Exercise Therapies for Parkinson's Disease: A Systematic Review and Meta-Analysis

Recently, rehabilitative exercise therapies have been described as an important method of overcoming the limitations of the conventional therapies for Parkinson's disease. The present study aimed to evaluate efficacy and safety of exercise therapies for Parkinson's disease. Randomized controlled trials that evaluated exercise therapies in patients with Parkinson's disease until December 2016 were searched for in five electronic databases: PubMed, CENTRAL, EMBASE, OASIS, and CNKI. Eighteen studies (1,144 patients) were included. The overall methodological quality was not high. Patients who underwent exercise therapies exhibited statistically significant improvements in the total UPDRS, UPDRS II and III, Berg Balance Scale, preferred walking speed, and Timed Up and Go Test compared to patients who underwent nonexercise therapies. In comparison to patients who performed regular activity, patients who underwent exercise therapies exhibited statistically significant improvements in the total UPDRS, UPDRS II, and UPDRS III. Exercise therapies were found to be relatively safe. Exercise therapies might promote improvements in the motor symptoms of Parkinson's disease. However, due to the small number of randomized controlled trials and methodological limitations, we are unable to draw concrete conclusions. Therefore, further studies with better designs will be needed.


Introduction
Parkinson's disease (PD) is a neurodegenerative neurological disease characterized by a decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc) and lowered dopamine concentrations in the basal ganglia [1]. Symptoms are divided into motor and nonmotor symptoms. Motor symptoms are characterized by bradykinesia, rigidity, resting tremor, and postural instability.
ere are also several nonmotor symptoms such as anosmia, sleep disorders, psychiatric symptoms, cognitive impairment, autonomic dysfunction, fatigue, and pain [2]. e motor symptoms of PD begin to appear in the early stage of the disease, leading to a decrease in the quality of life (QOL) [2,3]. PD patients stay in hospital for about 1.45 times longer than healthy persons for about 2-14 days. Furthermore, they are more likely to be exposed to emergency situations such as falls [4]. e prevalence and incidence of PD has been increased gradually [5,6]. According to the statistics up to 2016, 6.1 million patients suffer from PD globally [6]. In general, anti-Parkinsonian medications such as levodopa, dopamine agonists, monoamine oxidase type B inhibitors (MAOBIs), amantadine, and anticholinergics are administered as first-choice treatment. However, longterm use of dopaminergic medications could lead to adverse effects such as peak-dose dyskinesia, on-off phenomenon, and wearing off [7]. Surgical treatment such as thalamotomy, chemopallidectomy, and deep brain stimulation has been used to reduce the physiological changes of brain tissue caused by PD [8,9]. However, it is expensive, it has high risk of side effects [10], and the possibility of reoperation cannot also be ruled out. erefore, complementary therapies such as rehabilitation exercises could be considered in a long-term perspective. Previous studies suggested that rehabilitation exercise therapies could activate the central and peripheral nervous systems, thereby maximizing body function and slowing the progression of the disease [11].
Recently, there has been a growing interest in constructing rehabilitation strategies for PD patients in a comprehensive and diverse manner, one of which is exercise. According to animal studies, exercise therapies have neuroprotective effects and an inhibitory effect on the progression of PD or the restoration of the disease in animals.
e neuroprotective effect of exercise on humans has not yet been clearly reported, but exercise therapy is most likely to be used in clinical practice [12]. e purpose of this systematic review and meta-analysis study was to investigate the effect and safety of exercise therapies on PD. To reflect the differences in exercise interventions used in each of the existing studies, we performed a meta-analysis by grouping them according to the nature of the exercise interventions.

Study Design.
is study is a systematic review and meta-analysis to examine the effect and safety of exercise therapies on patients with PD.

Data Sources and Search Strategy.
is study was carried out according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [13] and the Cochrane Handbook for Systematic Reviews of Interventions [14]. e systematic literature search was conducted using Pubmed (Medline), Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), the Oriental Medicine Advanced Searching Integrated System (OASIS), and Chinese medical databases (CNKI-Chinese Academic Journal). e articles reported until December 2016 were searched, and there was no language limitation. Various exercise terms and MeSH terms were used for searching. e search strategies used in each database are presented in Table 1.

Study Selection.
e criteria for the selection of the literature were as follows: randomized controlled trials which evaluated the effect of walking training, strength or flexibility training, balancing training, and aerobic training on patients with PD. We excluded nonrandomized or uncontrolled trials, in vivo or in vitro studies, statistical studies, or protocol papers. In the case of duplicate documents, when more than two studies were available, the most recently reported or more complete literature was selected.

