Correlation between motor and cognitive functions in the progressive course of Parkinson s disease

doi:10.1111/ncn3.53 ORIGINAL ARTICLE Correlation between motor and cognitive functions in the progressive course of Parkinson s disease Hidetomo Murakami,* Yoshiyuki Owan,* Yukiko Mori,* Kazuhisa Fujita,* Akinori Futamura,* Azusa Sugimoto,* Mutsutaka Kobayakawa, Machiko Kezuka,* Akira Midorikawa* and Mitsuru Kawamura* *Department of Neurology, School of Medicine, Showa University, Tokyo, Japan, and Department of Informatics, Tokyo University of Information Sciences, Chiba, Japan Key words cognitive impairment, correlation, cortical and subcortical structures, motor dysfunction, Parkinson s disease. Accepted for publication 12 September 2013. Correspondence Mitsuru Kawamura, Department of Neurology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. Email: kawa@med.showa-u.ac.jp Abstract Aim: Correlations between motor function and frontal-executive function in Parkinson s disease (PD) have been examined previously, but correlations with other cognitive domains remain unknown. We examined the correlation between motor dysfunction and cognitive impairment with regard to their precise domains. Methods: Motor and cognitive functions were assessed in 61 patients. To assess motor function, the Unified Parkinson s Disease Rating Scale (UPDRS) was administered. The UPDRS score was assessed as general motor function with a sum of Parts II and III, and as subscores of individual motor symptoms (rigidity, tremor, akinesia and postural instability). To assess cognitive function, the Montreal Cognitive Assessment (MoCA) and the Frontal Assessment Battery (FAB) were administered. MoCA was assessed by a total score and subscores of six cognitive subdomains: visuospatial, executive, attention/concentration/working memory, language, memory and orientation. The correlation coefficients of both MoCA and FAB with patient background and motor symptoms were compared using Spearman s correlation coefficient. Results: General motor function and the subscore of postural instability showed significant negative correlations with MoCA, FAB, and the subdomains of visuospatial, executive and orientation skills. Tremor and rigidity showed no significant correlation with any cognitive assessment. Akinesia showed significant negative correlation with MoCA, and the subdomains of visuospatial and orientation skills. Conclusions: In patients with PD, specific motor and cognitive functions correlate, with particular regard to postural instability and visuospatial skills. The correlations suggest functional links between a number of cerebral cortices and subcortical structures, and a common pathophysiology for motor and cognitive impairments in PD. Introduction Motor dysfunction has been the main target of therapeutic interventions in Parkinson s disease (PD). However, cognitive impairment is also a problem in PD. Furthermore, PD with mild cognitive impairment (PD-MCI) has attracted attention as a pre-dementia state, 1 and might be relieved by anti-dementia drugs. Henceforth, both motor and cognitive impairments will be treated together from an early stage. Therefore, assessments of correlation between them are important. The correlation between cognitive and motor dysfunction in PD have been examined by calculating correlation coefficients of various testing tools (Table 1). In 1988, Huber et al. 2 showed a significant correlation between motor dysfunction and intellectual impairment using the complete clinical condition scale, a scale of global motor function in PD, and the Mini-Mental State Examination (MMSE), a widely used global cognitive assessment scale. Recently, specific domains of motor or cognitive function have attracted attention in similar studies. Green et al. 3 and Riggeal et al. 4 reported frontal lobe function correlates with motor function. Williams et al. reported that both bradykinesia and postural instability are significantly correlated with global cognitive function. 5 Amboni et al. reported that freezing of gait correlates with frontal lobe functions. 6 Nocera et al. reported that postural instability correlates with dorsolateral frontal lobe functions. 7 Thus, frontal lobe function is attracting attention in correlation with motor symptoms, especially akinesia and postural instability. However, a 172 Neurology and Clinical Neuroscience 1 (2013) 172 176

