IMPRESSIVE BENEFITS: Exercise as a Treatment for Parkinson's Disease

Jonathan Artz, MD

Despite intensive research and ongoing clinical trials, there is still no effective cure for the two most common neurodegenerative diseases: Alzheimer’s disease (AD) and Parkinson’s disease (PD). For the last decade, clinicians have prescribed acetylcholinesterase inhibitors to ameliorate and temporize the cognitive, behavioral and memory-related deficits of these diseases, yet these medications have not been shown to either delay the underlying neurodegenerative process or prevent brain decay.

Neurologists prescribe dopamine-modulating compounds—such as carbidopa/levodopa, dopamine agonists and monoamine oxidase inhibitors (MAOIs)—to enhance motor system activity in the extrapyramidal pathways and alleviate features such as tremor, bradykinesia, rigidity and, to a much lesser extent, postural instability. Some questionable and hotly debated data suggest that the MAOI Azilect may “protect” against declining motor functioning in patients with PD, yet the drug does not prevent or treat the underlying neurodegenerative process. There is, however, evidence that a supplemental exercise regimen can improve walking and transferring abilities and reduce the risk of falls, even as the primary neurodegenerative process continues.

The benefits of exercise are impressive. Animal studies have found that it can help with learning and memory¹ and may enhance neurogenesis.^2–5 Sustained exercise may facilitate axonal transport of acetylcholinesterase and other proteins;⁶ it may even alter the antioxidant status of the brain under certain circumstances.⁷  

Exercise may induce dopamine release and enhance dopamine transmission via upregulation of DA-D2 receptors.^8,9 A systematic review on the effects of exercise in the elderly showed that moderate-intensity exercise can effectively increase peripheral brain-derived neurotrophic factor (BDNF). Serum BDNF crosses the blood-brain barrier, so these results may have implications for brain neurotrophin levels.¹⁰ One animal study found that exercise increased BDNF in the brain’s striatum.¹¹ A recent review on the benefit of exercise to improve cognition emphasized the potential neuroprotective effects of vigorous exercise in PD.¹²

Even with all our knowledge about exercise, there is still no agreement concerning the optimal exercise intensity or prescription strategy for patients suffering from AD or PD. Basic guidelines for an exercise regimen for PD patients include vigorous exercise in patients who are capable, as well as a structured program for cognitively impaired patients.¹² There is now a national movement in the Parkinson’s community to encourage exercise, given its benefits for mobility and cognitive function. Importantly, the effects of vigorous exercise can last up to 60 days.^13,14 Studies have found a high retention rate for PD patients committing to a 2–3 times per week exercise program, suggesting that these interventions could be implemented as a treatment strategy.

A recent meta-analysis showed that very light to vigorous exercise seems to have a small effect on cognition in the acute phase following exercise, but that larger and longer-lasting effects are possible with more intense exercise.¹⁵ Preclinical studies have shown that exercise results in behavioral and corresponding neurobiological changes in the basal ganglia related to cognition. Specifically, learning and memory improved after exercise in rodents, although the exact mechanisms remain unclear.

Other preclinical studies have shown that any exercise is better than inactivity and that forced exercise has a greater impact than self-paced voluntary exercise. Clinical studies have shown that various types of exercise—including aerobic, resistance and dance—can improve cognitive function, especially executive function, in PD patients. Nonetheless, the “best” type, amount, mechanisms and duration of exercise are still unknown. The evidence from clinical studies suggests that a more intensive aerobic exercise program, including strength and balance training, can promote greater cognitive gains; but low-intensity exercise and balance-based exercises also showed benefits.  

