ABSTRACT
Objectives: The aim of this study was to investigate the clinical usefulness
of the Cube Copying Test (CCT) for quantitative assessment of visuo-spatial function in
patients with Alzheimer’s disease (AD).
Methods: The CCT, Raven’s Colored Progressive Matrices (RCPM), and other
neuropsychological tests were administered to 152 AD outpatients. For the quantitative
assessment of CCT, we scored the points of connection (POC) and the number of
plane-drawing errors (PDE) and categorized the pattern classification (PAC). We also
measured Functional Assessment Staging (FAST) to assess the severity of AD. The
relationships among CCT, RCPM, and FAST were then analyzed.
Results: The mean POC and PDE scores were 2.7 and 3.6, respectively, and the
median PAC score was 6.0. PDE and PAC showed a linear relationship, but POC and PDE, and
POC and PAC did not. Each component of CCT showed a significant correlation with RCPM
scores. PDE and PAC had closer correlations with RCPM scores than POC did. The PDE and PAC
results were significantly different among most of the FAST stages.
Conclusions: Quantitative assessment using CCT may be effective for the
quick determination of the visuo-spatial function in AD patients.
INTRODUCTION
From the early phases of Alzheimer’s disease (AD), visuo-spatial impairments such as
topographical disorientation and constructional disability are seen in addition to
progressive memory loss as the core symptoms of AD.1,2,3,4,5,6) These abilities deteriorate gradually according to the
progression of symptoms.7)
Topographical disorientation in AD patients has several relevant outcomes such as patients
becoming lost, despite, in some cases, recognition of landmarks.1)
Many examinations, such as Raven’s Progressive Matrices (RPM),8) the Rey-Osterrieth Complex Figure,9) and the Clock Drawing
Test,10) are useful for
clinically assessing the visuo-spatial functions of dementia patients. In RPM, which is one
of the most frequently used nonverbal visual neuropsychological tests, detection of the
correct response involves identifying sameness, symmetry, and analogy, and requires the
ability to analyze form, color, and linear slope.11,12) Raven’s Colored Progressive Matrices (RCPM),8) one of the components of RPM, is a
test for elderly people and children. The RCPM results are correlated with the cognitive
function of dementia patients.13) RCPM includes the subtests Set-A, Set-AB, and
Set-B. Set-A mainly identifies figural problems and is associated with simple visuo-spatial
functions, whereas Set-B requires an analytic technique for answering correctly.14,15) RCPM is a clinically useful test, but it takes
15–20 min to complete. The Cube Copying Test (CCT), which requires the examinee to copy a
picture of the Necker Cube, is a very simple and easy copying test. It can be done in a few
seconds, and no preparation is needed except for the availability of a piece of paper and a
pencil. This test is easily repeated. Unlike other copying tests, the various methods of
assessing CCT are not solely subjective but also involve quantitative scoring and/or
categorized scoring.15,16,17,18) However, no systematically gathered data for dementia
patients undergoing scoring methods of CCT are available.
In this study, we discuss the clinical usefulness and detailed scoring methods of CCT in AD
patients and compare the CCT results with those of RCPM. Additionally, we consider
differences in the ability to copy cubes on CCT according to the severity of AD.
MATERIALS AND METHODS
Ethics
The Ethics Committee of the National Center for Geriatrics and Gerontology approved this
study (No. 1247). Written informed consent was obtained from all subjects before they were
enrolled in the study.
Participants
The participants in this study were 807 outpatients who came to our hospital between
January and December 2013 with the chief complaint of cognitive decline. For all
participants, we obtained their demographic and clinical backgrounds, including age, sex,
years of education, and duration of disease. We diagnosed 276 patients with AD according
to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.19) AD patients who also had another
type of dementia and/or other problems that contributed to cognitive decline were
excluded. Also, patients who did not complete the CCT because they could not understand
the instructions at all due to aphasia or could not draw at all due to apraxia were
excluded. Finally, 152 AD patients met these criteria. Figure 1 summarizes the flow of exclusions of potential participants, and Table 1 gives detailed background clinical data
and the results of neuropsychological tests of the AD participants. Of the 152
participants, 39 were men and 113 were women, and the average age was 77.6 ± 7.1 years
old. For an AD severity scale, we used Functional Assessment Staging (FAST).20) FAST is an observational
behavior scale that is classified into seven groups by staging the level of activities of
daily living (ADL). FAST 1 is defined as no cognitive dysfunction, FAST 2 as aging
deterioration, FAST 3 as borderline area (MCI or early AD), FAST 4 as mild AD, FAST 5 as
moderate AD, FAST 6 as moderately severe AD, and FAST 7 as severe AD. The participants
were classified into four groups based on their FAST stage: FAST 3 (n=14), FAST 4 (n=120),
FAST 5 (n=14), and FAST 6 (n=4). No patients were classified as FAST 1, 2, or 7.