Table 1 Previous reports examining the correlation between motor and cognitive functions in Parkinson s disease Reports correlation between motor function and cognitive domains, except frontal-executive skill, has not been examined. The Montreal cognitive assessment (MoCA) is more sensitive than the MMSE for screening mild cognitive impairment. 8 Furthermore, MoCA has proved sensitive to detect early cognitive impairment in PD patients, because it includes tests assessing frequently impaired cognitive domains in PD, such as visuospatial and executive skills, and memory. 9 As far as we know, the MoCA has not been used to study a possible correlation between motor and cognitive functions in PD. Therefore, we examined this using MoCA for cognitive assessment. Methods Year Scale of motor function assessment Scale of cognitive assessment Huber et al. 2 1988 Complete clinical MMSE condition scale Green et al. 3 2002 UPDRS total score Mattis dementia rating scale total score UPDRS total score Latter fluency UPDRS total score Category fluency UPDRS total score Boston naming test UPDRS (bradykinesia, Stroop interference gait) UPDRS (bradykinesia) Wisconsin card sorting test number of errors Riggeal 2007 UPDRS total score MMSE et al. 4 UPDRS total score Trail Making Test B, et al. Williams et al. 5 2007 UPDRS (total score, bradykinesia and postural/gait items) MMSE UPDRS (total score, bradykinesia and postural/gait items) Amboni 2008 Freezing of gait et al. 6 questionnaire Freezing of gait questionnaire Freezing of gait questionnaire Nocera 2010 Center of pressure et al. 7 displacement Center of pressure displacement Center of pressure displacement Dementia Rating Scale-2 FAB Stroop test Verbal fluency Controlled word association Digit span backward Stroop color word FAB, Frontal Assessment Battery; MMSE, Mini-Mental State Examination; UPDRS, Unified Parkinson s Disease Rating Scale. Participants. A total of 61 patients (31 men, 30 women) with PD, PD-MCI or PD with dementia (PDD) were recruited from outpatients and inpatients diagnosed at Showa University Hospital or Showa University East Hospital in Tokyo, Japan. Diagnosis of PD was made using clinical diagnostic criteria of the United Kingdom Parkinson s Disease Society Brain Bank. 10 With the exception of four patients, all were being treated with levodopa or a dopamine agonist. The other four patients were de novo, and no medication was used before the present study. No patient was taking an anti-dementia drug, such as an acetylcholinesterase inhibitor or N-methyl-Daspartic acid (NMDA) receptor antagonist. Three patients were taking antidepressants (mianserin hydrochloride, sertraline hydrochloride or escitalopram oxalate: each patient using one of these drugs), but none had depression likely to affect cognitive assessment. There was no patient with a history of impulse control disorder. No patient had undergone deep brain stimulation. None had a disease that affected motor and cognitive functions except PD, PD-MCI and PDD. The study was approved by the Ethics Committee of Showa University School of Medicine. Clinical assessment. Motor and cognitive functions were assessed in each participant. To assess motor function, the Unified Parkinson s Disease Rating Scale (UPDRS) was administered. General motor function was assessed as a total score of UPDRS Parts II and III, and individual motor symptoms (rigidity, tremor, akinesia and postural instability) were assessed as the sum of related UPDRS items (Table 2). To assess cognitive function, the MoCA and the Frontal Assessment Battery (FAB), 11 a scale of frontal lobe function, were administered. MoCA was assessed by a total score and by dividing the subtests into six subdomains. We used the domain-based subscore presented in the original MoCA proposal, 8 which is a recombination of the subscores-based subscore shown in the current MoCA test paper. The domain-based subscore has six domains: visuospatial, executive, attention/concentration/working memory, language, memory and orientation. Evaluation was carried out in the on state of medication for each patient. Correlations with both MoCA (its total score and 6 individual subdomains) and FAB were compared with patient backgrounds (education, age at PD onset, current age, PD duration and levodopa equivalent dose 12 ) and motor symptoms (general motor function and 4 individual motor symptoms) using Spearman s correlation coefficient. Table 2 Related Unified Parkinson s Disease Rating Scale items for each motor symptom Related UPDRS items Tremor Items 16, 20 and 21 Rigidity Item of 22 Akinesia Items of 23 to 26 and 31 Postural Instability Items of 27 to 30 UPDRS, Unified Parkinson s Disease Rating Scale. Neurology and Clinical Neuroscience 1 (2013) 172 176 173

