Authors: Antonia Pierobon, PsyD Anna Giardini, PsyD Roberto Maestri, MS Cristiano Farina, PsyD Simona Callegari, PsyD Valeria Torlaschi, PsyD Gabriella Bertotti, PT Giuseppina Majani, PsyD Giuseppe Frazzitta, MD
Affiliations: From the Psychology Unit (AP, AG, CF, SC, VT, GM), Department of Neurorehabilitation (GB, GF), and Department of Biomedical Engineering (RM), Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Montescano, Montescano, Pavia, Italy; and Department of Parkinson Disease Rehabilitation, BMoriggia-Pelascini[ Hospital, Gravedona ed Uniti, and Fondazione Europea Ricerca Biomedica FERB, BS.Isidoro[ Hospital, Trescore Balneario, Bergamo, Italy (GF).
Correspondence: All correspondence and requests for reprints should be addressed to: Antonia Pierobon, PsyD, Servizio di Psicologia, Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Montescano, 27040 Montescano, Pavia, Italy.
Disclosures: Funded by S. Maugeri Foundation, IRCCS (ricerca corrente 2010). Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9309-0764 American Journal of Physical Medicine & Rehabilitation Copyright * 2014 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000092
Parkinson_s Disease
ORIGINAL RESEARCH ARTICLE
Disexecutive Functions and Depression in Patients with Parkinson Disease The Impact on Rehabilitation Outcome ABSTRACT Pierobon A, Giardini A, Maestri R, Farina C, Callegari S, Torlaschi V, Bertotti G, Majani G, Frazzitta G: Disexecutive functions and depression in patients with Parkinson disease: the impact on rehabilitation outcome. Am J Phys Med Rehabil 2014;93:764Y773.
Background: Studies relating to patients with Parkinson disease that assess neuropsychologic, psychologic, and clinical aspects are very uncommon. Objective: The aim of this study was to analyze the impact of executive functioning (impaired vs. not impaired) or depression (depressed vs. nondepressed) on the outcome of rehabilitation treatment in patients with Parkinson disease without dementia at the medium stage of disease.
Methods: Forty consecutive inpatients affected by Parkinson disease were psychologically and neuropsychologically assessed by means of standardized tests during the first week of admission and at discharge after undergoing an intensive rehabilitation training. Results: At baseline, the patients (mean [SD] age, 70.1 [8.0]; MiniYMental State Examination [MMSE], Q24) showed impairment in the following executive functions: frontal functions (32.5%), selective and divided attention (55.0% and 41.9%, respectively), and word fluency (17.5%). Depressive symptoms reported using the Geriatric Depression Scale were distributed as follows: mild (n = 13), 32.5%; moderate (n = 4), 10.0%; and severe (n = 5), 12.5%. As for the outcome of the intensive rehabilitation treatment, a general improvement in the Unified Parkinson’s Disease Rating Scale, the Berg’s scale, the 6-min walking test, and the Timed Up and Go test was observed (P G 0.0001). The improvement was homogeneous for all groupings of the patients for all of the considered variables, indicating that the changes in performance as a result of treatment were unaffected by the presence of executive function deficits or moderate-to-severe depression. Conclusions: The patients’ executive function impairment or moderate-tosevere depressive symptoms did not seem to interfere with the outcome of the intensive physical and occupational rehabilitation. Therefore, these aspects in patients without dementia should not be considered a contraindication to an intensive rehabilitation program. Furthermore, despite the presence of impaired executive functions and/or of depressive symptoms, the 4-wk multidisciplinary rehabilitation program resulted to be highly effective. Key Words: Parkinson Disease, Neurorehabilitation, Executive Functions, Depression, Rehabilitation Outcome
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P
arkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms associated with cognitive deficits, even at an early stage of the disease.1Y3 Cognitive and behavioral dysfunction in patients with PD include deficits in executive functions, visuospatial and visuoconstructive abilities, attention, skill learning, depression, and apathy.4,5 Executive functions are called upon when novel plans of action must be formulated and conducted and allow to optimize the performance in situations requiring the simultaneous operation of different processes.2 Few studies analyze the effects of executive functions in health-related quality-of-life and daily activities,2,6 and to date, there are no studies that analyze the influence of alteration in executive functions on the efficacy of an intensive rehabilitation treatment. Moreover, although many studies have taken into account the effectiveness of rehabilitation on depression,7,8 not a single study considers the effects of depression on the overall outcome of rehabilitation. Several studies report the efficacy of rehabilitation in reducing specific impairments and in improving functional limitations in individuals with PD,9Y14 but none considers the impact of disexecutive functions and depression on rehabilitation outcome or considers these variables as exclusion criteria for rehabilitation treatment.8,15 The authors have developed an intensive rehabilitation protocol in which standard physicaltherapy techniques were associated with treadmill coupled with auditory and visual cues (treadmill plus) and a stabilometric platform.16,17 The aim of this study was to analyze the effects of executive functioning (impaired vs. not impaired) or depression (depressed vs. nondepressed) on rehabilitation treatment outcome in patients with PD without dementia at the medium stage of disease.
METHODS Subjects Forty consecutive inpatients with a diagnosis of Bclinically probable[ idiopathic PD according to Gelb et al.,18 admitted to the authors’ hospital for rehabilitation treatment, were enrolled into the study. All patients were in Hoehn-Yahr stage 3,19 none had severe cognitive impairment (MMSE of Q24),20 and all had antiparkinsonian medications stable for more than 4 wks. Subjects were excluded if they were treated with deep brain stimulation or if they had underlying neurologic conditions, severe cardiovascular disorders, diabetes, musculoskeletal disorders, www.ajpmr.com
or vestibular dysfunction limiting locomotion or balance and if the psychologic or neuropsychologic assessment was deemed unperformable (because of sensorial impairment, psychotic disorder, refusal to be assessed). The study was approved by the local ethical committee, and all subjects gave their written informed consent before participation.
