Modified Six Elements Test: Earlier diagnosis of the correlation between motor and executive dysfunction in Parkinson s disease without dementia

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1 doi: /ncn ORIGINAL ARTICLE Modified Six Elements Test: Earlier diagnosis of the correlation between motor and executive dysfunction in Parkinson s disease without dementia Hidetomo Murakami, 1 Yoshiyuki Owan, 1 Tatsunori Oguchi, 1 Shohei Nomoto, 1 Hidenobu Shozawa, 1 Satomi Kubota, 1 Yukiko Mori, 1 Keita Mizuma, 1 Akinori Futamura, 1 Mutsutaka Kobayakawa, 2 Machiko Kezuka, 1 Akira Midorikawa, 1 Michael W Miller 3 and Mitsuru Kawamura 1 1 Department of Neurology, School of Medicine, Showa University, Tokyo, 2 Department of Informatics, Tokyo University of Information Sciences, Chiba, and 3 Medical Sciences Program, University of Tokyo Postgraduate School of Medicine, Tokyo, Japan Key words executive dysfunction, gait, Modified Six Elements Test, motor function, Parkinson s disease. Accepted for publication 18 April Correspondence Hidetomo Murakami Department of Neurology, School of Medicine, Showa University, Hatanodai, Shinagawa-ku, Tokyo , Japan. hidneu@yahoo.co.jp Abstract Background: In patients with Parkinson s disease, executive deficits are known to correlate with motor dysfunctions, such as gait and postural instability. However executive deficits are sometimes difficult to detect using common frontal assessment batteries. Behavioral Assessment of Dysexecutive Syndrome includes six subtests to evaluate different aspects of executive function required in daily life. Among these the Modified Six Elements Test examines higher levels of executive function with regard to prospective memory and organization of behavior. Aim: Using Behavioral Assessment of Dysexecutive Syndrome we examined which types of executive dysfunction correlate with motor symptoms in Parkinson s disease without apparent dementia. Methods: A total of 54 Parkinson s disease patients with Mini-Mental State Examination scores over 24 were assessed with the Unified Parkinson s Disease Rating Scale (total score of parts II and III as general motor function, subscores of tremor, rigidity, bradykinesia, gait disturbance and postural instability) for motor assessment, and both the Behavioral Assessment of Dysexecutive Syndrome (total raw score of all subtests and subscores of each of the 6 subtests) and Frontal Assessment Battery for executive function. Correlation coefficients for executive and motor assessments were compared. Results: Among the Behavioral Assessment of Dysexecutive Syndrome subtests, the Modified Six Elements Test showed the strongest correlation with the Unified Parkinson s Disease Rating Scale subscore of gait disturbance, but did not correlate with patient background factors, such as age. Conclusion: Even in Parkinson s disease without apparent dementia, deficits in complex executive functions, such as prospective memory and organization of behavior, correlate with motor dysfunctions, especially gait. We believe the Modified Six Elements Test is useful to evaluate early executive deficits. Introduction Recent reports show patients with Parkinson s disease (PD) present different kinds of cognitive impairment, and executive deficits are frequent. 1,2 Furthermore, there is a correlation between frontal/executive function and motor symptoms. For example, Green et al. 3 and Riggeal et al. 4 show a correlation between frontal/executive assessment and the Unified Parkinson s Disease Rating Scale (UPDRS) total score as a general assessment of motor function. Freezing of gait 5 and postural instability 6 also correlate with frontal/ executive assessments. Thus, frontal/executive function now attracts interest as a correlative factor with motor symptoms, especially gait and postural stability. Such executive deficits in patients with PD are linked both to the frontal lobes and to subcortical structures. This is due to functional continuity between the basal ganglia and frontal cortex in performance of executive functions. 7,8 Correlation between executive deficits and motor symptoms is possibly linked to impairment of the fronto-striate circuit. 9 In the aforementioned studies, executive function was assessed using common assessment batteries such as the Stroop test, the Wisconsin card sorting test, verbal fluency, the Frontal Assessment Battery (FAB) and others. 3 6 However, we Neurology and Clinical Neuroscience 3 (2015)

2 Executive and motor dysfunction in PD H Murakami et al. believe such standard cognitive assessment tests might be insensitive to executive deficits experienced in daily life. 10 In contrast, BADS is designed to examine such executive function, and includes six subtests to evaluate different aspects of executive function required in daily life (Table 1). 