Type of Participants.
Studies involving patients with PD were selected. UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria was used as the PD diagnostic criteria [15]. ere were no restrictions on sex, age, race, or disease duration. Patients with other diseases such as dementia, chronic medical illnesses, and atypical or secondary Parkinsonism were excluded.

Type of Interventions.
Studies that used exercise therapy as an intervention for PD were included. We also included studies that used an auxiliary device for exercise such as a treadmill, but excluded studies in which the device was used as a core intervention, such as Nintendo or robot. ere were no limitations on program content, such as exercise treatment methods, progress, frequency, duration, and intensity, but we only included studies which had the program of activity developed in detail. Qigong therapy in East Asian traditional medicine such as tai chi was not included neither.
In this study, the studies were classified according to each type of exercise treatment; meanwhile, they were classified as complex exercise when two types of exercises were used. e types of exercise are as follows: walking exercise either on a treadmill or on flat ground; balancing exercise, referring to the movement that shifts from one movement to another, holds a posture, and delays adjustment through physical cooperation; aerobic exercise, referring to the movement that involves stepping with a partner, tapping the ground, crossing the foot, or moving weight from one leg to the other; and dancing were included in this category; strength exercises, referring to training that prevents muscle weakness through the contraction of muscle fibers by external loads [16], and exercises that strengthen the quadriceps, hamstrings, gastrocnemius, and rectus abdominis muscles were included in this category.

Type of Comparisons.
According to the type of the control group, the studies were divided into two categories. e first was for the conventional drug treatment (standard of care) and no exercise treatment. In this case, the experimental group performs the exercise therapy as an adjunctive intervention, and the control group continues the usual medication just as before the trial. Second, the control group performed a regular activity with a regular program.

Type of Outcome
Measures. e symptoms of PD were evaluated and divided into motor function, balance function, gait, quality of life (QOL), and general symptoms. In general, the Unified Parkinson's Disease Rating Scale (UPDRS) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPRDS [17,18]) were used to evaluate the symptoms of Parkinson's disease. To assess motor function, the UPDRS and MDS-UPRDS part III were used, and total UPDRS and UPDRS part I/II were used to evaluate general symptoms in this study. e evaluation of balance function was carried out using the Berg Balance Scale (BBS) [19] and Timed Up and Go Test (TUGT) [20]. Gait function was assessed by the gait velocity and the 6-minute walk test. e gait velocity was evaluated in two ways: the preferred walking speed (m/s) and the fast walking speed (m/s). e preferred walking speed (m/s) was the measurement of the patient's most comfortable walking speed, while the fast walking speed (m/s) was the patient's maximum walking speed. Reported adverse effects were also extracted.

Data
Extraction. Data extraction was conducted by two researchers (Hyun-young Choi and Seungwon Kwon), and an arbiter (Ki-Ho Cho) made the final decision if there was a disagreement between the 2 researchers. e first author, characteristics of the study (i.e., year, nation (English/Chinese), setting, and design), characteristics of participants (i.e., sex, sample size, Hoehn and Yahr scale (H&Y scale), disease duration, and medication), intervention details of the experimental and control groups, measured outcome, intergroup differences, and adverse events were extracted. If any of the abovementioned data was unclear, efforts were made to contact the authors of the study.

Quality Assessment in Individual Studies.
Cochrane's risk of bias tool was used for the quality evaluation [21]. It is a tool for evaluating the bias of research included in the creation of systematic reviews and meta-analyses. It consists of 7 sections, and each was divided into "low risk of bias," "unclear risk of bias," and "high risk of bias." e quality of the literature was assessed based on what is described in the literature. Risk of bias (ROB) assessment was conducted by two independent authors (Hyun-young Choi and Seungwon Kwon). In the event of a disagreement while extracting data or assessing the ROB, the third author (Ki-Ho Cho) resolved the discrepancy.

Synthesis of Data and Meta-Analysis.
Meta-analysis was performed using Cochrane review manager software version 5.3 (RevMan 5.3). Based on the study design, a meta-analysis was conducted on the comparative study of the exercise with conventional drug treatment combination and conventional drug monotherapy groups. Separately, a meta-analysis was conducted on the comparative study of exercise and conventional drug treatment combination and on the regular activity and conventional drug treatment combination groups. e efficacy estimates were obtained from the relative risk (RR) for dichotomous variables and from the mean difference (MD) for continuous variables. A random effect model was used based on clinical heterogeneity between studies. e statistical significance of the effect estimates was verified based on the total effect test, 95% confidence interval (CI), and significance level of 5%. Meta-analysis was conducted by the classification of each outcome.
e Chi-square test and the Higgins I 2 statistics were used to assess statistical heterogeneity. In the Chi-square test, it was verified that there was significant heterogeneity when the p value was less than 0.05 or the I 2 value was greater than 50.