The benefits of exercise to human brain tissue and its cognitive functions are voluminous, and have been thoroughly reviewed.^1,16,17 In AD patients, recent trials have shown that exercise can help slow disease progression both directly and indirectly.^18-20 It is postulated that exercise could help to clear amyloid-beta peptide (main pathological driver) in AD patients.²¹ Exercise-induced nerve growth factor production could prevent the death of cholinergic neurons and perhaps attenuate cognitive decline.²²

Cognitive dysfunction in PD is commonly associated with impaired executive function. However, evaluating research on executive function in PD is challenging because mild cognitive impairment in PD has only recently been defined, and formal diagnostic criteria are still being developed.²³

Selecting and interpreting measures of executive function in PD is equally challenging, and the clinical implications are not yet fully appreciated.²⁴  

Executive function is generally related to goal-directed behaviors processed by the frontal lobes of the brain. The function has four components: planning, purposive action, effective performance and volition.²⁵ The most effective frequency, intensity, type or timing of exercise needed to improve executive function in PD is unknown. There is, however, evidence in older adults without PD that light aerobic exercise (walking)—but not anaerobic exercise (stretching and toning)—selectively improves executive functions processed in the frontal and prefrontal areas of the brain.²⁶ The effects of aerobic and anaerobic exercise on cognition in PD have not yet been studied. 

Muscular strength is reduced in Parkinson’s patients, but the cause of the decrease is unclear.^27,28 Central mechanisms may be responsible because of the reduction of facilitative stimulus of motor neurons.²⁹ Patients with PD often complain of weakness in their lower limbs; clinically, researchers have observed an inability of proximal and axial muscles to generate adequate power, especially the extensors of the trunk and hip. The ability of PD patients to perform various functional activities, such as sitting to standing and walking, can be compromised due to muscle weakness in the lower limbs.³⁰

One study found that strength training programs are effective in increasing muscular strength and, in some cases, mobility of patients with PD.³¹ The study programs were implemented in a short period of time with a training frequency of 2–3 times per week. They included one set of exercises per muscle group and involved only concentric contraction. A later study showed that functional gains and muscular strength are greater with high-intensity protocols that primarily involve eccentric contraction.³² The principle of this type of exercise is that high levels of force are generated during muscle stretching, with minimal oxygen consumption in relation to the amount of work produced.³³

Some studies have found that high-intensity strength training is better for motor and functional performance in patients with PD than training based on flexibility exercises, balance and concentric strength training of limbs.³² High-intensity training can minimize loss in bone integrity, preserve eccentric muscular strength and promote structural plasticity in the musculoskeletal system.³⁴ Thus, it is reasonable to believe that high-intensity exercises are most desirable to minimize the progressive dysfunction of PD.  

About five years ago, researchers developed an exercise program with the goal of delaying progressive loss of mobility associated with balance and gait disorders in patients with PD.³⁵ Movements using Tai Chi, Pilates and other methods were combined in order to facilitate sensory integration in postural control. Somatosensory information was encouraged by large, coordinated movements in order to move the center of mass with speed, safety and balance.35 A further study showed that PD patients who practiced Tai Chi for 13 weeks achieved gains in balance and functional performance when compared to a control group without intervention.³⁶ The authors concluded that Tai Chi can be a safe and beneficial exercise for treating moderately to severely affected PD patients.

Physical disability in PD is often related to gait impairment and transferring from a sitting to a standing position. Ambulation and transfer problems are considered the most disabling aspects of the motor features of PD. Gait-related mobility problems in particular have a negative impact on the quality of life and well-being of patients with PD.³⁷

Several physical therapy studies have emphasized the value of specific exercises and intervention strategies to improve gait in PD patients. Two studies found that treadmill training can promote a more stable and dynamic gait pattern, and the authors suggested that treadmill training is more effective in improving gait than other traditional approaches.^38,39 Training on a treadmill can be seen as a kind of external cue to trigger the motor activity to be performed.⁴⁰ Long-term treadmill training without weight bearing is a safe and economical method to increase gait speed, restore gait rhythm and improve quality of life for PD patients; these effects can last for several weeks after the end of training.⁴¹  

In PD patients, exercise may alter the course of the disease.^16,34,42,43 Exercise can also improve postural stability, balance and tremor, and it can help overcome musculoskeletal deficiencies.^34,44,45 It could also possibly alleviate the depression or negative mood often associated with PD.⁴⁶ In addition, exercise-induced growth hormone changes may play a role in promoting neuroregeneration by increasing neural stem cells.⁴⁷

The benefits of exercise on cognition in PD are comparable to those seen in healthy older adults. A recent review showed that endurance and resistance exercise can improve cognition in healthy seniors.⁴⁸ There is less research on the effects of exercise in frail older adults, but recent evidence showed that a three-month physical activity intervention improved physical abilities, executive functions, processing speed and working memory.⁴⁹ The effects in older adults with mild cognitive impairment are less promising: a recent meta-analysis showed that exercise had only limited potential to improve cognition in this population.⁵⁰ Whether cognition in PD is improved due to dopaminergic mechanisms of exercise or other mechanisms—such as increased neurotrophic factor availability or reduced neuro-inflammation—remains to be determined.  