Study Protocol Patients were examined by the same neurologist expert in movement disorders in the morning, 1 hr after they had taken levodopa (best Bon[ state), at baseline, and at the end of the rehabilitation treatment. The clinical evaluation was based on the Unified Parkinson’s Disease Rating Scale Motor Section (UPDRS-III),21 the Berg Balance Scale (BBS),22 the Timed Up and Go Test (TUG), and the 6-min walking test (6MWT). Measurements were performed at the start and at the end of the 4-wk rehabilitation program. During treatment, drug dosage was stable. In addition, during the first few days of hospitalization, the patients were psychologically and neuropsychologically assessed. The test presented in this study constitutes merely a part of a wider assessment performed routinely by the Psychology Unit. The patients were supported throughout the testing period to maintain motivation and to elicit the optimal level of performance; a break if needed was always allowed. Tests were carried out by senior psychologists, in accordance with standardized administration and scoring procedures.
Rehabilitation Protocol All patients underwent a 4-wk cycle of physiotherapy and occupational therapy that consisted of three daily sessions (two in the morning and one in the afternoon), 5 days a week. The first session (physiotherapy) comprised cardiovascular warm-up activities, relaxation exercises, muscle stretching exercises, exercises to improve spinal function, and postural changes in the supine position. During the second session, the patients used different devices: a stabilometric platform with a visual cue (the patients were asked to follow a circular pathway on the screen using a cursor sensitive to the movements made by the feet on the platform), a treadmill plus (treadmill associated with auditory and visual cues), a press leg, and a cycloergometer. The last session involved occupational therapy. The global duration of the three sessions was approximately 3 hrs per day. Functions and Depression in Parkinsonian Patients
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Psychologic and Neuropsychologic Assessment The patients were psychologically assessed by means of the following.
Parkinson Disease QuestionnaireY39 The Parkinson Disease QuestionnaireY39 is a well known disease-specific self-completed instrument designed to measure aspects of health-related quality-of-life that are relevant to patients with PD.23 The scores range from 0 (best health-related qualityof-life possible) to 100 (worst health-related qualityof-life possible). The Italian version presents good psychometric properties, and normative data are also available.24
Geriatric Depression Scale The 30-point Geriatric Depression Scale (GDS) is a questionnaire specifically aimed at assessing depression in old patients.25 A routinely comprehensive battery of neuropsychologic tests measuring a broad range of cognitive functions (memory and learning, verbal and nonverbal logical abilities, executive functions, fluency, ideomotor apraxia) were administered to each patient. Moreover, and coherent with the authors’ hypothesis that considers the executive functions exclusively, after excluding patients with MMSE20 score (adjusted for age and years of school) of less than 24, the following cognitive aspects were considered.
Frontal Functions Frontal functions were assessed by the Frontal Assessment Battery. The test consists of six subtests screening six functions related to the frontal lobes (similarities, conceptualization; phonological verbal fluency, mental flexibility; motor series, motor programming; conflicting instructions, sensivity to interference; go-no-go task, inhibitory control; prehension behavior, environmental control).26
Attention Attention (selective and divided) was assessed by the Trail-Making Test (TMT; parts A and B). The subject has to connect, in the proper order, 25 encircled numbers randomly arranged on a page (part A). Part A requires visual search processes and assesses selective attention. In part B, in which the subject has to connect, in the proper order, 25 encircled numbers and letters, requires switching/ cognitive flexibility and assesses divided attention.27
Phonemic Fluency Phonemic fluency was assessed by the Word Fluency test, which belongs to the wider Mental
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Deterioration Battery.28 It assesses the lexical memory store by means of a fluency task (fluency requested on F, A, and S). All tests have good psychometric properties and are validated on the Italian population, and normative data are also provided. The attribution of neuropsychologic test scores was performed as follows: raw scores of the neuropsychologic tests were transformed into adjusted scores for age, sex, and educational level and then into standardized equivalent scores (ESs). The ESs range from 0 to 4, where 0 and 1 indicate the presence of a cognitive deficit. This standardization procedure allows comparisons between tests with different scales and of different difficulty levels. To investigate the association between executive functioning (impaired vs. not impaired) and the rehabilitation treatment outcome, the patients were divided into subgroups according to the following criteria: criterion 1, patients impaired vs. patients not impaired at the TMT-A and TMT-B or at the Frontal Assessment Battery or at the Word Fluency. Similarly, the association between depression and rehabilitation treatment outcome was studied, classifying patients according to criterion 2, patients with mild or no depressive symptoms vs. patients presenting severe/moderate depressive symptoms. No criterion considering patients with depression plus executive dysfunction vs. patients with no depression and no executive dysfunction was analyzed because of sample size (only four patients showed depression and impairment in executive functions). Further studies on this specific topic are needed.
