Evidence of Rehabilitative Impact of Progressive Resistance Training (PRT) Programs in Parkinson Disease: An Umbrella Review

Parkinson disease (PD) is a chronic neurodegenerative condition that leads to progressive disability. PD-related reductions in muscle strength have been reported to be associated with lower functional performance and balance confidence with an increased risk of falls. Progressive resistance training (PRT) improves strength, balance, and functional abilities. This umbrella review examines the efficacy of PRT regarding muscular strength in PD patients. The PubMed, PEDro, Scopus, and Cochrane Library databases were searched from January 2009 to August 2019 for systematic reviews and meta-analyses conducted in English. The populations included had diagnoses of PD and consisted of males and females aged >18 years old. Outcomes measured were muscle strength and enhanced physical function. Eight papers (six systematic reviews and meta-analyses and two systematic reviews) were considered relevant for qualitative analysis. In six of the eight studies, the reported severity of PD was mild to moderate. Each study analyzed how PRT elicited positive effects on muscle strength in PD patients, suggesting 10 weeks on average of progressive resistance exercises for the upper and lower limbs two to three times per week. However, none of the studies considered the postworkout follow-up, and there was no detailed evidence about the value of PRT in preventing falls. The possibility of PRT exercises being effective for increasing muscle strength in patients with PD, but without comorbidities or severe disability, is discussed. Overall, this review suggests that PRT should be included in rehabilitation programs for PD patients, in combination with balance training for postural control and other types of exercise, in order to preserve cardiorespiratory fitness and improve endurance in daily life activities.


Introduction
Parkinson disease (PD) is a progressive neurodegenerative chronic disease that is characterized by tremor, muscle rigidity, and bradykinesia [1]. Patients can present with postural instability, leading to an increased risk of falls, social isolation, and a decline in quality of life [2]. PD is characterized by Lewy bodies containing alpha-synuclein and a reduction in dopamine concentrations in the substantia nigra. Additionally, PD involves dysfunctional cholinergic transmission due to neuronal loss in the nucleus basalis of Meynert and noradrenergic and serotoninergic ascending systems [3]. ese impairments result in neurovegetative disorders, mood disturbances, and cognitive dysfunction [4]. PD affects 1-2 per 1000 persons in the population at any time, and its prevalence increases with age, affecting 1% of those aged over 60 years. In 90% of PD cases, the cause is sporadic, whereas the remaining 10% of PD cases involve mutations in one or more genes, which may lead to earlier onset [5]. It is important to emphasize how PD negatively impacts quality of life due to increased motor disability, loss of independence, and social isolation [2]. In the early stages, due to the greater risk of falls, patients limit their ambulation out of the home [6] and their participation in outdoor activities [7]. e value of rehabilitation is thus fundamental, in combination with drug therapy, to preserve functional ability and a minimum level of autonomy through simple and complex Activities of Daily Life (ADLs) [8]. An integrated rehabilitative program with physical activities, therapeutic exercises, and fall prevention strategies could slow the progression of disability [9]. Innovative techniques, such as virtual reality (VR), motor imagery (MI), action observation therapy (AOT), and robot-assisted physiotherapy, have been used recently [10] with good results and good compliance by patients. New technologies could improve motor performance and promote the learning of motor tasks [11]. However, physical activity has a positive effect on both motor and nonmotor symptoms in PD and is beneficial, cost-effective, and low-risk [12], with neuroprotective and neurorestorative effects [13]. For example, Bhalsing et al. recommend physical activity in PD, considering a patient's specific factors (motor symptoms, risk of fall, apathy, fatigue, depression, and cognitive dysfunction) [12], and Fayyaz et al. showed that "physical exercise" can be used as an adjuvant treatment to help a PD patient's limitations [14]. Subsequent therapeutic exercise improves transfers, gait cycle, balance, aerobic endurance, and the early stage of movements [8], especially in the initial phases of PD.
Practitioners prescribe physical therapy coupled with drugs and cognitive treatments [15] because cognitive difficulties often increase disabilities, especially impaired attention [16]. In the physical exercise program designed to prevent falls, resistance training (RT) and endurance training (ET) enhance muscle strength and improve range of motion, muscle power, and balance [17]. An effective physical therapy method is "movement strategy training" (MST), which teaches patients to use compensation strategies to improve their motor abilities and cognitive resources in order to initiate and execute functional activities [18].
Similarly, progressive resistance training (PRT) can enhance muscle strength, which is frequently reduced in PD due to bradykinesia and disuse of muscles for immobilization [19]. PRT was developed in the 1940s to rehabilitate veterans of World War II. After that, it became an efficient treatment for rehabilitating young people and athletes, improving pain and muscle strength [20]. Recent data describe PRT as an effective rehabilitation method in PD, improving joint mobility, endurance, and performance in daily living activities [21]. Moreover, PRT increases endurance during gait training [22], prevents falls [8], and might have beneficial effects on nonmotor symptoms, such as cardiovascular autonomic dysfunction [23], which are often disabling in PD patients. Unilateral PRT optimizes improvements in strength in the contralateral limb, "cross-education phenomenon" [24]. Further, PRT improves sensorimotor coordination, leading to adjustments in the areas that control voluntary movements [25].
Based on these premises and the increasing number of systematic reviews on the efficacy of PRT in PD, we performed this umbrella review to highlight the specific goals of PRT in rehabilitation in PD and examine the efficacy of PRT regarding muscular strength in PD patients.

