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Parkinson’s disease (PD), a progressive neurodegenerative disorder affecting motor and nonmotor function, is the fastest growing neurodegenerative disorder, having doubled in incidence from 1990 to 2015. In the United States alone, PD will affect more than 1 million people by 2030, and projections estimate another doubling of incidence by 2040, raising further interest in strategies for prevention and treatment. We previously discussed exercise as method of early intervention to help delay the motor symptoms of PD (see Episode #236 of The Drive). However, as a 2022 meta-analysis shows, exercise has utility for PD even after disease emergence, until well into its moderate severity stages.
What is Parkinson’s disease?
PD is associated with degeneration of the dopamine-producing neurons within one of the movement centers of the midbrain, called the substantia nigra pars compacta, which can occur as a result of genetics, environmental toxicant exposure, or other factors. Dopamine-producing neurons within this region are important for both allowing intentional movements and preventing unintentional movements. The loss of these neurons results in the typical motor symptoms associated with PD: tremor, stiffness (called rigidity), slow movement (called bradykinesia), and impaired balance, gait and posture. These neurons are also important for cognition, and loss of dopaminergic influence in the brain can thus impact cognitive function, including decision making and attention processes, as well as mood and sleep. In fact, nonmotor symptoms of PD are very common, and cognitive impairment in particular affects up to 80% of PD individuals.
The standard of care for PD includes dopamine replacement (via levodopa, the precursor to dopamine), dopamine receptor agonists, and other forms of medications and interventions (e.g., deep brain stimulation) that increase dopamine levels in the brain. However, over time, medications for PD become less effective, and escalating doses are needed to achieve symptom control. As the disease progresses, these medications wear off more quickly and can lead to a slew of side effects including the development of dyskinesia (involuntary movements). For this reason, non-pharmacological interventions for PD are of high interest, and exercise in particular appears to be an effective option. Exercise has the ability both to protect the remaining intact dopaminergic neurons, as well as modulate dopamine neurotransmission, and it is therefore in a position to serve not only as a powerful therapy on its own, but also as a complement to other standard-of-care PD practices.
About the study
For their meta-analysis, investigators Zhen and colleagues aggregated randomized controlled trials studying the impact of aerobic exercise on PD symptoms from the last three decades. Studies were eligible for inclusion if they met the following criteria: (i) must be a randomized controlled trial, (ii) must be conducted in PD patients, (iii) must possess both an aerobic exercise and control group, and (iv) must use motor function and/or quality of life assessments as outcome measures. Motor assessments included measures of balance, mobility, gait (walking speed, stride length), and PD motor symptom severity.
After excluding studies that used multiple interventions, the final analysis included 20 studies, from which the authors conducted a pooled analysis to assess the effect of aerobic exercise on any given domain, reporting results as standardized mean differences (SMD). At its most basic level, SMD is a measure of effect size, calculated by dividing a difference in means between groups by a pooled standard deviation to create a summary of the difference between an intervention and control condition. In other words, SMD creates a uniform unit that can be pooled across studies investigating the same outcome, even if those studies vary in cohort sizes and their specific units or instruments of measurement. An SMD of zero, for instance, means there is no difference in effect between an intervention group and a control group, while in most cases, an SMD over zero indicates that an intervention is more effective than control conditions, and an SMD below zero indicates that an intervention is less effective than control conditions, though sometimes these relationships are reversed, depending on the instrument of measurement. Conventionally, an SMD with an absolute value between 0.2 and <0.5 is considered a small effect, between 0.5 and <0.8 is considered a moderate effect, and ≥0.8 is considered a large effect.
The authors observed that aerobic exercise interventions in people with PD improved many measures of motor function relative to control individuals, including: (i) faster timed up-and-go speed (SMD: -0.41, 95% CI: -0.61, -0.22), (ii) improved scores on the berg balance scale, which is particularly important because balance issues are not addressed by PD pharmacotherapy (SMD: 0.99, 95% CI: 0.76, 1.23), (iii) improvements to several components of gait, including longer stride length (SMD: 0.32, 95% CI: 0.03, 0.61), and faster gait velocity (SMD: 0.49, 95% CI: 0.20, 0.78), and (iv) greater distances achieved on the 6-minute walk test (SMD: 0.35, 95% CI: 0.13, 0.56). The authors also reported that aerobic exercise improved PD-related motor symptoms relative to controls according to scores on part III of the Unified Parkinson’s disease rating scale (SMD: -0.40, 95% CI: -0.55, -0.24). This assessment measures the severity of a variety of motor symptoms, including tremor, rigidity, spontaneous movements at rest, and others, and is the most universally used motor rating scale.