Description of the Included Studies.
A total of 4,047 studies were retrieved by electronic search. After eliminating duplicates, the 2,795 studies left were screened by abstract. Among them, 71 studies were selected for eligibility assessment. After reviewing the full texts, 18 studies (1,144 patients) were finally selected for the meta-analysis. Fiftythree studies were excluded due to the following reasons: improper interventions such as robot therapies (n � 9), inappropriate outcome measures (n � 27), ineligible study design (n � 3), and inappropriate control group which contained more than 2 active control groups (n � 14) ( Figure 1, Table 2).
Among the 18 final studies, 12 were reported in English and 6 were reported in Chinese (Table 3).
ree studies carried out exercise once a week [26,33,38], two studies twice a week [32,35], other three studies five times a week [28,37,39], two studies every day [27,36], one study four times a week [23], and another study five or six times a week [29]. However, there was one study that did not report exercise frequency [40].

Risk of Bias within Studies.
In most studies, the risk of bias was not high. Among the risk of bias domains, blinding of the participants and personnel and selective reporting revealed methodological concerns. Nine articles [23-25, 27, 29, 31, 33, 39, 40] were classified as 'unclear risk of bias' in the random sequence generation because there was no specific description of the randomization method. Eight studies [24, 27-29, 32, 33, 39, 40] were classified as "unclear risk of bias" in the allocation concealment. Another study [35] that did not conceal the assignment order was classified as "high risk of bias." Most studies were classified as "high risk of bias" in the blinding of participants (performance bias) [23][24][25][26][28][29][30][31][32][33][34][35][36][37][38][39][40]. In the incomplete outcome data (attrition bias), one study [32] was evaluated as "high risk of bias" and all the remaining studies were evaluated as "low risk of bias". In the selective reporting (reporting bias), one study [26] was rated as "high risk of bias" and the rest of the studies were evaluated as "unclear risk of bias." A summary of the risk of bias is shown in Figure 2.

UPDRS I Scores.
Two studies [24,31] used UPDRS I. ere was a study [31] evaluating the effect of balancing exercise and it compared the UPDRS I subscore in ET and NE. ET showed a positive effect in the total UPDRS I (MD −0.10, 95% CI (−0.26, 0.06)) ( Figure 3(c)). ere was another study [24] that used walking exercise and compared the UPDRS I subscore between ET and RA. In this study, ET did not show a positive effect in the UPDRS I (MD 0.50, 95% CI (0.36, 0.64)) ( Figure 3(d)).
ere was a significant difference in the preferred walking speed between the two groups (MD 0.11, 95% CI (0.10, 0.12)). In the subgroup analysis, only balancing exercise [30] revealed a significant effect ( Figure 5(a)).

Total (95% CI)
Test for overall effect: Z = 6.99 (P < 0.00001) Favours (exercise) Favours (nonexercise)    did not show a significant effect in the 6 MWT (Figure 8(a)). Another study (including 17 patients) [25] compared ET with RA. In this analysis, ET did not show a significant effect in the 6 MWT (Figure 8(b)).

