Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease

We thank Dr. Grippe and colleagues for the constructive comment on our article.¹ Along with highlighting important references,^2,3 they reasonably urged caution in the interpretation of our results based on the inherent limitation of observational studies that "reverse causation" cannot be ruled out. These authors also note concern for the use of the Physical Activity Scale for the Elderly questionnaire to quantify regular physical activity and exercise habits. We fully agree with these points.

We believe that the only way to overcome these two limitations is to conduct a well-designed intervention trial combined with objective monitoring of exercise intensity. Although our study only examined association, we believe it provides important indications of the importance of maintaining physical activity, and the possibility that different physical activities may be beneficial for different clinical symptoms. We hope that the results of our study will help guide future trials to place emphasis on continuous exercise, which is possible now that internet-based applications are developed and widespread,^4,5 as well as the differential effects of exercise.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease. Neurology. 2022;98(8):e859-e871. doi:10.1212/WNL.0000000000013218
2. van Nimwegen M, Speelman AD, Hofman-van Rossum EJ, et al. Physical inactivity in Parkinson's disease. J Neurol. 2011;258(12):2214-2221. doi:10.1007/s00415-011-6097-7
3. Mantri S, Wood S, Duda JE, Morley JF. Comparing self-reported and objective monitoring of physical activity in Parkinson disease. Parkinsonism Relat Disord. 2019;67:56-59. doi:10.1016/j.parkreldis.2019.09.004
4. Ellis TD, Cavanaugh JT, DeAngelis T, et al. Comparative Effectiveness of mHealth-Supported Exercise Compared With Exercise Alone for People With Parkinson Disease: Randomized Controlled Pilot Study. Phys Ther. 2019;99(2):203-216. doi:10.1093/ptj/pzy131
5. van der Kolk NM, de Vries NM, Kessels RPC, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(11):998-1008. doi:10.1016/S1474-4422(19)30285-6

We thank Dr. Gupta for the comment on our article,¹ which requested further elucidation of the biological basis of the effect of exercise, especially in relation to α-synuclein toxicity.² The comment also highlighted the importance of motivation for continued engagement in physical activities.
The results of our study support the long-term effects of exercise, although the possibility of reverse causality cannot be denied. Whether these effects are "symptomatic" or "disease-modifying" warrants further studies in future. In this respect, further clinical trials with a delayed-start design, imaging studies exploring changes in the brain network after exercise, and animal studies exploring the effect of exercise on disease-relevant changes in Parkinson disease (PD) including α-synuclein pathology are important.^3-5

In addition, we believe that future research should clarify the impact of different motivations for exercise in the course of PD and strategies to support long-term motivation of PD patients; for example, through remote supervision using mobile applications. We hope that further research in this direction will eventually lead to the establishment of strategies that enable PD patients to live better lives through physical activity and exercise.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease [published online ahead of print, 2022 Jan 12]. Neurology. 2022;10.1212/WNL.0000000000013218.
2. Tsukita K, Sakamaki-Tsukita H, Tanaka K, Suenaga T, Takahashi R. Value of in vivo α-synuclein deposits in Parkinson's disease: A systematic review and meta-analysis. Mov Disord. 2019;34(10):1452-1463. doi:10.1002/mds.27794
3. Rascol O. "Disease-modification" trials in Parkinson disease: target populations, endpoints and study design. Neurology. 2009;72(7 Suppl):S51-S58. doi:10.1212/WNL.0b013e318199049e
4. Mak MK, Wong-Yu IS, Shen X, Chung CL. Long-term effects of exercise and physical therapy in people with Parkinson disease. Nat Rev Neurol. 2017;13(11):689-703. doi:10.1038/nrneurol.2017.128
5. Espay AJ, Kalia LV, Gan-Or Z, et al. Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?. Neurology. 2020;94(11):481-494. doi:10.1212/WNL.0000000000009107

We thank Darweesh et al. for their comment on our article.¹ Due to the observational nature of our study, the possibility of reverse causality or that it reflects a symptomatic effect cannot be denied. However, in light of the recent highlighted evidence,² it is quite possible that the results demonstrate the disease-modifying effects of physical activities. In addition to our study, a recent study showed that exercise may change the brain network to some extent, thus providing additional support for the possible disease-modifying effects of exercise and physical activities.³