Statistical Methods Data are reported as mean (standard deviation) or as ESs. The normality of the distribution of all variables was assessed by the Shapiro-Wilk statistic. Patients unable to perform part B not because of motor problems were considered impaired and included in the ES 0Y1 group. To test whether the effect of rehabilitation treatment on each outcome variable considered was the same in the patients classified according to the different conditions (cognitive deficit/moderate-to-severe depression), a two-factor analysis of variance was carried out. The first factor was the group of patients (patients with and without cognitive deficit/moderate-to-severe depression), and the second factor was time (admission vs. discharge), with repeated measurements in the time factor. A P value of less than 0.05 was considered statistically significant. All analyses were carried out
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using the SAS/STAT statistical package, release 9.2 (SAS Institute Inc, Cary, NC).
RESULTS The rehabilitation treatment attendance rate was 97%, and all patients completed the 4-wk program without modification in pharmacologic dosages. Demographic and clinical characteristics of the patients are reported in Table 1. Depressive symptoms reported at the GDS were distributed as follows: mild (n = 13), 32.5%; moderate (n = 4), 10.0%; and severe (n = 5), 12.5%. The patients’ neuropsychologic characteristics (distribution of tests of executive functions) are reported in Table 2. As to criterion 1, a total of 18 patients (45%) were impaired and 22 patients (55%) were not impaired at the TMT-A and TMT-B or at the Frontal Assessment Battery or at the Word Fluency. As to criterion 2, a total of 31 patients (77.5%) reported mild or no depressive symptoms and 9 patients (22.5%) presented severe/moderate depressive symptoms. Considering the effects of rehabilitation, the analysis of variance showed an improvement in the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT in the patients with and without cognitive deficit or depression (time effect, P G 0.0001 for all variables). The improvement was homogeneous for all groupings of patients for all of the considered variables, as assessed by a not significant time group interaction in repeated-measures analysis of variance (all P 9 0.15), indicating that the changes in performance as a result of treatment were not affected by the presence of deficits in executive functions or depression. A graphical representation of UPDRS-total, UPDRS-III, BBS, TUG, and 6MWT results is reported in Figures 1 to 5. It
can be observed that, at admission, all variables were very similar whatever grouping strategy is considered and that the slope of the lines joining the mean value at baseline and after treatment are almost the same, suggesting no difference in treatment efficacy relating to executive function impairment or moderate-to-severe depression.
DISCUSSION As for sex, the patients in this study are equally distributed, and the patients are affected by PD in Hoehn-Yahr stage 3 (duration since diagnosis: mean of 9 yrs). Considering self-reported health and qualityof-life, assessed by means of the Parkinson Disease QuestionnaireY39, the patients in this study do not differ from the Italian normative sample,27 and therefore, significant consequences, in terms of impairment and perceived disability, are referred in many aspects of daily life, such as mobility, discomfort in communication and social interaction, emotional well-being, and stigma. As for depression, half of this sample reported depressive symptoms (22.5% moderate to severe), coherent with literature.29 Some considerations are noteworthy: given the fact that diagnostic difficulties are present because of the considerable overlap between symptoms of PD and depression, the test that was adopted (GDS) is considered to be one of the most useful in rating depression symptom severity in old patients with chronic PD, although mainly for screening purposes.30 In the literature, the mean prevalence of major depressive disorder in PD is substantial but lower than generally assumed.29 Therefore, even if the GDS does not substitute the Diagnostic and Statistical Manual of
TABLE 1 Demographic, clinical, and neuropsychologic/psychologic characteristics Variable
Admission
Male/female Duration since diagnosis, yrs Age, yrs UPDRS-total (0Y199) UPDRS-III (0Y75) BBS (0Y56) TUG, secs 6MWT, m PDQ-39 GDS
20/20 8.7 (6.4) 70.1 (8.0) 41.2 (10.4) 21.4 (5.3) 44.6 (8.6) 12.1 (5.5) 282 (76) 40.3 (21.2) 11.1 (6.7)
Discharge
27.2 (8.6) 14.8 (4.3) 51.4 (5.0) 9.5 (3.3) 382 (104)
UPDRS-total: 0, no disability; 199, total disability; UPDRS-III: 0, no disability; 75, total disability; BBS: 0Y56 (higher score indicates an independent performance). PDQ-39, Parkinson Disease QuestionnaireY39.
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TABLE 2 Distribution of ESs of the tests of executive functions PD Patients (N = 40), n (%) Tests of Executive Functions FAB TMT-A TMT-B WF
ES 0Y1 Cognitive Deficit
ES 2Y4 No Cognitive Deficit
13 (32.5) 22 (55.0) 16a (41.9) 7 (17.5)
27 (67.5) 18 (45.0) 24 (58.1) 33 (82.5)
ES: 0Y1, deficit; 2Y4, no deficit. a In this group, the patients not able to perform the task are considered impaired and therefore included. FAB, Frontal Assessment Battery; WF, Word Fluency.