11 Therefore, it is a useful tool for identifying deficits in patients who are otherwise generally unimpaired, although it does take longer (approximately min) compared with the Mini-Mental State Examination (MMSE) and FAB. 12 We examined correlates of specific executive dysfunctions with motor symptoms in PD patients without apparent dementia using BADS. Methods Participants. A total of 54 PD patients with a MMSE score of 25 or above were recruited from outpatients and inpatients diagnosed at Showa University Hospital or Showa University East Hospital, Tokyo, Japan. The cut-off MMSE score was determined, because the sensitivity and usefulness of BADS is shown in patients with a MMSE score of more than Diagnosis of PD was made using the clinical diagnostic criteria of the United Kingdom Parkinson s Disease Society Brain Bank. 14 With the exception of 26 patients, all were being treated with levodopa or a dopamine agonist. The other 26 were de novo, and no medication was used before the present study. All de novo patients were diagnosed by clinical history and neurological findings before medication, and confirmed as having PD after dopaminergic drugs were administered. Motor symptoms of all de novo patients improved, but the diagnosis was unchanged. No patient was taking an antidementia drug, such as an acetylcholinesterase inhibitor or N-methyl-Daspartic acid receptor antagonist. No patient was on an anticholinergic drug, such as trihexyphenidyl. One female patient was taking mianserin hydrochloride, but none had depression likely to affect cognitive assessment. There was no patient with a history of impulse control disorder. Four patients had wearing-off. No patient had undergone deep brain stimulation. None had a disease that affected motor and cognitive functions except PD. The ethics committee of Showa University School of Medicine approved the study, and it was carried out according to the Declaration of Helsinki. Clinical assessment. Motor and cognitive functions were assessed for each participant. The UPDRS was administered to assess motor function. General motor function was assessed as a total score of UPDRS parts II and III. Individual motor symptoms (rigidity, tremor, bradykinesia, gait disturbance and postural instability) were assessed as a total score of related UPDRS items as follows: tremor (items 16, 20 and 21), rigidity (item 22), bradykinesia (items and 31), gait disturbance (items 13 5 and 29) and postural instability (items 27, 28 and 30). MMSE was carried out to screen cognitive level in patients with PD. To assess executive function in patients with a MMSE score of 25 or above, the FAB and the Japanese version of BADS were administered. BADS includes six subtests as follows: the Rule Shift Cards Test, Action Program Test, Key Search Test, Temporal Judgment Test, Zoo Map Test and the Modified Six Elements Test. The details are given in Table 1. Results of each subtest are described as a profile score that ranges from 0 (severe) to 4 (normal). We used profile scores of each of the six subtests and a total raw score of all the subtests. Although an age-adjusted BADS total score is available in the BADS manual, we used the total raw score because physiological aging affects both cognitive and motor systems as noted by Hausdorff et al. 15 Motor assessments by UPDRS cannot be adjusted for age. All assessments were carried out during the on-medication phase in four patients with wearing-off. Spearman s correlation coefficients of both BADS scores (total raw score and score of 6 individual subtests) and FAB score were compared with patient background factors (age, education, PD duration and levodopa equivalent dose), 16 and each motor assessment (general motor function and individual motor symptom). Table 1 Range of executive abilities examined by each subtest in Behavioral Assessment of the Dysexecutive Syndrome Subtest Contents of each subtest 11 Measurable abilites 10,11 Rule Shift Cards Test Respond yes or no according to the prescribed rules when Cognitive flexibility a series of 20 playing cards is turned over one at a time Action Program Test Take the cork from the tall tube using a set of materials according Planning, problem solving to the prescribed rules Key Search Test Draw the path the patient would take to search inside the square Planning, monitoring patient s own behavior in order to find a lost key Temporal Judgment Test Estimate the time length for activities experienced in daily life Judgment, estimation Zoo Map Test Visit the ordered places in the map according to the prescribed rules Planning, problem solving Modified Six Elements Test There are two sets of arithmetic problems, two dictation tasks and two sets of pictures that have to be named, making six subtasks in total. The subject is required to attempt to do at least some of all six sections within 10 min according to the rules. However, they are not allowed to do the two parts of the same task consecutively. BADS, Behavioral Assessment of the Dysexecutive Syndrome. Planning, problem solving, prospective memory, organizing and monitoring patient s own behavior 210 Neurology and Clinical Neuroscience 3 (2015)