We hope that this study will motivate patients with Parkinson's disease to keep engaging in physical activities and inspire future randomized clinical trials (RCTs) to focus on sustained exercise, for example, via remote supervision.^2,4 We also hope that in the future those RCTs will include many ethnic groups through international multi-center studies,⁵ and a way to modify the pathogenesis of PD and delay its onset through exercise and physical activities will eventually be found for PD patients and "prodromal" subjects all over the world.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease [published online ahead of print, 2022 Jan 12]. Neurology. 2022;10.1212/WNL.0000000000013218.
2. de Vries NM, Darweesh SKL, Bloem BR. Citius, Fortius, Altius-Understanding Which Components Drive Exercise Benefits in Parkinson Disease. JAMA Neurol. 2021;78(12):1443-1445. doi:10.1001/jamaneurol.2021.3744
3. Johansson ME, Cameron IGM, Van der Kolk NM, et al. Aerobic Exercise Alters Brain Function and Structure in Parkinson's Disease: A Randomized Controlled Trial. Ann Neurol. 2022;91(2):203-216. doi:10.1002/ana.26291
4. van der Kolk NM, de Vries NM, Kessels RPC, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(11):998-1008. doi:10.1016/S1474-4422(19)30285-6
5. Lau YH, Podlewska A, Ocloo J, et al. Does Ethnicity Influence Recruitment into Clinical Trials of Parkinson's Disease? [published online ahead of print, 2022 Jan 21]. J Parkinsons Dis. 2022;10.3233/JPD-213113. doi:10.3233/JPD-213113

Dr. Tsukita and colleagues’ PPMI database analysis reports the effects of physical activity on the progression of PD clinical parameters, measured using the Physical Activity Scale for the Elderly (PASE). It confirms prior studies showing that regular exercise is associated with improved outcomes.² Although the study uses rigorous statistical methods, the reported association between maintained physical activity and concurrent slower deterioration of postural and gait stability should be interpreted carefully.

The authors emphasize the mechanisms by which exercise may improve outcomes; the title implies causation. However, impaired postural and gait stability are well known to affect physical activity in PD.³ Many of the activities listed in the PASE require good balance. Thus, postural and gait impairments could be responsible for reducing exercise. We believe this reverse causation is a critical factor to consider before assuming that the reduced rate of posture and gait deterioration is a direct effect of the amount and regularity of the exercise performed.

Additionally, the PASE questionnaire, based on a 1-week recall, is limited by lower reliability than questionnaires with longer timeframes and only moderate correlation with objective activity monitoring in people with PD.^4,5 Psychometrically strong, clinical measures of physical activity are needed.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease [published online ahead of print, 2022 Jan 12]. Neurology. 2022;10.1212/WNL.0000000000013218.
2. Rafferty MR, Schmidt PN, Luo ST, et al. Regular Exercise, Quality of Life, and Mobility in Parkinson's Disease: A Longitudinal Analysis of National Parkinson Foundation Quality Improvement Initiative Data. J Parkinsons Dis. 2017;7(1):193-202. doi:10.3233/JPD-160912
3. van Nimwegen M, Speelman AD, Hofman-van Rossum EJ, et al. Physical inactivity in Parkinson's disease. J Neurol. 2011;258(12):2214-2221. doi:10.1007/s00415-011-6097-7
4. Ånfors S, Kammerlind AS, Nilsson MH. Test-retest reliability of physical activity questionnaires in Parkinson's disease. BMC Neurol. 2021;21(1):399. Published 2021 Oct 15. doi:10.1186/s12883-021-02426-y
5. Mantri S, Wood S, Duda JE, Morley JF. Comparing self-reported and objective monitoring of physical activity in Parkinson disease. Parkinsonism Relat Disord. 2019;67:56-59. doi:10.1016/j.parkreldis.2019.09.004

Tsukita et al. emphasize the value of regular physical activity and exercise habits for improving the clinical course of Parkinson disease (PD), with each type of physical activity offering different benefits. Their study also recommends a change in attitude towards exercise as therapy.¹

In the absence of further evolution of the interrelated pathophysiologic processes linked to PD, exercise (like stress) remains a mechanistic euphemism.² The greater the lack of clarity on related alteration of pathophysiological mechanisms, the more attractive the therapeutic role for exercise (high/low impact) becomes.^2,3 Even randomized controlled trials or meta-analyses including exercise do not supplant the need for the therapy to be placed in a biologically-plausible, overarching theoretical matrix.^3,4 In order for exercise to emerge as a scientifically valid therapy for non-motor and motor symptoms of PD, it is essential to maintain hyperfocus on toxicity and the spread of α-synuclein.