Table 1.
Background data and neuropsychological test results of 152 patients with
Alzheimer's disease
|
AD participants (n=152) |
| Age (years): mean ± SD (range) |
77.6 ± 7.1 (60−95) |
| Sex: number of participants |
|
| Male |
39 |
| Female |
113 |
| Education (years): mean ± SD (range) |
10.6 ± 2.6 (4−18) |
| Duration (months): mean ± SD (range) |
25.7 ± 23.8 (2−216) |
| Barthel index: mean ± SD (range) |
95.6 ± 9.3 (50−100) |
| MMSE total score (/30): mean ± SD (range) |
19.7 ± 4.3 (7−28) |
| FAB (/18): mean ± SD (range) |
9.5 ± 3.1 (0−16) |
| WFT (words): mean ± SD (range) |
2.7 ± 2.0 (0−5) |
| Digit Span: mean ± SD (range) |
|
| Forward |
5.2 ± 1.2 (3−9) |
| Backward |
3.1 ± 1.2 (0−6) |
| ADAS-Jcog: mean ± SD (range) |
17.5 ± 6.4 (5.7−40.7) |
| FAST: number of participants |
|
| FAST 3 |
14 |
| FAST 4 |
120 |
| FAST 5 |
14 |
| FAST 6 |
4 |
AD, Alzheimer's disease; MMSE, Mini-Mental State Examination; FAB, Frontal Assessment
Battery; WFT, Word Fluency Test; ADAS-Jcog, Alzheimer's Disease Assessment Scale −
cognitive subscale Japanese version; FAST, Functional Assessment Staging.
The participants were asked to perform the CCT. Two attempts at copying were allowed,
with no time limit. If participants drew the cube twice, we scored the first cube
drawing.
Scoring Methods of CCT
To assess cube copying, we adopted one of the scoring methods of Maeshima et
al.15) and one of the
categorized scoring methods of Shimada et al.17) Because the reliability and suitability of both
assessments have already been reported,21) a dementia specialist scored the CCT using these two
methods.
Maeshima et al.15) reported
quantitative scoring assessments of CCT. For quantitative assessment of construction
ability, points of connection (POC) and the number of plane-drawing errors (PDE) were
evaluated by the method (see Appendix 1). A POC was defined as a point at which three
lines met to form a vertex (lines less than 3 mm distant from the point were considered to
be accurate). Subjects could score up to eight points, because eight points of connection
exist in a cube. For PDE, each plane, defined by two pairs of parallel lines, was
evaluated in terms of the number of lines and the extent to which they were parallel. No
plane-orientation errors were scored if the cube was copied accurately (PDE=0).
Next, the categorized scoring assessment of CCT reported by Shimada et al.17) was performed. In the current
study, we name this method “pattern classification” (PAC) for descriptive purposes (see
Appendix 2). It has eight original criteria: Patterns 0–7. Pattern 7 means a perfect copy.
Pattern 0 is lines only. Patterns 0–2 were assessed as being two-dimensional. The
remaining patterns, 3–6, were assessed as being three-dimensional (3D).
Neuropsychological Tests and Other Evaluation Tools
The following neuropsychological tests were administered to patients during a single
session. Neuropsychological tests included the Mini-Mental State Examination
(MMSE),22) the Frontal
Assessment Battery (FAB),23)
the Word Fluency Test (WFT),24) the Digit Span Test (forward, backward), and
RCPM.8) The MMSE was
conducted to assess the generalized cognitive function. RCPM was used to examine visual
perception and consisted of three sub-tests, i.e., Set-A, Set-AB, and Set-B.
Each test has a score of 12 points, and the total maximum score is 36 points. The WFT is a
test in which participants have to say as many words as possible from a given category
(e.g., vegetables) in 1 min.
We also performed the Alzheimer’s Disease Assessment Scale − cognitive subscale Japanese
version (ADAS-Jcog). The ADAS25) was designed to measure the severity of the most important
symptoms of AD. One of the subscales, ADAS-cog, is one of the most frequently used tests
to measure cognition. The maximum total score of ADAS-Jcog is 70 points. A higher score
means more severe AD.25)
Additionally, to assess ADL, the Barthel Index26) was used.
Statistical Analyses
Spearman’s rank correlation coefficient was used to assess relationships among variables.
In this study, we used non-parametric statistical methods, because the assumptions about
the underlying population were questionable. We used the Kruskal-Wallis Test to assess the
significance of the differences between the groups classified by FAST. A P value of less
than 0.05 was considered to indicate statistical significance. All statistical analyses
were performed with the use of the Statistical Package for Social Sciences software
(version 18.0 for Windows; SPSS Inc.).