Discussion
e results of this systematic review and meta-analysis show that ET improved motor and nonmotor symptoms in PD compared with NE or RA. ET showed a significant improvement in UPDRS (total, II, III, and MDS-UPDRS III) scores, BBS, preferred walking speed, and TUGT compared to NE and UPDRS (total, II, and III) compared to RA.
Previously, several meta-analyses had been reported which evaluated exercise interventions in patients with PD [10,[41][42][43][44][45]. e differences between the previous studies and the present study are as follows. First, in this study, various interventions and outcomes were investigated. Most of the previous studies were limited in the specific type of exercise  therapy [10,43,44] or the specific type of outcome measure [45]. Another study only showed the characteristics, intervention delivery, retention rates, adherence, and adverse events of exercise therapies [42]. However, there was no report about improvement of PD symptoms. In this study, we aimed to comprehensively evaluate the effects of various types of exercise therapies on PD and to evaluate the effects of each type of exercise therapy through subgroup analysis. erefore, we tried to classify exercise interventions into 5 groups according to four types of exercise therapy and to provide a summary effect estimate of the individual exercise types. At the same time, we extracted various outcome measures such as total UPDRS and UPDRS part I, II, III, and IV, BBS, TUGT, and gait velocity (preferred speed, fast speed, 6MWT). erefore, the relationship between the improvement of motor or nonmotor symptoms of PD and exercise therapies could be evaluated. e degree of improvements of symptoms according to the type of exercise could be known. Based on these results, it is possible to apply it to clinical care. Second, this study analyzed a larger number of literature, being an update of existing studies.
ere were 495 PD patients included in 14 articles in the previous studies of various exercise interventions as classified in this study [41]. In this study, we included 1,144 PD patients in 18 studies. erefore, it could be assessed that the reliability of our study was increased. Finally, we tried to reduce the heterogeneity and to obtain accurate results by dividing the results into two groups according to whether regular activity was performed in the control group or not. In addition to the nonexercise group (NE), we evaluated the regular activity (RA) group to confirm that the results are different. We found that even simple activities could also help to improve symptoms of PD.
In this study, exercise therapies have been shown to be effective in improving the overall symptoms of PD, the activities of daily life (ADLs) related to motor function, overall motor symptoms, balance, and gait disturbance. e effects of each exercise type are as follows: walking exercises showed significant effects on ADLs related to motor function and motor symptoms compared with RA; strength and flexibility exercises revealed significant effects on ADLs related to motor function (compared with NE and RA) and balance (compared with NE); balancing exercise has significant effects on motor symptoms and gait disturbance (compared with NE); aerobic exercise showed significant effects on motor symptoms and balance (compared with NE); and complex exercise revealed a significant effect on motor symptoms. As mentioned above, depending on the type of exercise, we could see the difference in the degree to which PD symptoms were improved. ere is a high heterogeneity of the resulting values because of differences in the duration and method of exercise therapy for each study included in the meta-analysis. Nonetheless, in clinical applications, clinicians will be able to make appropriate and flexible use of the results of this study, depending on the circumstances and experience (Table 4). Adverse events such as falling and fatigue have been reported. Among them, the most common was falling in two articles [30,35]. Falling was observed only in balancing and aerobic exercise, 13 out of 14 occurred during balancing exercise. According to a review article [46], postural instability is known to be observed in 16% of PD patients. Postural instability gradually deteriorates as the disease progresses, which is the main cause of falling [47]. If there are patients with severe postural instability, the balancing exercise should be considered carefully. Other types of exercise (besides the balancing  exercise) did not show any severe adverse effects other than fatigue. erefore, they could be applied to PD patients relatively more safely. e limitations of this study are as follows: first, there is a bias in the literature included in the aspects of qualitative research methodology. Selection bias may exist because random sequence generation or allocation concealment were not specifically addressed [23-25, 27-29, 31-33, 39, 40] or one study [35] was evaluated as "high risk of bias" because of the absence of blinding of participants (performance bias). Only one study [27] conducted blinding of participants. Also, in the blinding of outcome assessment, two studies [35,38] were evaluated as "high risk of bias." erefore, selection bias and detection bias may have influenced the result of this study. Second, heterogeneity is high. is is thought to be because there was a huge difference in the quality of the studies, the patients participating in the study, and the exercise treatment and regular activity in each literature. ird, the sample sizes of the literatures included in this study are still small. is study was divided into two groups according to whether regular activity was performed in the control group and subgrouped by the types of intervention (walking, strength, balancing, aerobic, and complex exercises). erefore, since a total of 18 articles were divided, the number of articles included in each evaluation index was quite small. is might have led to the lower test effectiveness. erefore, further follow-up research with additional exercise therapy intervention clinical papers should be conducted.

Conclusions
Exercise therapies might promote improvements in the motor symptoms and related ADLs of PD. Overall, exercise therapies showed significant effects on motor function of PD patients compared to NE group or RA group. In contrast, exercises did not show a statistically significant effect on nonmotor symptoms compared to the NE group or RA group. ese results suggest that exercise therapy is more effective for motor symptoms of PD patients rather than nonmotor symptoms. However, due to the small number of randomized controlled trials and methodological limitations, we are unable to draw concrete conclusions. erefore, further studies with better designs will be needed.

Data Availability
Data can be obtained from the corresponding author on request.
Disclosure is paper is based on Hyun-young Choi's theses for the Master's degree.