Questions remain regarding the optimal prescription of exercise. Understanding the mechanism of benefit from exercise could help us harness its potential as a viable neuroprotectant. In any case, the findings discussed above provide further rationale for asking patients to increase their daily physical activity, whether that be riding a bike, swimming, walking, jogging, dancing or doing yoga and Tai Chi. With growing support for exercise to improve not only the motor symptoms of PD, but also its cognitive and mood-related impairments, health care providers and health systems should promote and recommend exercise as part of routine management and neurorehabilitation for this disease.

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Dr. Artz is a neurologist at Kaiser San Rafael.
Email: jonathan.artz@kp.org

References
1. Winter B, et al, “High impact running improves learning,” Neurobiol Learn Mem, 87:597-609 (2007).  
2. Aberg E, et al, “Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus,” Hippocampus, 18:785-792 (2008).  
3. Naylor A, et al, “Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain,” Proc Nat Acad Sci, 105:14632-37 (2008).  
4. Van Praag H, et al, “Neurogenesis and exercise,” Neuromolecular Med, 10:128-140 (2008).  
5. Wu C, et al, “Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice,” J Appl Physiol, 105:1585-94 (2008).  
6. Jasmine B, et al, “Fast axonal transport of labeled proteins in motoneurons of exercise-trained rats,” Am J Physiol, 255:C731-736 (1988).  
7. Ozkaya Y, et al, “Effect of exercise on brain antioxidant status of diabetic rats,” Diabetes Metab, 28:377-384 (2002).  
8. Petzinger GM, et al, “Effect of treadmill exercise on dopaminergic transmission,” J Neuroscience, 27:5291-5300 (2007).  
9. Vuckovic MG, et al, “Exercise elevates dopamine D2 receptor in a mouse model of PD,” Mov Disord, 25:2777-84 (2010).  
10. Sartorius A, et al, “Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats,” Pharmacopsychiatry, 42:270-276 (2009).  
11. Tajiri N, et al, “Exercise exerts neuroprotective effects on PD model of rats,” Brain Res, 1310:200-207 (2010).  
12. Ahlskog J, “Does vigorous exercise have a neuroprotectant effect in PD?” Neurology, 77:288-294 (2011).  
13. Dos Santos Mendes FA, et al, “Motor learning, retention and transfer after virtual reality based training in PD,” Physiotherapy, 98:217-223 (2012).  
14. Mckee KE, et al, “Effects of adapted tango on spatial cognition and disease severity in PD,” J Motor Behav, 45:519-529 (2013).  
15. Chang YK, et al, “Effects of acute exercise on cognitive performance,” Brain Res, 1453:87-101 (2012).  
16. Dishman RK, et al, “Neurobiology of exercise,” Obesity, 14:345-356 (2006).   
17. Ang ET, et al, “Potential therapeutic effects of exercise to the brain,” Curr Med Chem, 14:2564-71 (2007).  
18. Rolland Y, et al, “Physical activity and Alzheimer’s disease,” J Am Med Dir Assoc, 9:390-405 (2008).  
19. Rolland Y, et al, “Exercise program for nursing home residents with Alzheimer’s disease,” J Am Geriat Soc, 55:158-165 (2007).  
20. Lautenschlager NT, et al, “Effect of physical therapy on cognitive function in older adults at risk for Alzheimer disease,” JAMA, 300:1027-37 (2008).  
21. Bates KA, et al, “Clearance mechanisms of Alzheimer’s amyloid-beta peptide,” Mol Psych, 14:469-486 (2008).  
