRS) sections II and III, an examination for motor function; and a modified scoring guideline to assess the CCT quantitatively in an effort to evaluate the relationship between the CCT and clinical profiles of patients with PD.
Between April and November 2010, we identified potential participants who presented at the Parkinson Disease Outpatient Center of the First Affiliated Hospital of China Medical University (Shenyang, China) with suspected idiopathic PD and were diagnosed according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (Hughes et al, 1992). For all potential participants, we obtained demographic and clinical information, including age, sex, disease duration years, symptoms at onset, and neuropsychological and motor function test results. We gave the 17-item Hamilton scale (Fleck et al, 2004) to identify depression and measure the severity of symptoms; we excluded from the study 15 patients whom we considered to have at least moderate depression because they scored >15 on the Hamilton scale.
We enrolled 102 patients in the study. We gave them sections II and III of the UPDRS to assess their motor ability, the Hoehn-Yahr scale to determine their disease stage, and the MoCA to assess their cognitive function. The CCT is part of the MoCA. The patients performed the CCT only once. They were not given a time limit. Although they were free to use their preferred hand, all of them used their right hand. Most left-handed people in China are taught to write and draw with their right hand.
All patients gave written informed consent, and the hospital’s Ethics Review Board approved the study protocol.
CCT Quantitative Assessment
We used Maeshima’s method (Buchhave et al, 2008; Maeshima et al, 1997; Maeshima et al, 2002; Maeshima et al, 2004; Palmqvist et al, 2008) for quantitative assessment of the CCT (Figure 1). Participants can make 2 kinds of errors on the CCT. A connection error can be made at any of the 8 points in a drawn cube where 3 lines meet to form a vertex; we considered lines more than 3 mm off the point to be inaccurate. A plane-drawing error can be made in the number of lines drawn and the extent to which they are parallel; to determine these errors, we evaluated each plane, defined by 2 pairs of parallel lines.
In Maeshima’s own works, both plane-drawing and connection-point scores have significant correlation with performance in “block design,” which measures visuospatial and motor skills (Maeshima et al, 1997; Maeshima et al, 2002). Maeshima also found a close relation between connection errors and plane-drawing errors; both types of errors indicate the same type of underlying dysfunction.
For this reason, we calculated the CCT error score by adding the number of connection errors and the number of plane-drawing errors. We classified a score of 0 as “normal” (a completely accurate drawing), indicating an intact constructional ability, and a score of >0 as “abnormal,” suggesting impaired constructional ability. The worst possible score of 20 would mean that a drawing had none of the required 12 lines or 8 connection points (Figure 1).
Cognitive and Motor Assessment
Because the MoCA’s cutoff score for normal cognition is 26, we used the following formula, as previously described (Luo et al, 2010), to assess the cognitive deterioration rate:
Our formula for the motor function deterioration rate was:
We defined the cognitive domains tested by the MoCA as follows (Harkness et al, 2011; McLennan et al, 2011; Nazem et al, 2009): visuospatial abilities (including clock drawing and cube copying), memory (including the 5-word delayed free recall), executive function (including line, verbal fluency, and abstraction tasks), attention (including alertness, serial calculation, and digit recitation and reverse recitation), language (including picture naming and sentence repetition), and orientation (including recall of time and place).
Because the cutoff values for each MoCA subscore are arbitrary, we established our cutoff values using the scores of a control group from another, parallel study (Luo et al, 2010). If patients scored 1.5 standard deviations below the mean subscore value for age- and education-matched controls, we considered them to be impaired in that domain (Luo et al, 2010; Mamikonyan et al, 2009). Because only integers ≥0 can be recorded for each item, we considered patients to have cognitive impairment if they scored ≤1 for the visuospatial domain, ≤4 for attention, 0 for memory, ≤1 for executive function, and ≤2 for language.
We used SPSS 17.0 (SPSS, Chicago, IL) software for statistical analyses. We used a Mann-Whitney U test to assess the significance of the differences between the 2 groups. We used χ2 analysis to test group differences found within the categorical data. We calculated Spearman rank correlation coefficients to determine the relationship between the quantitative assessment of constructional ability and each clinical feature. We considered a P value <0.05 to be statistically significant.