Results Patient backgrounds are shown in Table 3. The majority of the participants had mild to moderate PD (Hoehn and Yahr stages II III). With regard to patient background, education and current age significantly correlated with both MoCA and FAB (Table 4). However, general motor function showed a more significant negative correlation (Table 4). As to individual motor symptoms, tremor and rigidity showed no significant correlation with MoCA and FAB. Akinesia showed a mildly significant negative correlation with MoCA, but not with FAB. Postural instability showed the most significant negative correlation with both MoCA and FAB (Table 4; Fig. 1). Table 5 compares the correlation coefficients for each motor function and the six cognitive subdomains. General motor function and postural instability (Fig. 2) showed a significant correlation with visuospatial, executive, memory and orientation skills. Akinesia showed a significant correlation with visuospatial and orientation skills. Correlations between postural instability, and both visuospatial and orientation skills were especially strong (P < 0.0001). Patients were almost equally distributed between scores of visuospatial and executive subtests. Of the 61 patients, 29 had a memory subscore of 0. In the other 32 patients, there was no significant correlation between memory and any motor assessment. A total of 44 of the 61 patients had an orientation subtest score of 6: full marks for the subdomain. In the other 17 patients, there was a significant negative correlation with orientation for general motor function (r = 0.675, P < 0.01), akinesia (r = 0.586, P < 0.05) and postural instability (r = 0.767, P < 0.001). Discussion Table 3 Patient backgrounds Male : female 31:30 Age 73.4 9.2 years Duration of PD 6.5 5.0 years Age at PD onset 67.0 8.9 years Education 12.9 0.9 years Hoehn and Yahr stage 2.9 0.9 I: 2 cases, II:19 cases, III:28 cases, IV: 9 cases, V: 3 cases UPDRS (II + III) 38.5 17.2 Patients with wearing-off 9 cases Patients taking antidepressants 3 cases PD, Parkinson s disease. Table 4 Correlation coefficients for Montreal Cognitive Assessment and Frontal Assessment Battery with patient backgrounds and motor symptoms MoCA FAB Backgrounds of patients Levodopa equivalent dose 0.117 0.107 Age at PD onset 0.221 0.214 PD duration 0.226 0.177 Education 0.308* 0.301* Current age 0.345** 0.326* General motor function 0.446*** 0.370** Tremor 0.074 0.202 Rigidity 0.199 0.070 Akinesia 0.272* 0.195 Postural instability 0.485*** 0.376** *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. FAB, Frontal Assessment Battery; MoCA, Montreal Cognitive Assessment; PD, Parkinson s disease. Figure 1 Distribution of raw data for Unified Parkinson s Disease Rating Scale (UPDRS; postural instability) scores and two other tests: (a) Montreal Cognitive Assessment (MoCA) and (b) Frontal Assessment Battery (FAB). The present results including frontal-executive assessments agree with previous reports 3,4,6,7 in showing that frontalexecutive functions correlate with motor function. Frontal lobe and basal ganglia are known to form frontal-subcortical circuits, and to mediate many aspects of behavior and cognition. 13 Executive deficits are shown to relate to dysfunction within the frontostriatal circuits. 14 The correlations seen in our study confirm the previous reports 6,7 that both motor and cognitive dysfunctions are caused by a common pathophysiology linked to frontal-subcortical circuits. Our present results show that postural instability correlate highly not only with frontal-executive functions, but also with visuospatial function and orientation. However, Waterston et al. reported that the postural control system integrates sensory information, such as visual, proprioceptive and vestibular information, and produces timely and accurately calibrated motor commands in response to change in the outer environment. 15 They suggested that this system is at the level of central motor processing. These functions include visuospatial and executive functions. Areas of the cerebral cortex, such as the parietal and frontal lobes, take part in integration of sensory information and generate response behavior. Visuospatial deficits, related to the parieto-occipito-temporal lobes, 16 18 can be caused by a lesion in the basal ganglia. 19 We believe that the correlation between postural instability, and both visuospatial and 174 Neurology and Clinical Neuroscience 1 (2013) 172 176