22. Scott SA, et al, “Nerve growth factor and Alzheimer’s disease,” Rev Neuroscience, 5:179-211 (1994).  
23. Litvan I, et al, “Diagnostic criteria for mild cognitive impairment in PD,” Mov Disord, 27:349-356 (2012).  
24. Kudlicka A, et al, “PD,” Mov Disord, 26:2305-2315 (2011).  
25. Lezak MD, Neuropsychological Assessment, Oxford Univ Press (1995).  
26. Kramer AF, et al, “Aging, fitness and neurocognitive function,” Nature, 400:418-419 (1999).  
27. Inkster LM, et al, “Leg muscle strength is reduced in PD,” Mov Disorders, 18:157-162 (2003).  
28. Allen NE, et al, “Bradykinesia, muscle weakness and reduced muscle power in PD,” Mov Disorders, 24:1344-51 (2009).   
29. Glendinning DS, “Rationale for strength training in patients in PD,” Neuro Rep, 21:132-135 (1997).  
30. Schiling BK, et al, “Impaired leg extensor strength in individuals with PD,” Parkinsonism & Rel Mov Disorders, 15:776-780 (2009).  
31. Scandalis TA, et al, “Resistance training and gait in patients with PD,” Am J Physical Med & Rehab, 80:38-43 (2001).  
32. Dibble LE, et al, “High intensity eccentric resistance training decreases bradykinesia,” Parkinsonism & Rel Mov Disorders, 15:752-757 (2009).  
33. Lastayo PC, et al, “Chronic eccentric exercises improvement in muscle strength can occur with little demand for oxygen,” Am J Physiology, 276:R611-615 (1999).  
34. Falvo MJ, et al, “PD and resistive exercise,” Mov Disorders, 23:1-11 (2008).  
35. King LA, et al, “Delaying mobility disability in people with PD,” Phys Ther, 89:1-10 (2009).   
36. Hackney ME, et al, “Tai Chi improves balance and mobility in people with PD,” Gait & Posture, 28:456-460 (2009).  
37. De Boar AG, et al, “Quality of life in patients with PD,” J Neurolog Neurosurg & Psych, 61:70-74 (1996).  
38. Miyai, et al, “Treadmill training with body weight support,” Arch Phys Med Rehab, 81:849-852 (2000).  
39. Miyai, et al, “Long-term effect of body weight-supported treadmill training in PD,” Arch Phys Med Rehab,  83:1370-73 (2002).  
40. Frenkel-Toledo, et al, “Effect of gait speed on gait rhythmicity in PD,” J Neuroengin & Rehab, 31:2-23 (2005).  
41. Herman T, et al, “Six weeks of intensive treadmill training improves gait and quality of life in patients with PD,” Arch Phys Med Rehab, 88:1154-58 (2007).  
42. Crizzle, et al, “Is physical exercise beneficial for persons with PD?” Clin J Sport Med, 16:422-425 (2006).  
43. Goodwin VA, et al, “Effectiveness of exercise interventions for people with PD,” Mov Disorders, 23:631-640 (2008).  
44. Dibble LE, et al, “Effects of exercise on balance in persons with PD,” J Neuro Phys Ther, 33:14-26 (2009).  
45. Schalow G, et al, “Integrative reorganization mechanism for reducing tremor in PD patients,” Electromyogr Clin Neurophys, 45:407-415 (2005).  
46. Peluso MA, et al, “Physical activity and mental health,” Clinics, 60:61-70 (2005).  
47. Blackmore DG, et al, “Exercise increases neural stem cell number in a growth hormone-dependent manner,” Stem Cells, 27:2044-52 (2009).  
48. Muller T, et al, “Cysteine elevation in levodopa-treated patients with PD,” Mov Disorder, 24:929-932 (2009).  
49. Langois, et al, “Benefits of physical exercise training on cognition and quality of life in frail old adults,” J Gerontol, 68:400-404 (2013).  
50. Gates, et al, “Effects of exercise training on cognitive function in older adults with mild cognitive impairment,” Am J Geriat Psych, 21:1086-97 (2013).