Mental Disorders, Fourth Edition, in rehabilitation, the data of this study suggest the utility of screening depression to give evidence of its clinical manifestations, which do not necessarily require pharmacologic treatment but may benefit from psychologic counseling and a supportive healthcare team,7,31Y33 and to prevent behavioral nonadherence after discharge. A high percentage of the patients in this study showed significant impairment in the executive functions considered in the study (selective and divided attention, screening of conceptualization, mental flexibility, motor programming, sensivity to interference, inhibitory control, environmental control constructional abilities), as shown in Table 2. This is a peculiar characteristic of PD as confirmed by many studies: cognitive deficits are common in
PD patients with Bnormal[ MMSE performance, suggesting that mild cognitive deficits are underrecognized in clinical practice because of routine use of insensitive screening instruments such as the MMSE.1,34 As for the outcome of the intensive rehabilitation, a general improvement in the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT was observed (see Table 1 and Figs. 1Y5) and consistent with the recent literature.10,13,17 Considering patients with and without cognitive deficits, the improvement in the rehabilitation outcome resulted homogeneous, thus indicating that the changes in scores as a result of treatment, in the five assessment domains considered, were not affected by the presence of an executive function deficit. This may be
FIGURE 1 A and B, UPDRS-total (tot) values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
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FIGURE 2 A and B, UPDRS-III values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
because of the fact that, as shown in the literature, procedural learning seemed to be independent of executive dysfunction35; therefore, although impaired
in executive functioning, the subgroup of patients in this study may have acquired the strategy instructions necessary to execute the motor rehabilitation
FIGURE 3 A and B, BBS values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval. www.ajpmr.com
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FIGURE 4 A and B, 6MWT values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
training. Moreover, although the patients in this study qualitatively reported a subjective satisfaction in the rehabilitation outcome, its impact on
everyday life requires further studies. The implementation of the International Classification of Functioning Disability and Health may lead to a
FIGURE 5 A and B, TUG values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
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deeper understanding of the relationship between executive abilities and functional contexts related to everyday life and to real-world behavior.36 Furthermore, the presence of moderate/severe depressive symptoms did not seem to influence the rehabilitation outcome assessed by the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT (see Table 1 and Figs. 1Y5). The patients homogeneously showed improvements in motor performance including overall aspects of daily living and symptoms. Although depressed, this subgroup of patients seemed to be motivated by the rehabilitation protocol, and adherence to the program by the nondepressed patients was extremely high during the 4 wks. Despite the presence of executive function deficits and depression in some patients, all displayed a significant functional improvement after the 4-wk intensive rehabilitation program. A possible intriguing explanation is based on the hypothesis of the neuroplastic effect of physical activity: animal experiments and clinical assays provide evidence that suggests that exercise has a neuroprotective effect against neurodegenerative diseases,37,38 and a direct effect of exercise on the level of several growth factors has been revealed.39,40 The finding that exercise leads to cognitive improvement in normal aging and Alzheimer disease is well established,41Y43 and functional MRI data suggest that aerobic exercise leads to more efficient neuronal activity in the prefrontal regions similarly affected in PD.44,45 Moreover, Tanaka and colleagues46 concluded that, after a 6-mo aerobic exercise program, individuals with PD showed improved executive function. This study presents some limitations: although homogeneous in terms of diagnosis and disease severity, sample size is not large and only inpatients were assessed; therefore, the results could not be generalized to the whole PD population. The results may not be applicable to individuals with dementia, in whom severe cognitive deficits may indeed influence rehabilitation outcome. Moreover, follow-up data on functionality are not available; therefore, the permanence of the rehabilitation outcome through time in patients with or without depressive symptoms or executive deficits deserves consideration in further studies. Meanwhile, its strengths should be highlighted: the evaluation in this study is concomitant with clinical assessment, and studies on this topic with so many domains simultaneously assessed (clinical, functional, psychologic, and neuropsychologic) are rare. Finally, the patients completed the self-report questionnaires with competent supervision, if necessary, www.ajpmr.com
which reduces the possibility of compromising validity of the results.
CONCLUSIONS Patients’ executive function impairment or patients’ depressive symptoms seemed not to interfere with the overall outcome of physical intensive rehabilitation. It may be hypothesized that comprehension and motivation of physiotherapic and occupational therapy tasks may not be mediated by executive functions or by depressive symptoms in PD inpatients without dementia. Therefore, these aspects should not constitute a contraindication to intensive rehabilitation program; despite the presence of executive function impairment and/or of depressive symptoms, the 4-wk multidisciplinary rehabilitation program proved to be highly effective. ACKNOWLEDGMENTS
As for the psychologic and neuropsychologic data, the authors thank Lucia Viola for data collection and Elisa Carrara and Irsida Zajmai for data entry. REFERENCES 1. Mamikonyan E, Moberg PJ, Siderowf A, et al: Mild cognitive impairment is common in Parkinson’s disease patients with normal Mini-Mental State Examination (MMSE) scores. Parkinsonism Relat Disord 2009;15:226Y31 2. Kudlicka A, Clare L, Hindle JV: Executive functions in Parkinson’s disease: Systematic review and metaanalysis. Mov Disord 2011;26:2305Y15 3. Muslimovic D, Post B, Speelman JD, et al: Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology 2005;65:1239Y45 4. Zgaljardic DJ, Foldi NS, Borod JC: Cognitive and behavioral dysfunction in Parkinson’s disease: Neurochemical and clinicopathological contributions. J Neural Transm 2004;111:1287Y301 5. Barone P, Aarsland D, Burn D, et al: Cognitive impairment in nondemented Parkinson’s disease. Mov Disord 2011;26:2483Y95 6. Koerts J, Van Beilen M, Tucha O, et al: Executive functioning in daily life in Parkinson’s disease: Initiative, planning and multi-task performance. PLoS One 2011;6:e29254 7. Gage H, Storey L: Rehabilitation for Parkinson’s disease: A systematic review of available evidence. Clin Rehabil 2004;18:463Y82 8. Goodwin VA, Richards SH, Taylor RS, et al: The effectiveness of exercise interventions for people with Parkinson’s disease: A systematic review and metaanalysis. Mov Disord 2008;23:631Y40
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40. Torres-Aleman I: Serum growth factors and neuroprotective surveillance: Focus on IGF-1. Mol Neurobiol 2000;21:153Y60 41. Hillman CH, Erickson KI, Kramer AF: Be smart, exercise your heart: Exercise eff ects on brain and cognition. Nat Rev Neurosci 2008;9:58Y65
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42. Kramer AF, Erickson KI: Capitalizing on cortical plasticity: Influence of physical activity on cognition and brain function. Trends Cogn Sci 2007;11:342Y8
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Affiliations: From the Psychology Unit (AP, AG, CF, SC, VT, GM), Department of Neurorehabilitation (GB, GF), and Department of Biomedical Engineering (RM), Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Montescano, Montescano, Pavia, Italy; and Department of Parkinson Disease Rehabilitation, BMoriggia-Pelascini[ Hospital, Gravedona ed Uniti, and Fondazione Europea Ricerca Biomedica FERB, BS.Isidoro[ Hospital, Trescore Balneario, Bergamo, Italy (GF).