Two measures in which the authors reported no impact of aerobic exercise in PD included step cadence (SMD: -0.08, 95% CI: -0.43, 0.27) and quality of life (as measured by the Parkinson’s disease questionnaire-39 (PDQ-39); SMD: -0.13, 95% CI: -0.39, 0.13). However, as the authors note, some weaknesses specific to their PDQ-39 analysis make it hard to draw conclusions on the true impact of aerobic exercise on quality of life in PD.
In particular, only four studies assessed quality of life, just one of which accounted for over 50% of data included in the analysis. This one study may have been unable to capture an impact of exercise on quality of life because their control group was an active control group, making whatever benefit aerobic exercise specifically had on quality of life marginal. That the largest study had no impact on quality of life likely had an outsized impact on the overall lack of an effect of aerobic exercise on PD quality of life. Additionally, it is likely that quality of life changes may take longer to detect than the interventions in some studies. This is supported by the fact that two of the three 24-week interventions did achieve a statistically significant quality of life improvement and that the follow up assessment in the 6-week intervention (conducted six weeks after intervention end or twelve weeks after study start) also showed a statistically significant quality of life improvement, despite the post-intervention assessment not showing a difference.
However, outside of issues with the nonsignificant quality of life findings, this meta-analysis provides a valuable opportunity to highlight why exercise is so important in PD.
The neuroprotective effects of exercise
Beyond its role as a therapeutic for PD-related motor symptoms, exercise appears to delay or prevent disease onset, as epidemiological studies have reported that individuals with the highest levels of physical activity have the lowest future risk for PD. For instance, one study followed 143,325 individuals (mean age: 63 years) over a 9-year period and found that individuals in the highest category of weekly moderate to vigorous physical activity (e.g., jogging, tennis, stationary bike) at baseline had a 40% lower relative risk of developing PD than those not exercising at baseline. A second study extended these findings, showing that in 48,574 men and 77,254 women, the highest levels of strenuous exercise from early adulthood were associated with a 60% and 50%, respectively, PD risk reduction in later life compared to those with the lowest levels.
Though these observational data are almost certainly subject to a degree of healthy user bias, mechanistic animal data indicate that aerobic exercise might support the survival of dopamine neurons, which would support the idea of a causal link and add a degree of certainty that exercise may have specific effects on the disease process underlying PD. This work has shown that aerobic exercise may protect dopamine neurons through a number of mechanisms, including increased brain derived neurotrophic factor (BDNF), decreased oxidative stress, or improved mitochondrial function. This protection would result in improved motor reserve. Though this dopamine neuroprotection has only been directly demonstrated with aerobic exercise, resistance-trained rodents also show higher BDNF and decreased oxidative stress relative to controls, so it is possible that similar benefit may be conferred by other forms of exercise, which have not been studied as rigorously.
Importantly, these benefits confer neuroprotection no matter whether the exercise is applied before or after animals have been induced to develop PD (typically with intracerebral administration of dopamine neuron-directed toxins). Exercise preceding administration of the toxin has been reported to result in a statistically significant reduction in dopamine cell death, while other studies (e.g., Shi et al, da Costa et al., and Tajiri et al.) have shown that exercise following administration of the toxin results in a significantly higher level of dopamine neuron survival, suggesting that exercise can also be neuroprotective even after dopamine cell death has begun. It is important to note, though, that these studies did not allow a long enough period of time for cell death to finish, and therefore do not represent neuro-restoration. Exercise may therefore be helping to protect the remaining cells rather than to restore cells that are already dead.
Though these results have yet to be replicated in human studies due to serious logistical challenges (it’s prohibitively difficult to obtain both post-mortem brain tissue and exercise data on any given individual with PD), it is very possible that given the impact of exercise on slowing the deterioration of several clinical symptoms (including postural and gait instability), a similar mechanism – that of extending the life of remaining neurons – may be in place in people with PD.
The bottom line
Outside of medications and typical clinical care, aerobic exercise is a form of lifestyle intervention that is not prohibitively difficult to integrate in PD and has immense benefits for its symptoms. It improves motor symptoms, but could also enhance quality of life, given the exercise is of sufficiently high intensity and implemented for a sufficiently long period of time. For individuals with mild or moderate PD, aerobic exercise of even moderate or high intensity is safe and well tolerated. Those with more severe disease may still reap the benefits of aerobic exercise but should employ supervision or close monitoring during exercise to prevent injury. Other forms of exercise, including strength training and stability exercises, are also important in PD, but were not addressed in the present study.
Yet even beyond the effectiveness of exercise in treating symptoms of PD, this intervention also has utility as a neuroprotective strategy that could reduce the risk of developing PD, as well as extending the lifespan of remaining dopamine neurons that are vulnerable to degeneration even after disease onset. Further evidence that exercise is the ultimate panacea – and one that is accessible to everyone.
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