Physical exercise for treating non-motor symptoms assessed by general Parkinson’s disease scales: systematic review and meta-analysis of clinical trials

Introduction

Parkinson’s disease (PD) is typically linked to movement deficits that result from dopamine insufficiency in the substantia nigra pars compacta. However, non-motor symptoms (NMS) have recently drawn increasing attention. They result from dopaminergic impairment and other neurotransmitter systems such as the P substance, acetylcholine, serotonin and norepinephrine. They can also be caused by disordered protein aggregation of Lewy bodies in several parts of the nervous system or by the secondary effects of motor compromise.1 These two facts make these symptoms even more relevant. First, some symptoms, such as hyposmia, REM sleep disorder, constipation and depression, may manifest many years before the motor symptoms.2 Second, at a later stage of the disease, NMS are the main sources of the functional decline observed in patients.1 2 Therefore, it is crucial to understand the clinical non-motor picture to develop diagnostic and early intervention strategies. This would lead to better clinical and functional management as well as an increase in the quality of life of patients at the early stages of the disease.3

Dysfunctions of the central and peripheral nervous systems and other organic systems vary in the intensity and sequence of manifestation.1 As a result, the pharmacological approach to these dysfunctions is still limited, leaving an important gap in the global treatment of people with PD, since the dopamine precursors and agonists that are currently used have little or no effect on NMS.3

A non-pharmacological strategy broadly known as beneficial to improve the motor function and, to some extent, the NMS in PD is the utilisation of physical exercises and their different modalities.4 5 Exercise is defined as a type of physical activity that consists of planned, structured and repetitive bodily movement done to improve and/or maintain one or more components of physical fitness, which can be health—or skill-related.6

Although the most effective exercise modalities and better prescription strategies are yet to be investigated scientifically, it is accepted that physical exercise plays an important role in the maintenance of functionality and quality of life of patients with PD.7 In particular, aerobic and resistance exercises are modalities that activate physiological mechanisms, such as the relief of certain hormones, neurotransmitters and cytokines locally and further in the blood chain and thereby in the central nervous system, generating changes at the muscular and central level.8 9

Given the systemic effect of physical exercise and its potential use as a symptomatic intervention in PD, it is important to understand the effects of these exercises (and the different modalities) on the NMS of PD. Some reviews have already highlighted this question.4 However, because of the diversity of NMS and the fact that many of them were not considered as primary outcomes in previous studies, systematic reviews that amplify the search to embody evidence from primary and secondary non-motor outcomes may contribute to a clearer picture of the current evidence surrounding the use of physical exercise as an intervention for those symptoms.

NMS are measured clinically through validated scales, such as Part I of the Unified Parkinson’s Disease Rating Scale (UPDRS I) and the Non-Motor Symptoms Scale for Parkinson’s Disease (NMSS). These scales measure the presence and severity of a wide range of problems at all stages of PD, although they do not differentiate the nature of these symptoms, that is, whether they are direct results of PD only, but their impact on the disease.4 They give a common score that can be used to evaluate the progress of NMS as well as their improvement, resulting from therapies. Thus, our aim was to verify the effects of physical exercise on the NMS of PD, as assessed by validated general symptom scales.

Methods

A systematic review approach and meta-analysis were performed and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Additionally, we assessed the methodological quality of the included studies. This review does not include a registered protocol.

Results

The database searches returned 886 papers. After the application of the eligibility criteria, 23 papers were finally included, and the data were extracted for descriptive analysis. Figure 1 shows the procedures and results of the systematic search in detail, including the number of papers not included, excluded and the respective reasons for that. Table 1 presents the characteristics of the studies included in this systematic review.13–35

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Given the heterogeneity of the interventions in the studies and to facilitate our understanding, we classified them into categories according to their main characteristics. The categories were as follows: ‘multimodal exercise’ (at least three modalities together), ‘aerobic training’ (continuous activities like biking, cycling or walking), ‘resistance exercise’ (progressive muscle strengthening exercises), ‘dance’ (individual, peered, group, multitype), ‘conventional physical therapy (PT) exercise’ (varied forms of mobility, stretching, positioning, active range of motion, monoarticular or polyarticular, low-moderate intensity, facilitation techniques and other passive techniques conventionally used) and ‘other forms of exercise’ (those that were not classified in the previous categories).