3 H Murakami et al. Executive and motor dysfunction in PD Results Table 2 Patient background Men:women 23:31 Age (years) Education (years) Duration of PD (years) LED 16 (mg/day) Hoehn and Yahr stage I: 6, II: 23, III: 21, IV: 4 cases UPDRS part II plus III LED, levodopa equivalent dose; PD, Parkinson s disease; UPDRS; Unified Parkinson s Disease Rating Scale. Table 3 Spearman s correlation coefficients for executive assessment and patient background in all participants Age Patient background Education Duration of PD LED 16 Assessment of BADS Total Raw Score 0.463*** Rule Shift Cards Test 0.391** Action Program Test Key Search Test Temporal Judgment ** Test Zoo Map Test 0.483*** Modified Six Elements Test Assessment of FAB Total score 0.327* ***P < 0.001, **P < 0.01, *P < BADS, Behavioral Assessment of the Dysexecutive Syndrome; FAB, Frontal Assessment Battery; LED, levodopa equivalent dose; PD, Parkinson s disease. The bold values are significant correlation coefficients. A total of 54 patients (23 men, 31 women) were included in the study, and their backgrounds are detailed in Table 2. The majority was moderately or mildly impaired as defined by Hoehn and Yahr stages II III. Correlation coefficients for executive assessment and background are shown in Table 3. Total raw score of BADS (P < 0.001), Rule Shift Cards Test (P < 0.01), Zoo Map Test (P < 0.001) and FAB (P < 0.05) all correlated with age. The Temporal Judgment Test correlated with education (P < 0.01). The Action Program Test, key search test and Modified Six Elements Test correlated with no background factor. Correlation coefficients with regard to motor symptoms, executive assessment and patient background are shown in Table 4. With regard to motor assessment, general motor function correlated with the Zoo Map Test and Modified Six Elements Test. However, these correlations, although significant, are weaker than those of general motor function with PD duration (Table 4). Gait disturbance showed a significant correlation with five BADS assessments (total raw score, Rule Shift Cards Test, Temporal Judgment Test, Zoo Map Test and Modified Six Elements Test) and age. However, correlations of gait disturbance with four BADS assessments (total raw score, Rule Shift Cards Test, Zoo Map Test and Modified Six Elements Test) were stronger than those with all patient background factors including age. Postural instability showed a significant correlation with four BADS assessments (total raw score, Rule Shift Cards Test, Zoo Map Test and Modified Six Elements Test). However, these correlations, although significant, were weaker than the correlation of postural instability with age and duration of PD. Both tremor and bradykinesia correlated with no executive assessment. For each BADS assessment, the correlations of total raw score of BADS with gait disturbance (P < 0.01) and postural instability (P < 0.05) were significant, but weaker than that with age (Table 3). Correlations of the Rule Shift Cards Test with gait disturbance (P < 0.01) and postural instability (P < 0.05) were also significant, but weaker than that with age (Table 3). A subscore of The Zoo Map Test correlated with general motor function (P < 0.05), gait disturbance (P < 0.01) and postural instability (P < 0.05). However, the Zoo Map Test showed stronger correlation with age (P < 0.001; Table 3). The subscore of the Modified Six Elements Test correlated with general motor function (P < 0.05), gait disturbance (P < 0.001) and postural instability (P < 0.05). The Modified Six Elements Test correlated strongly with gait disturbance. Distributions of real scores are shown in Fig. 1. In contrast, the Modified Six Elements Test correlated with no patient background factor (Table 3). The action program test did not correlate with motor assessment. The only executive assessment showing a stronger correlation with gait disturbance than all patient backgrounds was the Modified Six Elements Test. Furthermore, to examine whether gait score and the Modified Six Elements Test were related, we carried out multiple regression analysis for the Modified Six Elements Test as the dependent variable, and both patient backgrounds (age, education, duration of PD and levodopa equivalent dose) and motor symptoms (general motor function, tremor, rigidity, bradykinesia, gait disturbance and postural instability) as independent variables. However, no patient background factor or motor symptom correlated with the Modified Six Elements Test. In the present study, 28 patients were taking dopaminergic drugs and 26 were not. Therefore, the effects of dopaminergic agents on the Modified Six Elements Test and gait needs consideration. To clarify the effect of the drugs, we compared scores and correlations of the Modified Six Elements Test between patient groups with and without dopaminergic drugs. Mean scores of UPDRS gait scores were in patients without dopaminergic drugs, and in patients with dopaminergic drugs. No significant difference was observed between the two groups. Mean scores of the Modified Six Elements Test were in patients without dopaminergic drugs, and in patients with dopaminergic drugs. In other words, there was no significant difference between them. Spearman s correlation coefficients of gait disturbance and the Modified Six Neurology and Clinical Neuroscience 3 (2015)