Materials and Methods
e PICO (Population, Intervention, Comparison, and Outcome) method was used to arrange this review. Population: eligible trials involved patients with Parkinson disease, regardless of gender or level of disability. Interventions: the experimental intervention was PRT exercises, defined as repetitive muscle contractions against increasing load, based on the patient's abilities. Comparison: reviews that compared PRT with placebo, no treatment, or another treatment (such as endurance training) were included. Outcome measures: the effect of PRT exercises on muscular strength was evaluated.

Inclusion Criteria.
We included systematic reviews and meta-analyses of randomized and other controlled studies from the past ten years that compared PRT with placebo or another form of exercise in PD. Selected populations had a diagnosis of PD at any level of severity, comprising males and females aged >18 years old. Outcomes measured were muscle strength and enhancement in physical function.

Exclusion Criteria.
We excluded all randomized controlled trials (RCTs) or experimental studies or reviews that were published until August 2019, articles that were not in English, those that did not have the full text available, and articles about other interventions not involving PRT (Table 1).

Data Sources and Search Strategy.
ree databases were searched by three independent reviewers in PubMed, PEDro, Scopus, and Cochrane Library with the following filters: "systematic review," "meta-analysis," and "practice guidelines." e search was based on reviews from 2009 to August 2019 that were written in English and based on a high level of evidence (systematic reviews and meta-analyses). e keywords were "Parkinson disease," "progressive resistance training," "resistance training," and "muscle strength."

Methodological
Quality. Methodological quality/bias risk was recorded using the Joanna Briggs Institute critical appraisal checklist for Systematic Reviews and Research Syntheses [26]. For data extraction, three investigators carried out the research autonomously, subsequently crossed the data to screen titles and abstracts, and independently assessed the risk of bias. Disputes were resolved by consensus ( Table 2).