Table 5 Correlation coefficients for motor function assessment and the six cognitive subdomains Visuospatial Executive Attention Concentration Working memory Language Memory (Delayed recall) Orientation Tests used Copy cube Draw clock Trail making Verbal fluency Abstraction Digit span Vigilance Serial 7s Naming of 3 animals Sentence repetition Delayed recall of 5 words Orientation Full marks 4 4 6 5 5 6 General motor assessment General motor function 0.494*** 0.316* 0.221 0.100 0.388** 0.428*** Tremor 0.146 0.047 0.136 0.115 0.144 0.145 Rigidity 0.125 0.183 0.055 0.043 0.159 0.200 Akinesia 0.344** 0.109 0.191 0.050 0.214 0.265* Postural instability 0.590**** 0.296* 0.214 0.217 0.435*** 0.506**** *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Figure 2 Distribution of raw data for Unified Parkinson s Disease Rating Scale (UPDRS; postural instability) scores and four subdomains of Montreal Cognitive Assessment (MoCA): (a) visuospatial, (b) executive, (c) memory and (d) orientation. executive function suggests that interaction of the frontoparieto-occipito-temporal lobes with the basal ganglia. Thus, postural instability and cognitive functions share a common pathophysiology, and cannot be separated. Furthermore, patients retain consciousness of postural stability, so it is not a pure motor symptom. Akinesia also showed a significant correlation with visuospatial skill. One hypothesis of the pathophysiology of akinesia is connected with the motor circuit theory. 20 This circuit consists of the motor association cortex, the putamen, the globus pallidus internal segment and the substantia nigra pars reticulata, among others. Nigroputaminal impairment is also shown to correlate with visuospatial abilities. 21 We believe a correlation between akinesia and visuospatial function suggests that the parieto-occipito-temporal lobes, which manage visuospatial function, 16 18 form a connection with the basal ganglia. Therefore, akinesia and visuospatial skill share a common pathophysiology. There is a possibility that motor dysfunctions in PD, such as slowness, secondarily influence cognitive test performance. However, we believe that cognitive impairments detected by testing are primary and not secondary to motor impairment. The present results showing that only a few cognitive domains correlate with specific motor dysfunction signify an underlying common pathophysiology related to specific motor and cognitive functions. If motor impairments, such as slowness, were to affect a patient s cognitive test performance, results in all cognitive domains would decrease regardless of test, and patients with mildly impaired motor function would show no impairment on cognitive assessment. 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. 22 The MoCA used in the present study is sensitive to cognitive impairments in the early phase of PD. 9 We believe that specific motor and cognitive impairments that share a common pathophysiology emerge together from an early phase of PD. Therefore, both motor and cognitive functions should not be separately evaluated in a clinical setting. Acknowledgments This study was supported by the Tamagawa University Center of Excellence under the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); a Grant-in-aid for Scientific Research on Innovative Areas, Face Perception and Recognition (MEXT, 23119720); and a Grantin-Aid for Scientific Research (MEXT, 23591283). This study was also supported in part by the Research Funding for Longevity Sciences (25-13) from National Centre for Geriatrics and Gerontology (NCGG), Japan. Neurology and Clinical Neuroscience 1 (2013) 172 176 175

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