4 Executive and motor dysfunction in PD H Murakami et al. Table 4 Spearman s correlation coefficients for executive assessment, motor function and patient background in all participants Motor function General motor function Tremor Rigidity Bradykinesia Gait disturbance Postural instability Assessment of BADS Total Raw Score ** 0.289* Rule Shift Cards Test ** 0.328* Action Program Test Key Search Test * Temporal Judgment Test * Zoo Map Test 0.301* ** 0.306* Modified Six Elements Test 0.303* *** 0.278* Assessment of FAB Total score ** Patient background Age * 0.364** Education Duration of PD 0.352** *** LED * ***P < 0.001, **P < 0.01, *P < BADS, Behavioral Assessment of the Dysexecutive Syndrome; FAB, Frontal Assessment Battery. The bold values are significant correlation coefficients. Figure 1 Distribution of subscores of the modified six elements test and gait disturbance. BADS; Behavioral Assessment of the Dysexecutive Syndrome, FAB; Frontal Assessment Battery; UPDRS, Unified Parkinson s Disease Rating Scale. Elements Test are shown in Table 5. In patients with dopaminergic drugs, gait disturbance correlated more with the Modified Six Elements Test than with all other patient background factors (Table 5). In patients without dopaminergic drugs, gait disturbance tended to correlate with the Modified Six Elements Test (P-value of 0.06; Table 5). In both groups, the Modified Six Elements Test correlated with no patient background factor (Table 5). Discussion Previous studies, including PD patients with a wider range of cognitive levels than in our own study, show a correlation between general motor functions with executive function. 4,9 These patients had a MMSE score of 18 24, 4 or PD, PD with mild cognitive impairment, or PD with dementia. 9 Common executive assessment tasks were used in these studies. For example, word fluency, 4 Stroop test, 4 Trail Making Test 4 and FAB. 9 Our own study, which only included PD patients with a high MMSE score of 25 or above, showed that only the Zoo Map Test and the Modified Six Elements Test correlated with general motor function. This finding agrees with the studies cited here. However, the other four BADS subtests and FAB showed no correlation with general motor function in the present study. A possible explanation for the difference is that only specific aspects of executive function evaluated by The Zoo Map Test and the Modified Six Elements Test correlate with general motor function in PD without apparent dementia. Of these two BADS subtests, the Modified Six Elements Test correlated with no patient background factor, such as age. In contrast, the Zoo Map Test did correlate with age. Thus, aspects of executive function evaluated by the Modified Six Elements Test specifically correlate with motor assessment in PD without dementia, although physiological aging affects cognition and motor symptoms. 15 In contrast, the Zoo Map Test is influenced by both motor function and age. Although BADS is a sensitive executive assessment tool, its six subtests measure different executive abilities. 12,13 For example, Perfetti et al. examined the sensitivity of the six subtests to detect executive deficits in PD, and showed that the Modified Six Elements Test is the most sensitive predictor of executive dysfunction in PD without dementia. 13 The Modified Six Elements Test examines wider executive ability than the other five subtests (Table 1). These are indicated by prospective memory, and problem solving including planning, organization and monitoring of self behavior. 11 They are high-level measures of complex executive function. 13 Therefore, the present results show that the sort of executive deficits specifically linked with motor dysfunction, independent of patient backgrounds, can be revealed by the Modified Six Elements Test. Another explanation is that the Behavioral Assessment of the Dysexecutive Syndrome (BADS) subtests, 212 Neurology and Clinical Neuroscience 3 (2015)

5 H Murakami et al. Executive and motor dysfunction in PD Table 5 Spearman s correlation coefficients of gait disturbance and Modified Six Elements Test in patients with and without dopaminergic drugs With dopaminergic drugs (28 cases) Patients Correlation coefficients of gait disturbance With the Modified Six Elements test 0.504** # With patient backgrounds Current age 0.394* Education Duration of PD LED NA Correlation coefficients of Modified Six Elements Test With patient backgrounds Current age Education Duration of PD LED NA Without dopaminergic drugs (26 cases) **P < 0.01, *P < 0.05, #P = LED, levodopa equivalent dose; NA, not available; PD, Parkinson s disease. The bold values are significant correlation coefficients. except the Zoo Map Test and Modified Six Elements Test, and FAB are insufficiently sensitive to detect subtle differences in executive function. In other words, all tests vary in their sensitivity to particular cognitive functions. However, FAB is one of the tools recommended for evaluating executive function. 17 In the present study, using Spearman s correlation coefficients, gait disturbance and postural instability correlated more with BADS subtests. Furthermore, recent studies suggest a relationship between executive function, and both gait and postural control. 5,6,15,17,18 Browner et al. suggested freezing of gait in PD is the result of primary cognitive and executive impairment. 19 Walking is a motor skill that utilizes sensory and conscious inputs, and executive activities such as estimation, planning and real-time adjustment. 15 The postural control system integrates sensory information; for example, visual, vestibular and proprioceptive information, and produces timely well calibrated motor commands in response to changes in patient environment. 