For multimodal exercises, three out of four studies showed no differences in comparison to control interventions,13 15 32 whereas one study did not compare groups, only reporting that the intervention group improved, while the control group worsened.19 For aerobic training (five studies), one study favoured Nordic walking over conventional care,30 while no differences were found over a conventional walking programme.14 Two studies reported no differences between aerobic training (treadmill and cycle-ergometer) and either usual routine or conventional motor rehabilitation.21 29 One study compared regimens of body weight-supported treadmill training and found no differences between them.22 Only one study reported results on resistance training,24 but it did not compare between groups for the relevant outcome, reporting that the resistance training group improved to the same level as the usual routine group (no exercise).

For dance, three studies compared, respectively, multitype, Qi dance and Tango with control (no exercise) and found no differences.23 25 34 However, one of them did not show statistical comparisons, reporting that the scores in the dance group were lower, indicating an improvement in UPDRS I.23 For conventional PT, one study favoured it over no intervention,33 while two studies reported that intensive conventional PT and theatre workshop classes were better for reducing NMS scores than conventional PT only. Additionally, conventional PT showed no difference compared with the Lee Silverman Voice Treatment exercises.16 35

Finally, other forms of exercise have been reported. In general, studies have reported no differences between Qi Gong and Hatha Yoga over sham or no intervention.20 31 Comparative studies have reported that land-based exercises are better than aquatic Ai Chi,28 and that there are no differences between individual Tai Chi and in-group practice.26 One study reported that the Kinesiology method was better than conventional rehabilitation therapy exercises; however, it did not show between-group comparisons, reporting that only the Kinesiology group improved at follow-up.18 No differences were found between exercises using the Mèziere method and home posture/mobility training.27

The majority of those studies used the UPDRS I as the instrument for outcome measurement, whereas only very few studies used the NMSS.14 16 26 30 The results of the methodological assessments are presented in table 2. Five of the 23 papers were rated as low-quality/high-risk of bias (ie, below 5 out of 10 on the PEDro scale). Two were rated with 3/10,31 33 and three with 4/10.15 23 30 The main items not met in these studies were items 5 and 6, as expected for exercise interventions (blinding of subjects and therapists), and items 7–9 (blinded assessors, adequate follow-up and intention-to-treat analysis).

Meta-analyses results

For our main analysis, four studies met the criteria comprising 159 participants with H&Y 1–3.13 25 29 33 They compared exercise interventions with non-exercise/usual routine controls (for 8–16 weeks). In total, four out of eight were excluded from the analysis due to: (1) data not extractable or available24 31 34 and (2) low-dose intervention.23 Difference was not found between exercise and control for NMS general-scale outcome, with a pooled small effect size of −0.26 (95% CI −0.58 to 0.05), I² = 0%. A trend favouring the exercise group is shown (figure 2A), with only a small arm of the CI indicating no effects on the outcome. On the other hand, one of the studies was rated as a high risk of bias (see table 2).33 A sensibility analysis (study exclusion) showed that this study had a relevant impact (44%) on the result, although the same pattern observed before was maintained (−0.20, 95% CI −0.62 to 0.22).

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Figure 2

Meta-analyses showing the pooled effects sizes of (A) exercise compared with no exercise/usual routine, (B) multimodal exercise with cognitive/leisure interventions and (C) aerobic exercise with conventional rehabilitation exercises for the NMS outcome assessed by general PD rating scales. NMS, non-motor symptoms; PD, Parkinson’s disease.

Two additional analyses were done, comparing multimodal exercise (for 8–16 weeks) with non-exercise leisure/cognitive interventions (two studies, n=128, H&Y 1–3),15 32 and aerobic exercise (for 12–16 weeks) with conventional non-aerobic exercises (stretching-balance, motor rehabilitation) (two studies, n=40, H&Y 1–3).29 30 For the first comparison, no difference was found between conditions with a pooled effect size of 0.21 (95% CI −0.14 to 0.55), I²=0% (figure 2B). The effect observed varied between an insignificant effect at the exercise arm and a moderate effect at the cognitive/leisure interventions, a pattern that is also observed within studies, sometimes reaching large effects in favour of the last. However, one of these studies was rated as having a high risk of bias (see table 2).15

For the second analysis, a significant difference was found between conditions with a near-large pooled effect size of −0.72 (95% CI −1.36 to −0.08), I²=0% (figure 2C). The data showed a common effect with low heterogeneity, indicating that the effect of aerobic exercise is small for some people but reaches large and very large effects for others, but is always superior to conventional exercise. Notably, one of these studies was rated as having a high risk of bias (see table 2).30