RESULTS
CCT Results (POC, PDE, PAC)
The measured POC and PDE values showed a nearly normal distribution, but the PAC results
did not. The mean ± standard deviation of POC and PDE were 2.7 ± 1.9 and 3.6 ± 2.4,
respectively. The median (quartile range) of the PAC score was 6.0 (6.0–3.5).
Relationship Between the Results of CCT Components
Patients who had a low PDE score had a wide variation of POC scores (e.g., patients with
PDE=0 scored POC=2–7, and those with PDE=1 scored POC=0–7). The relationship between POC
and PAC was very similar. In contrast, PDE and PAC showed a linear relationship (ρ=−0.864)
(Fig. 2).
Total RCPM Scores and Subtest Scores
The mean ± standard deviation of the total RCPM score of all participants was 22.4 ± 5.6.
The scores for the subtests (Set-A, Set-AB, and Set-B) were 8.6 ± 2.2, 8.0 ±
2.4, and 6.2 ± 2.0, respectively.
Correlations Between CCT Results (POC, PDE, PAC) and the RCPM Results
The results of each component of the CCT were mainly significantly correlated with the
scores of the RCPM (Table 2). The PDE and PAC
results were highly correlated with the RCPM results, but the POC results were less highly
correlated with those of RCPM. Moreover, the PAC results were highly correlated with the
total RCPM score, the score of Set-A, and the score of Set-AB, but less so with
the score of Set-B. The PDE results showed the same pattern. In contrast, the POC results
had similar and consistently lower correlations with all the RCPM subtest results (Table 2).
Table 2.
Correlation between the results of each CCT scoring method and the
neuropsychological test results and background data
|
|
POC |
PDE |
PAC |
| Age (years) |
(ρ) |
–0.263** |
0.246** |
–0.182* |
| Sex |
(ρ) |
0.314** |
–0.308** |
0.311** |
| Education (years) |
(ρ) |
0.314** |
–0.308** |
0.311** |
| Duration (months) |
(ρ) |
–0.070 |
–0.081 |
0.064 |
| MMSE Total score |
(ρ) |
0.15 |
–0.32** |
0.27** |
| FAB |
(ρ) |
0.15 |
–0.26** |
0.22** |
| WFT (words) |
(ρ) |
–0.06 |
–0.03 |
–0.10 |
| Digit Span Test |
|
|
|
|
| Forward |
(ρ) |
0.12 |
–0.14 |
0.17* |
| Backward |
(ρ) |
0.28** |
–0.31** |
0.29** |
| RCPM |
|
|
|
|
| Total |
(ρ) |
0.26** |
–0.48** |
0.45** |
| Set-A |
(ρ) |
0.26** |
–0.45** |
0.42** |
| Set-AB |
(ρ) |
0.27** |
–0.42** |
0.43** |
| Set-B |
(ρ) |
0.23** |
–0.36** |
0.33** |
Spearman's rank correlation coefficient (ρ).
RCPM, Raven's Colored Progressive Matrices; POC, points of connection; PDE,
plane-drawing errors; PAC, pattern classification.
*P <0.05, ** P <0.01.
The scores of each neuropsychological test gradually worsened as the FAST stage increased
(Table 3). The patients’ sex, years of
education, and duration of disease showed no significant differences across the FAST
stages. However, a significant difference was found for age, but the mean age did not
monotonously increase according to disease progression. Furthermore, PDE and PAC showed
significant differences between FAST stages except between FAST 4 and FAST 5 [FAST 3 to 4:
P (PDE/PAC)=0.030/0.007, FAST 4 to 5: P (PDE/PAC)=0.389/0.250, FAST 5 to 6: P
(PDE/PAC)=0.033/0.017, FAST 3 to 5: P (PDE/PAC)=0.024/0.012, FAST 3 to 6: P
(PDE/PAC)=0.010/0.003, FAST 4 to 6: P (PDE/PAC)=0.030/0.013, respectively]. On the other
hand, POC showed significant differences only between FAST 3 and 5 and between FAST 3 and
6 (FAST 3 to 5: P=0.047, FAST 3 to 6: P=0.015).
Table 3.
Comparison between the groups classified by FAST
DISCUSSION
Recently, symptoms of AD patients, such as wandering and becoming lost, have attracted
attention as serious social problems.27) Visuo-spatial function is impaired from the early phase of
AD.2) It is known that the
focus of route finding is associated with the function of the retrosplenial cortex and the
medial parietal lobe.28)
Furthermore, the entorhinal cortex and its connected regions are also known as the place
cell–heading direction cell–grid cell (PHG) system, which is a network in the brain
providing navigators with knowledge of their current location and a representation of
environmental scenes.29,30) These neural structures overlap the regions that are damaged
in the initial stages of AD.31)
However, the mechanistic details of symptoms such as wandering and becoming lost are not yet
known. Maksimenko et al.32)
reported that the precuneus and parahippocampal gyrus were active while deciding the
orientation of the Necker cube under a priming condition. Therefore, in AD, low scores on
the CCT and impaired route finding may have the same neural basis. The CCT is a very simple
neuropsychological test that can evaluate visuo-spatial functions in a short time. It is
also employed as a part of ADAS, but in ADAS, the CCT is only assessed as “It could be drawn
correctly or not”. Similarly, few studies have focused on the degree of accuracy and the
details of the shapes of the copied cube. Therefore, we examined the CCT in detail in 152 AD
patients and analyzed the association of lines, points of connections, and the formation of
copied figures. Additionally, we evaluated the correlations between the CCT results and
those of other neuropsychological tests, including RCPM, based on the severity of dementia.