20 Therefore, both walking and posture require cognitive and executive functions. We also believe gait and postural control are not pure motor functions, but involve cognition both conscious and unconscious. Furthermore, correlation of gait disturbance with the four BADS assessments (Total Raw Score, Rule Shift Cards Test, Zoo Map Test and Modified Six Elements Test) were stronger than those with all patient background factors, such as age. Thus, gait relates to executive function rather than patient background factors. Of the BADS assessment tests, the Modified Six Elements Test correlated most with gait. This test requires the ability to monitor, plan and organize one s own behavior while concurrently remembering and carrying out a task. Executive functions required for carrying out the Modified Six Elements Test resemble those required for gait with regard to integrating internal and external information, and producing motor commands. Recent imaging studies show executive function is linked with the basal ganglia, and both gait and cognitive impairments share cortical and subcortical damage. 24,25 Correlating motor and executive dysfunctions are thought to share a common pathophysiology linked to cortical-subcortical circuits, and emerge simultaneously. 3,9,26 It is possible that performance on the Modified Six Elements Test might be influenced by motor impairment in PD, but we do not believe so. The score is calculated by measuring: (i) the number of subtasks partially attempted in 10 min (maximum of 6), each of which does not require completion; (ii) whether or not a rule is broken; and (iii) the maximum amount of the time spent on any one subtask, but speed of processing is not measured. Thus, a decrease on the Modified Six Elements Test is not a result of motor impairment. We believe the cognitive impairment detected by testing is primary and not secondary to motor impairment. Loranger et al. have a similar opinion, that cognitive impairments in PD cannot be explained by peripheral motor disability, because patients still cannot achieve the correct solution, even when given as much time as they want. 27 Furthermore, the Modified Six Elements Test did not correlate with any patient background factor. Therefore, the present results suggest gait disturbance emerges with executive dysfunction. In contrast, multiple regression analysis showed no correlation between the Modified Six Elements Test and patient background or motor symptoms including age and gait. This dissociation between statistical methods means the Modified Six Elements Test has no direct connection with patient background and motor function including age and gait. However, executive and gait dysfunctions might be directly mediated by factors unknown to current clinical practice. With regard to current practice, the Modified Six Elements Test and gait do correlate, and assessing the Modified Six Elements Test is useful in evaluating gait. A total of 28 of our patients were using dopaminergic drugs and 26 were not. Therefore, we considered the effects of dopaminergic agents on correlation between executive and gait functions. In patients with dopaminergic drugs, gait disturbance correlated with the Modified Six Elements Test more than all other patient background factors (Table 5). In patients without dopaminergic drugs, the correlation between gait disturbance and the Modified Six Elements Test was not significant by a narrow margin (P-value of 0.06; Table 5). We believe the correlation of gait disturbance with the Modified Six Elements Test is still valid whether or not patients are taking dopaminergic drugs. This is because patients not taking dopaminergic drugs were in the early phase. In patients with early disease, UPDRS is relatively insensitive in establishing motor dysfunction as noted by Olanow et al. 28,29, and in the present study distribution of UPDRS gait scores in de novo patients was small so significance was difficult to establish. Therefore, the correlation between the Modified Six Elements Test and gait is the same regardless of dopaminergic drugs. We believe the Modified Six Elements Test is, therefore, valuable for assessing executive deficits in PD without apparent dementia. Neurology and Clinical Neuroscience 3 (2015)

6 Executive and motor dysfunction in PD H Murakami et al. Acknowledgments This study was supported by Grant-in-aids for Scientific Research on Innovative Areas, Face Perception and Recognition (MEXT, ), and The Science of Mental Time (MEXT, ); and a Grant-in-Aid for Scientific Research (MEXT, ). This study was also supported in part by the Showa University Medical Foundation and the Research Funding for Longevity Sciences (25-13) from National Centre for Geriatrics and Gerontology (NCGG), Japan. The authors declare no conflict of interest. References 1 Caviness JN, Driver-Dunckley E, Connor DJ et al. Defining mild cognitive impairment in Parkinson s disease. Mov. Disord. 2007; 22: Goldman JG, Weis H, Stebbins G, Bernard B, Goetz CG. Clinical difference among mild cognitive impairment subtypes in Parkinson s disease. Mov. Disord. 2012; 27: Green J, McDonald WM, Vitek JL et al. Cognitive impairments in advanced PD without dementia. 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