Correspondence: All correspondence and requests for reprints should be addressed to: Antonia Pierobon, PsyD, Servizio di Psicologia, Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Montescano, 27040 Montescano, Pavia, Italy.
Disclosures: Funded by S. Maugeri Foundation, IRCCS (ricerca corrente 2010). Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9309-0764 American Journal of Physical Medicine & Rehabilitation Copyright * 2014 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000092
Parkinson_s Disease
ORIGINAL RESEARCH ARTICLE
Disexecutive Functions and Depression in Patients with Parkinson Disease The Impact on Rehabilitation Outcome ABSTRACT Pierobon A, Giardini A, Maestri R, Farina C, Callegari S, Torlaschi V, Bertotti G, Majani G, Frazzitta G: Disexecutive functions and depression in patients with Parkinson disease: the impact on rehabilitation outcome. Am J Phys Med Rehabil 2014;93:764Y773.
Background: Studies relating to patients with Parkinson disease that assess neuropsychologic, psychologic, and clinical aspects are very uncommon. Objective: The aim of this study was to analyze the impact of executive functioning (impaired vs. not impaired) or depression (depressed vs. nondepressed) on the outcome of rehabilitation treatment in patients with Parkinson disease without dementia at the medium stage of disease.
Methods: Forty consecutive inpatients affected by Parkinson disease were psychologically and neuropsychologically assessed by means of standardized tests during the first week of admission and at discharge after undergoing an intensive rehabilitation training. Results: At baseline, the patients (mean [SD] age, 70.1 [8.0]; MiniYMental State Examination [MMSE], Q24) showed impairment in the following executive functions: frontal functions (32.5%), selective and divided attention (55.0% and 41.9%, respectively), and word fluency (17.5%). Depressive symptoms reported using the Geriatric Depression Scale were distributed as follows: mild (n = 13), 32.5%; moderate (n = 4), 10.0%; and severe (n = 5), 12.5%. As for the outcome of the intensive rehabilitation treatment, a general improvement in the Unified Parkinson’s Disease Rating Scale, the Berg’s scale, the 6-min walking test, and the Timed Up and Go test was observed (P G 0.0001). The improvement was homogeneous for all groupings of the patients for all of the considered variables, indicating that the changes in performance as a result of treatment were unaffected by the presence of executive function deficits or moderate-to-severe depression. Conclusions: The patients’ executive function impairment or moderate-tosevere depressive symptoms did not seem to interfere with the outcome of the intensive physical and occupational rehabilitation. Therefore, these aspects in patients without dementia should not be considered a contraindication to an intensive rehabilitation program. Furthermore, despite the presence of impaired executive functions and/or of depressive symptoms, the 4-wk multidisciplinary rehabilitation program resulted to be highly effective. Key Words: Parkinson Disease, Neurorehabilitation, Executive Functions, Depression, Rehabilitation Outcome
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P
arkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms associated with cognitive deficits, even at an early stage of the disease.1Y3 Cognitive and behavioral dysfunction in patients with PD include deficits in executive functions, visuospatial and visuoconstructive abilities, attention, skill learning, depression, and apathy.4,5 Executive functions are called upon when novel plans of action must be formulated and conducted and allow to optimize the performance in situations requiring the simultaneous operation of different processes.2 Few studies analyze the effects of executive functions in health-related quality-of-life and daily activities,2,6 and to date, there are no studies that analyze the influence of alteration in executive functions on the efficacy of an intensive rehabilitation treatment. Moreover, although many studies have taken into account the effectiveness of rehabilitation on depression,7,8 not a single study considers the effects of depression on the overall outcome of rehabilitation. Several studies report the efficacy of rehabilitation in reducing specific impairments and in improving functional limitations in individuals with PD,9Y14 but none considers the impact of disexecutive functions and depression on rehabilitation outcome or considers these variables as exclusion criteria for rehabilitation treatment.8,15 The authors have developed an intensive rehabilitation protocol in which standard physicaltherapy techniques were associated with treadmill coupled with auditory and visual cues (treadmill plus) and a stabilometric platform.16,17 The aim of this study was to analyze the effects of executive functioning (impaired vs. not impaired) or depression (depressed vs. nondepressed) on rehabilitation treatment outcome in patients with PD without dementia at the medium stage of disease.
METHODS Subjects Forty consecutive inpatients with a diagnosis of Bclinically probable[ idiopathic PD according to Gelb et al.,18 admitted to the authors’ hospital for rehabilitation treatment, were enrolled into the study. All patients were in Hoehn-Yahr stage 3,19 none had severe cognitive impairment (MMSE of Q24),20 and all had antiparkinsonian medications stable for more than 4 wks. Subjects were excluded if they were treated with deep brain stimulation or if they had underlying neurologic conditions, severe cardiovascular disorders, diabetes, musculoskeletal disorders, www.ajpmr.com
or vestibular dysfunction limiting locomotion or balance and if the psychologic or neuropsychologic assessment was deemed unperformable (because of sensorial impairment, psychotic disorder, refusal to be assessed). The study was approved by the local ethical committee, and all subjects gave their written informed consent before participation.