Comparison of the Normal Versus Abnormal CCT Groups
Table 1 presents our 102 patients’ demographic features and clinical profiles. We divided the patients into 2 groups by their CCT scores: 34 (33.3%) with normal scores (no errors) and 68 (66.7%) with abnormal scores (≥1 error). The patients with abnormal CCT scores had significantly lower MoCA scores (P<0.001) and significantly higher cognitive deterioration rate scores (P<0.001) and UPDRS II and III motor scores (P=0.034). The abnormal CCT group was also significantly older (P=0.010). The 2 groups did not differ significantly by sex, duration of disease, or motor deterioration rate.
The patients with an abnormal CCT tended to exhibit more severe PD symptoms, as suggested by their Hoehn-Yahr stage (P=0.061). We did not find significant differences between the 2 groups for motor laterality and symptoms at onset (tremor vs rigidity), motor subtype (tremor-predominant vs postural instability and gait disorder-predominant) (Alves et al, 2006), or the predominant side (Nys et al, 2010) as determined by the UPDRS (data not shown).
The average scores of most MoCA subitems were significantly lower in the abnormal CCT group (P<0.05), the exceptions being recitation, verbal fluency, repeat, and orientation (Table 2). To investigate the relationship between the CCT and comprehensive cognition, we studied the correlation between CCT errors and each cognitive domain (Table 3). We found a significant negative correlation between CCT errors and all cognitive domains except orientation. We found a significant positive correlation between CCT errors and the cognitive deterioration rate.
Analyses of Cognitive Impairment Subtypes
Table 4 shows the subtypes of cognitive impairment by CCT group. In the normal group, we found cognitive impairment in 9 patients (26.5%) in a single domain and in 6 (17.6%) patients in multiple domains. In the abnormal CCT group, we found cognitive impairment in 16 patients (23.5%) in a single domain and in 46 (67.6%) patients in multiple domains. There was a significant difference in the proportion of single- or multiple-domain cognitive impairment between the 2 CCT groups (P<0.05), with much more multiple-domain cognitive impairment in the abnormal group.
Executive function was most commonly involved in either single- or multiple-domain cognitive impairment in both groups. Neither group had single-domain cognitive impairment of language, visuospatial abilities, or attention, suggesting that these domains are most likely not involved in early-stage PD.
Correlation of CCT with Motor Ability as Evaluated with the UPDRS
CCT errors correlated highly with cognitive deterioration rate, motor disability assessed by UPDRS II and III, and motor deterioration rate. Moreover, we found a positive correlation between CCT errors and the score on some subitems in the UPDRS examination, including “arising from chair,” “posture,” “gait,” and “body bradykinesia,” as well as a composite score for postural instability and gait disorder, indicating that a higher CCT error score represents a higher level of motor dysfunction. Interestingly, we also found a moderate but significant relationship between CCT errors and impaired performance by the left limbs (including left finger taps, left-hand movements, and left-leg agility) and fine hand movement (Table 5).
We used a quantitative assessment of the CCT to see whether test performance reflects the cognitive and motor profiles of patients with PD. Our results showed that patients with abnormal CCT performance had poor cognitive function, impaired motor ability, and a higher cognitive deterioration rate. We believe that the simple CCT may be predictive of the cognitive and motor profiles of patients with PD.
Our patients with an abnormal CCT had a higher cognitive deterioration rate and were significantly older at disease onset than those with a normal CCT. This finding is consistent with our previous study that reported greater susceptibility to cognitive impairment in patients who were older at PD onset (Luo et al, 2010). In this study, the MoCA score and, in particular, many of its subitem scores were significantly higher in our normal than our abnormal CCT group. Not surprisingly, we found the most prominent differences in subitems involving lines, most likely because both the CCT and other line tasks involve both visuospatial and executive components.
At the same time, we found a significant inverse correlation between CCT errors and cognitive domains other than orientation, as shown in Table 3. Confirming other research (Metzler-Baddeley, 2007; Palmqvist et al, 2009), our finding suggests strong consistency between the CCT and the general cognitive profiles of examinees with PD.