Results
After duplicates were removed, the search resulted in 144 records; 135 records were screened on the basis of their titles and abstracts, and one article was rejected because it was not a systematic review [33]. Eight papers (six systematic reviews and meta-analyses and two systematic reviews) were considered to be relevant for qualitative analysis [21,22,[27][28][29][30][31][32] because they fulfilled the inclusion criteria ( Figure 1).
e key features of the papers are summarized in Table 3; Table 4 summarizes the rehabilitation programs in each paper. e aforementioned studies examined how progressive training benefits muscle strength. Various assessment measures were used in these reviews, such as one RM (one repetition maximum; the maximum weight that can be lifted once [34]) and the dynamometer, which is considered the standard for testing muscle strength [35]. e first systematic review to examine the effects of resistance training in PD was by Brienesse and Bhalsing. e authors reviewed five studies, where they found that resistance training improves muscle strength and endurance, mobility, and performance on functional tasks and increases fat-free mass. is modality can be a part of the rehabilitation program in patients with mild-to-moderate PD [21]. In the same year, Lima et al. performed a systematic review and meta-analysis showing positive and moderate effect sizes on strength in people with PD (SMD � 0.50, CI 0.05-0.95; I 2 � 10%). According to the authors, PRT should be a part of the exercise program to increase strength in mild and moderate PD and more studies are needed to determine the beneficial effects of PRT on physical performance, such as walking capacity [22].
In their systematic review and meta-analysis, Saltychev et al. examined whether there was evidence on the effectiveness of PRT on the spine and lower limb muscles. e authors analyzed 12 RCTs that studied the effects of PRT on fast and comfortable walking speed, the Timed Up and Go Test, the 6-min walk test, and maximum oxygen consumption. ey found statistical but clinically insignificant results in favor of PRT and concluded that RCTs with larger sample sizes and longer follow-up periods that compared with other types of physical training were needed to make clinical recommendations [27].
Tillman et al. evaluated the impact of PRT on gait, balance, and leg strength in PD.
e study showed significant results of PRT with regard to lower limb muscle strength (p � 0.0014, SMD 1.42; 95% CI 464-2.376) in mild/moderate PD. e proposed PRT regimen lasted 8 to 24 weeks. e authors did not find conclusive evidence for PRT enhancing balance or gait [28]. Roeder et al. conducted a systematic review and meta-analysis in 2015, examining nine RCTs that evaluated muscle strength, focusing on knee extension and flexion by leg press. e most effective physical activity program was composed of PRT and aerobic/balance/stretching exercises [30].
A systematic review and meta-analysis by Uhrbrand et al. in 2015 evaluated resistance training, endurance training, and other training modalities in PD. e authors found strong evidence of improved resistance training strength (Q � 1.844, d.f. � 5, p � 0.870). Moreover, resistance training prevented strength from   deteriorating.
e group did not observe a linear correlation between lower extremity strength and walking performance, but when muscle strength was low, walking performance decreased. e combination of resistance and endurance training can improve muscle strength and cardiorespiratory fitness [32].
Chung et al., in their systematic review and metaanalysis (401 participants in seven RCTs) conducted in 2016, confirmed the effectiveness of PRT in PD. According to the meta-analysis, PRT had positive effects on muscle strength (p < 0.001; 95% CI, 0.35-0.87), balance (p � 0.01; 95% CI, 0.08 to 0.64), and motor disorders (p < 0.001; 95% CI, 0.21 to 0.75) but did not elicit gains in walking performance. e authors suggested that moderate-intensity resistance training be performed in group and in the patient's home [29].
A systematic review and meta-analysis by Cruickshank et al. examined papers on PD (six RCTs and three non-RCTs) and multiple sclerosis (five RCTs and two non-RCTs) and showed that strength training significantly improved muscle strength (15% to 83.2%) and mobility (11.4%) in PD patients. Furthermore, Cruickshank et al., in accordance with the American College of Sports Guidelines, recommended "progressive submaximal strength training (whole-body single and multi-joint resistance exercises) on at least 2 nonconsecutive days per week for an hour under direct supervision (physiotherapist, exercise physiologist, strength and conditioning specialist)." Moreover, strength training slowed disease progression in patients with mild-to-advanced disability; these data also suggested that strength exercise has positive impacts on the progression of PD at all disease stages. However, the authors expressed doubts about the beneficial effects of strength training in the advanced stages of PD, concluding that future trials should include patients with severe levels of disability [31].