Study Protocol Patients were examined by the same neurologist expert in movement disorders in the morning, 1 hr after they had taken levodopa (best Bon[ state), at baseline, and at the end of the rehabilitation treatment. The clinical evaluation was based on the Unified Parkinson’s Disease Rating Scale Motor Section (UPDRS-III),21 the Berg Balance Scale (BBS),22 the Timed Up and Go Test (TUG), and the 6-min walking test (6MWT). Measurements were performed at the start and at the end of the 4-wk rehabilitation program. During treatment, drug dosage was stable. In addition, during the first few days of hospitalization, the patients were psychologically and neuropsychologically assessed. The test presented in this study constitutes merely a part of a wider assessment performed routinely by the Psychology Unit. The patients were supported throughout the testing period to maintain motivation and to elicit the optimal level of performance; a break if needed was always allowed. Tests were carried out by senior psychologists, in accordance with standardized administration and scoring procedures.
Rehabilitation Protocol All patients underwent a 4-wk cycle of physiotherapy and occupational therapy that consisted of three daily sessions (two in the morning and one in the afternoon), 5 days a week. The first session (physiotherapy) comprised cardiovascular warm-up activities, relaxation exercises, muscle stretching exercises, exercises to improve spinal function, and postural changes in the supine position. During the second session, the patients used different devices: a stabilometric platform with a visual cue (the patients were asked to follow a circular pathway on the screen using a cursor sensitive to the movements made by the feet on the platform), a treadmill plus (treadmill associated with auditory and visual cues), a press leg, and a cycloergometer. The last session involved occupational therapy. The global duration of the three sessions was approximately 3 hrs per day. Functions and Depression in Parkinsonian Patients
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Psychologic and Neuropsychologic Assessment The patients were psychologically assessed by means of the following.
Parkinson Disease QuestionnaireY39 The Parkinson Disease QuestionnaireY39 is a well known disease-specific self-completed instrument designed to measure aspects of health-related quality-of-life that are relevant to patients with PD.23 The scores range from 0 (best health-related qualityof-life possible) to 100 (worst health-related qualityof-life possible). The Italian version presents good psychometric properties, and normative data are also available.24
Geriatric Depression Scale The 30-point Geriatric Depression Scale (GDS) is a questionnaire specifically aimed at assessing depression in old patients.25 A routinely comprehensive battery of neuropsychologic tests measuring a broad range of cognitive functions (memory and learning, verbal and nonverbal logical abilities, executive functions, fluency, ideomotor apraxia) were administered to each patient. Moreover, and coherent with the authors’ hypothesis that considers the executive functions exclusively, after excluding patients with MMSE20 score (adjusted for age and years of school) of less than 24, the following cognitive aspects were considered.
Frontal Functions Frontal functions were assessed by the Frontal Assessment Battery. The test consists of six subtests screening six functions related to the frontal lobes (similarities, conceptualization; phonological verbal fluency, mental flexibility; motor series, motor programming; conflicting instructions, sensivity to interference; go-no-go task, inhibitory control; prehension behavior, environmental control).26
Attention Attention (selective and divided) was assessed by the Trail-Making Test (TMT; parts A and B). The subject has to connect, in the proper order, 25 encircled numbers randomly arranged on a page (part A). Part A requires visual search processes and assesses selective attention. In part B, in which the subject has to connect, in the proper order, 25 encircled numbers and letters, requires switching/ cognitive flexibility and assesses divided attention.27
Phonemic Fluency Phonemic fluency was assessed by the Word Fluency test, which belongs to the wider Mental
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Deterioration Battery.28 It assesses the lexical memory store by means of a fluency task (fluency requested on F, A, and S). All tests have good psychometric properties and are validated on the Italian population, and normative data are also provided. The attribution of neuropsychologic test scores was performed as follows: raw scores of the neuropsychologic tests were transformed into adjusted scores for age, sex, and educational level and then into standardized equivalent scores (ESs). The ESs range from 0 to 4, where 0 and 1 indicate the presence of a cognitive deficit. This standardization procedure allows comparisons between tests with different scales and of different difficulty levels. To investigate the association between executive functioning (impaired vs. not impaired) and the rehabilitation treatment outcome, the patients were divided into subgroups according to the following criteria: criterion 1, patients impaired vs. patients not impaired at the TMT-A and TMT-B or at the Frontal Assessment Battery or at the Word Fluency. Similarly, the association between depression and rehabilitation treatment outcome was studied, classifying patients according to criterion 2, patients with mild or no depressive symptoms vs. patients presenting severe/moderate depressive symptoms. No criterion considering patients with depression plus executive dysfunction vs. patients with no depression and no executive dysfunction was analyzed because of sample size (only four patients showed depression and impairment in executive functions). Further studies on this specific topic are needed.