Thus, the CCT may provide an estimate of the occurrence or severity of cognitive impairment. Given that we found no significant difference between disease duration and disease severity as assessed by the Hoehn-Yahr stages, an abnormal CCT might signal a subset of patients who have faster cognitive deterioration and multiple-domain cognitive impairment at an earlier stage of PD.
To determine whether CCT errors were related to specific motor symptoms in our patients, we analyzed the correlation between the CCT error rate and each subitem under UPDRS II and III. Not surprisingly, we found a significant correlation between CCT performance and impaired limb movement on the left side, including finger taps, hand movement, and leg agility (Table 5). The more impaired the left-limb movement, the more CCT errors we found, indicating an association between left-sided motor symptoms and visuospatial impairment in PD.
Traditionally, it has been thought that the right hemisphere is specialized for visuospatial processing. This belief is consistent with our findings: Impaired left-sided motor function might be affected by a defect in the right hemisphere and thus impair visuospatial ability during the CCT (Corballis, 2003). Cooper et al (2009) found a significant association between right-sided motor impairment and verbal memory, visuoperceptual skills, and verbal fluency in patients with PD, while left-sided motor symptoms were not related to any cognitive domains. The lack of investigation into a specific cognitive ability, such as the visuospatial domain, may explain the different outcomes between our studies.
We also found a significant correlation between CCT errors and right- and left-handed dexterity, including finger taps and fine hand movements. Physical activities have been connected with cognitive ability (Scherder et al, 2005), and, in an aging population, higher levels of physical activity are linked to enhanced cognitive function. Hand movements activate not only the primary motor and cingulate cortices (Paus et al, 1993) but also other brain areas used in cognition (Iacoboni et al, 2001), eg, the superior temporal sulcus, which is involved in facial recognition (Haxby et al, 2000). This sulcus is connected to the prefrontal cortex, an area central to cognition, especially executive function (Petrides and Pandya, 2006).
Eggermont et al (2009) investigated the relationship of hand movements to cognition and mood in people with dementia. The authors found a positive effect between a hand movement program and mood, and suggested that these effects might have broader implications. By activating certain neural circuits, hand movements may affect cognition and emotion. However, there have been few reports about this relationship in patients with PD. Our finding of an association between hand motor activity and CCT errors indicates potential for improving cognition in patients with PD by promoting hand exercise.
In our study, CCT errors also correlated with the postural instability and gait disorder score, UPDRS II and III motor scores, and motor deterioration rate. These results were consistent with other studies of cognitive impairment in PD in associating older age, later disease onset, and more severe motor symptoms with a higher risk of cognitive impairment (Aarsland et al, 2001; Emre et al, 2007; Hobson and Meara, 2004; Hughes et al, 2000).
We also found that executive function was most commonly affected in either single- or multiple-domain cognitive impairment in both the normal and abnormal CCT groups, suggesting that executive function may be the earliest domain affected by PD—and the most vulnerable cognitive domain. Our findings that executive function is most commonly impaired in patients with PD is also consistent with previous studies (Caviness et al, 2007; Mosimann et al, 2004; Muslimovic et al, 2005).
Neither of our groups had single-domain cognitive impairment of language, visuospatial abilities, or attention, suggesting a low probability that these domains are involved at an early stage of PD.
Our study design had some limitations. First, compared with more formal and time-consuming cognitive tests, the MoCA provides only a relatively rough estimate that may not fully and accurately assess a person’s cognitive state. Second, we cannot completely rule out the possibility that our patients had some other form of dementia, such as Alzheimer disease, in addition to PD. Third, the cognitive deterioration rate and motor deterioration rate are defined retrospectively as average speeds of decline, relative to disease duration; these calculations are considered inferior to data collected during a prospective longitudinal study. Finally, the cutoff values of MoCA subscores that we borrowed from another, parallel study were derived from a small population, which limited their power to serve as normative values.
Nevertheless, our results indicate that the CCT may be a clinically fast and useful way to assess cognitive and motor dysfunction in patients with PD and may aid in both determining prognosis and monitoring disease progression.
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Keywords:© 2013 by Lippincott Williams & Wilkins.
Parkinson disease; cube-copying test; cognitive function; motor function