Discussion
e aim of this umbrella review was to provide evidence that PRT improves strength in PD, and the results favor the inclusion of strengthening exercises in the rehabilitation of PD patients through the improvement in muscle strength, and patients performed better in ADLs. Considering that muscle weakness can be a primary symptom of PD [36], which contributes to postural instability and gait difficulties [37,38] and has been identified as a secondary cause of bradykinesia [39], this is an important insight and emphasizes the value of PRT in the treatment of PD. Furthermore, since muscle weakness and bradykinesia in PD have the same neuro-physio-pathological mechanisms [40], Systematic review and meta-analysis (7 RCTs) PEDro scale On measures of gait and balance no evidence to support or refute PRT prescription; in conjunction with balance and task-specific functional training to improve these measures e reduced sample size, which has been selected for the feasibility of conducting a oneto-one, 6-week exercise intervention.
Chung et al. [29] Systematic review and meta-analysis (7 RCTs PRT can increase the power-generating capacity of the muscle, thus directly affecting muscle weakness. Improvements in muscle strength and power also have a significant impact on bradykinesia [19] and could facilitate independence in the community, improve functional mobility, and reduce the risk of falls [33]. To maximize the benefits of PRT, one must follow three key points: (1) progressive overload, which is the gradual increase in physical stress to which the body is subjected during training, (2) specificity, which refers to how the body responds and adapts to different variables of the training program with reference to the objective that has been set, and (3) variation, which is a change in one or more variables in the program for the training stimulus to remain optimal [41,42]. e latter concept is based on Selye's theory of "general adaptation syndrome," which describes how the body adapts through three phases in response to the stress of training (shock, adaptation, and, without variation in the training stimulus, staleness) [43].
Exercise improves the health of the brain, including increased expression of neurotrophic factors, greater blood flow, altered immune response, increased neurogenesis, and altered metabolism [44]. Such changes may enhance the neuronal circuitry between the basal ganglia and its cortical and thalamic connections, ultimately improving motor, nonmotor, and cognitive behavior in patients with PD [45].
In which phase of PD could PRT be suggested? In six of eight studies [21,22,[27][28][29]31], the reported severity of the disease was mild to moderate; in the remaining two studies [30,32], disease severity was not specified. ese results suggest that progressive resistance exercises can be effective in PD patients who lack comorbidities and severe disability. Additionally, physical activity has been associated with increased survival rates of individuals with PD [46]. In their review, LaStayo et al. emphasized how the two properties that define eccentric muscle contractions, that is, the potential for high muscle strength production at a uniquely low energy cost, should be revisited as exercise countermeasures to muscle atrophy, weakness, and physical functional deficits in chronic diseases such as cardiac and obstructive pulmonary disease, cancer, and neurological conditions [47]. Which exercise protocol should be adopted with respect to PRT? e trials [21,22,[27][28][29][30][31][32] in our study suggest that, on average, 10 weeks of progressive resistance exercises for the upper and lower limbs should be performed two to three times a week. e most frequent upper limb exercises are bicep curl, chest press, triceps extension, and dumbbell side raise. Lower limb exercises are leg press, leg curl, half squat, hip abductors, hip flexors, and lateral step-up [27,28]. During physical therapy, the patient plays a central role, choosing with the therapist which exercises and how many series and repetitions they will perform together. From our analysis, two to three series for each exercise, composed of 8-12 repetitions, is ideal for a patient with mild-to-moderate PD [22,27,28,31,32]. e training session should last from 45 to 90 minutes, including the recovery time. All exercises are performed at 30% of 70% of one RM. e load is increased by 5% to 10% of one RM when the patient is able to perform 10 repetitions at 60% of one RM [29] ( Table 5).
In support of the proposed PRT program, Shu et al. analyzed aerobic exercise for PD conditions, including treadmill training, dancing, walking, and Tai Chi, showing that aerobic exercise has immediate beneficial effects on improving motor action, balance, and gait in patients [48]. Also, Bhalsing et al. highlighted the importance of physical activity prescribed like nonpharmacological therapy to manage the inherent decline that is associated with PD, It is a beneficial, cost-effective, and low-risk intervention that improves the overall health with regard to motor and nonmotor symptoms [12].
A major limitation of these studies is their lack of the duration of recovery times, which is an important training feature. None of the studies dealt with postworkout followup, which could help establish a proper training session. e postworkout follow-up can give important data about the long-term effectiveness of PRT. Moreover, there was no detailed evidence about the value of PRT in fall prevention, given that it is a rehabilitation goal in PD. Further, the data on improved walking performance after PRT are not clear, and practitioners should know how PRT influences gait and balance in various stages of disability between patients [22,27]. Good walking capacity allows the patient to have a minimum level of autonomy. Our analysis suggests that PRT should be a part of the rehabilitation program, in combination with other types of exercise to preserve cardiorespiratory fitness. In summary, these findings demonstrate the effectiveness of progressive training in mild-to-moderate PD. It would be appropriate to find a standard assessment for measuring strength that can lead to homogeneous results. Following a clear rehabilitation program could facilitate comparisons between studies. Further research is needed to clarify this issue and determined whether it could be helpful in the late stages of PD.

Conclusion
PD is a complex disease that can compromise physical performance. Positive evidence for physiotherapy is growing, showing beneficial impact on functional activities that involve gait, transfers, and balance [49]. For the PD patient, exercise has reported benefits for controlling motor and nonmotor symptoms, with the use of pharmacological interventions [50]. is umbrella review also shows that PRT has benefits particularly in the early stages of PD, with lowto-moderate impact training exercises. In general, exercises should be prescribed and encouraged in all PD patients. When an increase in physical activity is recommended, several specific factors should be considered for patients with PD: motor symptoms (bradykinesia, tremor, and dystonia), risk of falls, apathy, fatigue, depression, and cognitive dysfunction. Each of these symptoms can reduce participation and contribute to a more sedentary lifestyle in PD patients [8]. Doctors should encourage and motivate PD patients to exercise regularly from the time of diagnosis and provide guidance with respect to the positive effects of physical exercise for the body and brain. Parkinson's Disease 7