A previous report showed that visuo-spatial function declines with age and is lower in those
with a lower educational level.17) Our CCT results (POC, PDE, PAC) showed a significant
correlation with age and education, and the results were similar to those of previous
studies. In contrast, we found no correlation between the CCT results and the duration of
disease. Most of the patients’ chief complaints were regarding memory loss; moreover, the
duration of illness, which mainly indicates the period from the appearance of memory loss,
may not be directly related to impaired visuospatial cognitive dysfunction.
Correlations Between CCT and RCPM Results
The relationships between the three components of the CCT (POC, PDE, PAC) were analyzed,
and PDE and PAC showed a linear relationship. In contrast, the correlations between POC
and PDE and between POC and PAC were significant, but the relationships were not clearly
linear. PAC reflects the pattern classification of the 3D structure, and PDE reflects the
accuracy of the spatial arrangement of each line. If lines are distorted and are in
erroneous positions, the cubic shape is not accurate. Consequently, PDE and PAC are
considered to estimate relatively pure visuo-spatial functions. This may be the reason for
the high correlation coefficients for PDE/PAC and RCPM. In contrast, POC enumerates errors
in connecting points and does not solely represent simple shape distortion and the absence
of lines. POC may be related to visuo-spatial attention, and it is considered that the
differences in the characteristics of POC, PDE, and PAC contributed to the strength of the
correlations with RCPM.
Analysis of the relationship between POC/PDE/PAC and RCPM showed a stronger correlation
between POC/PDE/PAC and the score of Set-A rather than Set-B of RCPM. Set-A mainly
reflects pure visuo-cognitive functions, and Set-B requires a more analytical
technique.12,13,14) Therefore, evaluation of CCT using POC/PDE/PAC
reflects the details of visuo-cognitive functions. Additionally, CCT may assess some
analytical abilities. Moreover, PDE and PAC were correlated with MMSE and FAB, and
POC/PDE/PAC were correlated with the backward Digit Span Test. Therefore, an association
between the results of CCT and frontal lobe function, including working memory and
attention, may be present. An association between dementia and frontal lobe function,
including working memory, has been previously reported.33) Consequently, the CCT may be useful for
estimation of these cognitive functions. Further studies that evaluate CCT in more detail
will be required.
Relationship Between POC/PDE/PAC and the Severity of AD
The participants were classified according to the severity of AD based on their FAST
stage. The POC/PDE/PAC results gradually declined with increasing AD severity. Because
patients’ sex, years of education, and duration of disease were not significantly
different among the severity groups, the association between the POC/PDE/PAC results and
the severity of AD may not be influenced by such background factors. In contrast, a
significant relationship with age was seen between the FAST stages; however, the average
age of the FAST 6 group was younger than that of the FAST 5 group, suggesting that reasons
other than age may explain the decline in CCT results. The PAC results suggested that, on
average, FAST 3 patients could copy a nearly perfect cube, FAST 4 patients could draw a 3D
figure but could not draw a cube or a figure in perspective, and FAST 6 patients could not
draw a 3D figure, which suggested that they could not recognize 3D structures. This last
finding may influence impairment of activities associated with visuo-spatial functions
such as putting on clothes and tying a necktie or shoelaces. Visuo-spatial function is
closely connected to instrumental ADL and ADL of AD patients. Therefore, briefly
evaluating the visuo-spatial function in patients with AD by analyzing CCT results in
detail may be of great value.
Limitations and Future Research
One limitation of this study is that CCT allows assessment of only one aspect of
visuo-constructional function. Furthermore, this was a retrospective and cross-sectional
study. We did not perform a longitudinal study of how the results of CCT change with the
progression of disease. Additionally, in this study, we did not consider any association
with neuroradiological findings. Therefore, a longitudinal study is needed in which the
changes in CCT are measured with the progression of disease and the associations with
other neuropsychological tests are evaluated. Furthermore, we believe that looking at the
relationship between other neuropsychological tests and imaging findings will contribute
to the elucidation of the pathophysiology of dementia.
ACKNOWLEDGMENTS
We would like to thank President Hidenori Arai and Hospital Director Yukihiko Washimi for
the opportunity to write this article.
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
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