Motivation is a key factor for evaluating benefits of staying physically active in health and disease.⁵ Basal and stimulated motivation for exercise varies widely between individuals. Comparison of a cohort of PD patients with and without motivation profile for a particular physical exercise is important to critically differentiate the value of such therapy.⁵

Disclosure

The author reports no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease [published online ahead of print, 2022 Jan 12]. Neurology. 2022;10.1212/WNL.0000000000013218.
2. Gupta VK. Pathophysiology of migraine: An increasingly complex narrative to 2020. Future Neurology. 2019;14(2). doi:10.2217/fnl-2019-0003
3. Barber M, Pace A. Exercise and Migraine Prevention: a Review of the Literature. Curr Pain Headache Rep. 2020;24(8):39. Published 2020 Jun 11. doi:10.1007/s11916-020-00868-6
4. Gupta VK. Patent foramen ovale closure and migraine: science and sensibility. Expert Rev Neurother. 2010;10(9):1409-1422. doi:10.1586/ern.10.125
5. Ferri-Caruana A, Millán-González L, García-Massó X, Pérez-Nombela S, Pellicer-Chenoll M, Serra-Añó P. Motivation to Physical Exercise in Manual Wheelchair Users With Paraplegia. Top Spinal Cord Inj Rehabil. 2020;26(1):1-10. doi:10.1310/sci2601-01

The study by Tsukita et al. explores the prolonged benefits of vigorous exercise for patients with Parkinson Disease over long intervals (>5 years).¹ This research builds on two recent trials, which demonstrate that engaging in vigorous exercise stabilizes the clinical progression of Parkinson’s Disease (PD) over 6 months.^2,3 The study also suggests that maintaining a high total volume of physical activities, even at low intensity, may yield additional benefits.

Since this was not a randomized controlled trial, some of the observed associations may reflect reverse causality. However, taken together with the results from animal models, previous observational studies, and two clinical trials, there is now converging evidence that regularly engaging in exercise may slow the progression of PD.⁴ This should not only motivate people with PD to be physically active, but could also open up avenues for prevention of PD.

Prospective studies show that vigorous exercise and a high total volume of physical activities are both associated with a reduced risk of PD.⁵ A possible explanation is that exercise may slow the pathological processes of PD already during the decade-long prodromal phase of the disease. The findings by Tsukita et al. should inspire intervention studies for patients suspected of having prodromal PD, to determine whether regular exercise over long intervals may prevent or delay the manifestation of overt clinical symptoms of PD.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Tsukita K, Sakamaki-Tsukita H, Takahashi R. Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease [published online ahead of print, 2022 Jan 12]. Neurology. 2022;10.1212/WNL.0000000000013218.
2. van der Kolk NM, de Vries NM, Kessels RPC, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(11):998-1008. doi:10.1016/S1474-4422(19)30285-6
3. Schenkman M, Moore CG, Kohrt WM, et al. Effect of High-Intensity Treadmill Exercise on Motor Symptoms in Patients With De Novo Parkinson Disease: A Phase 2 Randomized Clinical Trial. JAMA Neurol. 2018;75(2):219-226. doi:10.1001/jamaneurol.2017.3517
4. de Vries NM, Darweesh SKL, Bloem BR. Citius, Fortius, Altius-Understanding Which Components Drive Exercise Benefits in Parkinson Disease. JAMA Neurol. 2021;78(12):1443-1445. doi:10.1001/jamaneurol.2021.3744
5. Fang X, Han D, Cheng Q, et al. Association of Levels of Physical Activity With Risk of Parkinson Disease: A Systematic Review and Meta-analysis. JAMA Netw Open. 2018;1(5):e182421. Published 2018 Sep 7. doi:10.1001/jamanetworkopen.2018.2421