Discussion

The assessment of NMS has been part of the PD rating scales, especially the most used UPDRS and NMSS. They give a gross measure of general manifestations of NMS. The UPDRS I is a 13-item subscale measuring a range of several symptoms and their impact on individuals’ daily living. Similarly, the NMSS is a 30-item rater-based scale that covers a similar range of symptoms. They are validated instruments that reflect the current frequency and severity of NMS in PD and can be used to measure the effect of different therapies.36 Since more emphasis has been placed on these symptoms, our aim was to systematically review the literature and synthesise evidence from clinical trials on the use of exercise interventions for treatment. We found a considerable number of papers that used general scales as primary or secondary outcome measures, mostly within the last 10 years. However, given the heterogeneity of interventions, exercise modalities, variations in intervention duration, frequency and timeframe, few studies could be grouped for meta-analysis. We identified six main modalities of physical exercise, classified as multimodal, aerobic, conventional PT, dance and other types (that varied from mind-body exercises to very specific techniques). These interventions frequently presented ambiguous results throughout the studies, warranting increased attention from exercise scientists.

Our main meta-analysis showed no differences between exercise and non-exercise/usual routines. Caution should be taken when interpreting this finding as an undoubtable trend was observed in the data, which was maintained after sensibility analysis. The effect observed was small, yet it showed a CI that indicates that the true effect could vary from null to moderate. Further studies are strongly recommended to investigate the effect of exercise on this outcome. Accumulated evidence has demonstrated the effect of physical activity on motor function and NMS in PD, although the most effective modalities are yet to be demonstrated.37 Large-sample and good-quality studies may confer sufficient statistical power to reveal the true effect. The general scales for NMS usually assess a diverse array of symptoms that can vary substantially between individuals.

Our secondary meta-analysis showed no difference between multimodal exercises and approaches based on cognitive and leisure activities. Again, a trend was observed in the data showing that these interventions may have a greater effect on general NMS than multimodal exercises. Accordingly, previous studies have suggested that cognitive-stimulating interventions have the potential to reduce many NMS, such as cognitive impairment, apathy, depression, anxiety, among others.38

On the other hand, a near-large effect size was found favouring aerobic training against more conventional forms of exercise. One frequent physiological effect of this modality is the systemic effect of neurotransmitter release and neuroendocrine system regulation,8 9 which may account for the positive impact on some NMS, like reduction of sleep disturbance, cognitive loss, anxiety and depression, cardiovascular and gastrointestinal dysfunction, among others, that is likely less emphasised by general or conventional exercise approaches.39 Our findings must be interpreted with some caution due to the methodological limitations of the studies (small size, low quality). Therefore, the superiority of aerobic training over other modalities must be further investigated for overall NMS and targeting-specific symptoms.

No studies investigating resistance training, conventional PT or dance met the criteria for the meta-analysis. However, from this systematic review, we can see that the results are inconclusive for the overall NMS score; hence, further investigation is required.

This systematic review and meta-analysis have some limitations. First, only randomised controlled trials were included, which means that non-randomised trials with likely favourable results to exercise interventions were not considered, and consequently, an evidence hierarchy could not be built, and some modalities of exercise may have been left out. However, by not including those studies, we ensured higher quality evidence. Second, some studies may have not been reached for being indexed in other databases, which was actually minimised because we adopted the main databases for indexation of health sciences studies. Third, health-related quality of life was not considered. This is because, from our understanding, it is not a function (or dysfunction), but a generic construct that reflects more than just the consequence of disease, being better gathered and discussed if addressed under specific considerations. Therefore, we did not include the results of studies that used quality of life questionnaires as outcome measures, which may have assessed in their subdomain aspects such as anxiety, emotion, pain ancognition, among other NMS.

Due to the small number of studies included in the meta-analyses, we opted not to show dispersion intervals and funnel plots for publication bias and did not perform further assessment of confidence on cumulative evidence and strength of recommendations. Future research targeting general scales for NMS as primary or secondary outcomes should focus on appropriate study design (especially power), methodological quality to avoid bias and standardisation of reporting interventions and controls (so they can be compared in the future). Finally, researchers must make more available and transparent raw data sets to enable the development of more accurate and concise syntheses of evidence.

Conclusion

Our findings indicate that exercise interventions may have an effect compared with non-exercise interventions in treating NMS of PD, as assessed by gross-symptom scales. However, further investigation is necessary for this outcome, as it seems that the power of the studies was insufficient to detect differences. Multimodal exercise was not better than cognitive approaches. A trend was observed in favour of the control intervention. Aerobic modalities show promise as effective strategies for managing general NMS with a moderate-to-large effect size in comparison to more conventional approaches. Further investigation through primary and synthetic studies is warranted to ascertain the optimal interventions for specific symptoms, thereby providing clearer guidance on the most effective modalities.