Statistical Methods Data are reported as mean (standard deviation) or as ESs. The normality of the distribution of all variables was assessed by the Shapiro-Wilk statistic. Patients unable to perform part B not because of motor problems were considered impaired and included in the ES 0Y1 group. To test whether the effect of rehabilitation treatment on each outcome variable considered was the same in the patients classified according to the different conditions (cognitive deficit/moderate-to-severe depression), a two-factor analysis of variance was carried out. The first factor was the group of patients (patients with and without cognitive deficit/moderate-to-severe depression), and the second factor was time (admission vs. discharge), with repeated measurements in the time factor. A P value of less than 0.05 was considered statistically significant. All analyses were carried out
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using the SAS/STAT statistical package, release 9.2 (SAS Institute Inc, Cary, NC).
RESULTS The rehabilitation treatment attendance rate was 97%, and all patients completed the 4-wk program without modification in pharmacologic dosages. Demographic and clinical characteristics of the patients are reported in Table 1. Depressive symptoms reported at the GDS were distributed as follows: mild (n = 13), 32.5%; moderate (n = 4), 10.0%; and severe (n = 5), 12.5%. The patients’ neuropsychologic characteristics (distribution of tests of executive functions) are reported in Table 2. As to criterion 1, a total of 18 patients (45%) were impaired and 22 patients (55%) were not impaired at the TMT-A and TMT-B or at the Frontal Assessment Battery or at the Word Fluency. As to criterion 2, a total of 31 patients (77.5%) reported mild or no depressive symptoms and 9 patients (22.5%) presented severe/moderate depressive symptoms. Considering the effects of rehabilitation, the analysis of variance showed an improvement in the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT in the patients with and without cognitive deficit or depression (time effect, P G 0.0001 for all variables). The improvement was homogeneous for all groupings of patients for all of the considered variables, as assessed by a not significant time group interaction in repeated-measures analysis of variance (all P 9 0.15), indicating that the changes in performance as a result of treatment were not affected by the presence of deficits in executive functions or depression. A graphical representation of UPDRS-total, UPDRS-III, BBS, TUG, and 6MWT results is reported in Figures 1 to 5. It
can be observed that, at admission, all variables were very similar whatever grouping strategy is considered and that the slope of the lines joining the mean value at baseline and after treatment are almost the same, suggesting no difference in treatment efficacy relating to executive function impairment or moderate-to-severe depression.
DISCUSSION As for sex, the patients in this study are equally distributed, and the patients are affected by PD in Hoehn-Yahr stage 3 (duration since diagnosis: mean of 9 yrs). Considering self-reported health and qualityof-life, assessed by means of the Parkinson Disease QuestionnaireY39, the patients in this study do not differ from the Italian normative sample,27 and therefore, significant consequences, in terms of impairment and perceived disability, are referred in many aspects of daily life, such as mobility, discomfort in communication and social interaction, emotional well-being, and stigma. As for depression, half of this sample reported depressive symptoms (22.5% moderate to severe), coherent with literature.29 Some considerations are noteworthy: given the fact that diagnostic difficulties are present because of the considerable overlap between symptoms of PD and depression, the test that was adopted (GDS) is considered to be one of the most useful in rating depression symptom severity in old patients with chronic PD, although mainly for screening purposes.30 In the literature, the mean prevalence of major depressive disorder in PD is substantial but lower than generally assumed.29 Therefore, even if the GDS does not substitute the Diagnostic and Statistical Manual of
TABLE 1 Demographic, clinical, and neuropsychologic/psychologic characteristics Variable
Admission
Male/female Duration since diagnosis, yrs Age, yrs UPDRS-total (0Y199) UPDRS-III (0Y75) BBS (0Y56) TUG, secs 6MWT, m PDQ-39 GDS
20/20 8.7 (6.4) 70.1 (8.0) 41.2 (10.4) 21.4 (5.3) 44.6 (8.6) 12.1 (5.5) 282 (76) 40.3 (21.2) 11.1 (6.7)
Discharge
27.2 (8.6) 14.8 (4.3) 51.4 (5.0) 9.5 (3.3) 382 (104)
UPDRS-total: 0, no disability; 199, total disability; UPDRS-III: 0, no disability; 75, total disability; BBS: 0Y56 (higher score indicates an independent performance). PDQ-39, Parkinson Disease QuestionnaireY39.
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TABLE 2 Distribution of ESs of the tests of executive functions PD Patients (N = 40), n (%) Tests of Executive Functions FAB TMT-A TMT-B WF
ES 0Y1 Cognitive Deficit
ES 2Y4 No Cognitive Deficit
13 (32.5) 22 (55.0) 16a (41.9) 7 (17.5)
27 (67.5) 18 (45.0) 24 (58.1) 33 (82.5)
ES: 0Y1, deficit; 2Y4, no deficit. a In this group, the patients not able to perform the task are considered impaired and therefore included. FAB, Frontal Assessment Battery; WF, Word Fluency.
Mental Disorders, Fourth Edition, in rehabilitation, the data of this study suggest the utility of screening depression to give evidence of its clinical manifestations, which do not necessarily require pharmacologic treatment but may benefit from psychologic counseling and a supportive healthcare team,7,31Y33 and to prevent behavioral nonadherence after discharge. A high percentage of the patients in this study showed significant impairment in the executive functions considered in the study (selective and divided attention, screening of conceptualization, mental flexibility, motor programming, sensivity to interference, inhibitory control, environmental control constructional abilities), as shown in Table 2. This is a peculiar characteristic of PD as confirmed by many studies: cognitive deficits are common in
PD patients with Bnormal[ MMSE performance, suggesting that mild cognitive deficits are underrecognized in clinical practice because of routine use of insensitive screening instruments such as the MMSE.1,34 As for the outcome of the intensive rehabilitation, a general improvement in the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT was observed (see Table 1 and Figs. 1Y5) and consistent with the recent literature.10,13,17 Considering patients with and without cognitive deficits, the improvement in the rehabilitation outcome resulted homogeneous, thus indicating that the changes in scores as a result of treatment, in the five assessment domains considered, were not affected by the presence of an executive function deficit. This may be
FIGURE 1 A and B, UPDRS-total (tot) values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
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FIGURE 2 A and B, UPDRS-III values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
because of the fact that, as shown in the literature, procedural learning seemed to be independent of executive dysfunction35; therefore, although impaired
in executive functioning, the subgroup of patients in this study may have acquired the strategy instructions necessary to execute the motor rehabilitation
FIGURE 3 A and B, BBS values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval. www.ajpmr.com
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FIGURE 4 A and B, 6MWT values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
training. Moreover, although the patients in this study qualitatively reported a subjective satisfaction in the rehabilitation outcome, its impact on
everyday life requires further studies. The implementation of the International Classification of Functioning Disability and Health may lead to a
FIGURE 5 A and B, TUG values in patients grouped according to the two criteria at the time of admission and at discharge. Data are plotted as mean T 95% confidence interval.
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deeper understanding of the relationship between executive abilities and functional contexts related to everyday life and to real-world behavior.36 Furthermore, the presence of moderate/severe depressive symptoms did not seem to influence the rehabilitation outcome assessed by the UPDRS-III, the UPDRS-total, the BBS, the TUG, and the 6MWT (see Table 1 and Figs. 1Y5). The patients homogeneously showed improvements in motor performance including overall aspects of daily living and symptoms. Although depressed, this subgroup of patients seemed to be motivated by the rehabilitation protocol, and adherence to the program by the nondepressed patients was extremely high during the 4 wks. Despite the presence of executive function deficits and depression in some patients, all displayed a significant functional improvement after the 4-wk intensive rehabilitation program. A possible intriguing explanation is based on the hypothesis of the neuroplastic effect of physical activity: animal experiments and clinical assays provide evidence that suggests that exercise has a neuroprotective effect against neurodegenerative diseases,37,38 and a direct effect of exercise on the level of several growth factors has been revealed.39,40 The finding that exercise leads to cognitive improvement in normal aging and Alzheimer disease is well established,41Y43 and functional MRI data suggest that aerobic exercise leads to more efficient neuronal activity in the prefrontal regions similarly affected in PD.44,45 Moreover, Tanaka and colleagues46 concluded that, after a 6-mo aerobic exercise program, individuals with PD showed improved executive function. This study presents some limitations: although homogeneous in terms of diagnosis and disease severity, sample size is not large and only inpatients were assessed; therefore, the results could not be generalized to the whole PD population. The results may not be applicable to individuals with dementia, in whom severe cognitive deficits may indeed influence rehabilitation outcome. Moreover, follow-up data on functionality are not available; therefore, the permanence of the rehabilitation outcome through time in patients with or without depressive symptoms or executive deficits deserves consideration in further studies. Meanwhile, its strengths should be highlighted: the evaluation in this study is concomitant with clinical assessment, and studies on this topic with so many domains simultaneously assessed (clinical, functional, psychologic, and neuropsychologic) are rare. Finally, the patients completed the self-report questionnaires with competent supervision, if necessary, www.ajpmr.com
which reduces the possibility of compromising validity of the results.
CONCLUSIONS Patients’ executive function impairment or patients’ depressive symptoms seemed not to interfere with the overall outcome of physical intensive rehabilitation. It may be hypothesized that comprehension and motivation of physiotherapic and occupational therapy tasks may not be mediated by executive functions or by depressive symptoms in PD inpatients without dementia. Therefore, these aspects should not constitute a contraindication to intensive rehabilitation program; despite the presence of executive function impairment and/or of depressive symptoms, the 4-wk multidisciplinary rehabilitation program proved to be highly effective. ACKNOWLEDGMENTS
As for the psychologic and neuropsychologic data, the authors thank Lucia Viola for data collection and Elisa Carrara and Irsida Zajmai for data entry. REFERENCES 1. Mamikonyan E, Moberg PJ, Siderowf A, et al: Mild cognitive impairment is common in Parkinson’s disease patients with normal Mini-Mental State Examination (MMSE) scores. Parkinsonism Relat Disord 2009;15:226Y31 2. Kudlicka A, Clare L, Hindle JV: Executive functions in Parkinson’s disease: Systematic review and metaanalysis. Mov Disord 2011;26:2305Y15 3. Muslimovic D, Post B, Speelman JD, et al: Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology 2005;65:1239Y45 4. Zgaljardic DJ, Foldi NS, Borod JC: Cognitive and behavioral dysfunction in Parkinson’s disease: Neurochemical and clinicopathological contributions. J Neural Transm 2004;111:1287Y301 5. Barone P, Aarsland D, Burn D, et al: Cognitive impairment in nondemented Parkinson’s disease. Mov Disord 2011;26:2483Y95 6. Koerts J, Van Beilen M, Tucha O, et al: Executive functioning in daily life in Parkinson’s disease: Initiative, planning and multi-task performance. PLoS One 2011;6:e29254 7. Gage H, Storey L: Rehabilitation for Parkinson’s disease: A systematic review of available evidence. Clin Rehabil 2004;18:463Y82 8. Goodwin VA, Richards SH, Taylor RS, et al: The effectiveness of exercise interventions for people with Parkinson’s disease: A systematic review and metaanalysis. Mov Disord 2008;23:631Y40
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