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Effects of Exercise on Non-motor Symptoms in Parkinson’s Disease

      Abstract

      Patients with Parkinson’s disease experience disabling non-motor symptoms, including autonomic dysfunction, cognitive decline, and sleep disorders. Pharmacologic treatments for these symptoms are often ineffective or have intolerable side effects. Therefore, non-pharmacologic interventions are an attractive alternative. Exercise in particular has the potential to alleviate the progressive impairment related to these non-motor symptoms. In this commentary, we explore available research that addresses the impact of exercise and physical activity on autonomic dysfunction, cognitive impairment, and sleep disorders in Parkinson’s disease and suggest areas in need of further study. Many gaps remain in our understanding of the most effective exercise intervention for these symptoms, the mechanisms underlying exercise-induced changes, and the best way to monitor response to therapy. However, available research suggests that exercise is a promising approach to improve non-motor symptoms in patients with Parkinson’s disease.

      Key words

      Introduction

      Parkinson’s disease (PD) is a progressive neurodegenerative disease diagnosed by its motor symptoms of bradykinesia, rest tremor, rigidity, and postural instability. In addition to these motor symptoms, patients with PD experience non-motor symptoms, including autonomic dysfunction (AutD), cognitive decline, sleep disorders, and neuropsychiatric symptoms such as depression, anxiety, and psychosis.
      • Martinez-Martin P.
      • Rodriguez-Blazquez C.
      • Kurtis M.M.
      • Chaudhuri K.R.
      NMSS Validation Group
      The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease.
      These non-motor symptoms adversely affect quality of life (QoL) and can be even more disabling than the motor symptoms.
      • Politis M.
      • Wu K.
      • Molloy S.
      • et al.
      Parkinson's disease symptoms: the patient's perspective.
      Medications used to treat these symptoms are often inadequately effective and can cause intolerable side effects.
      • Amara A.W.
      • Chahine L.M.
      • Videnovic A.
      Treatment of sleep dysfunction in Parkinson's disease.
      • Goldman J.G.
      • Weintraub D.
      Advances in the treatment of cognitive impairment in Parkinson's disease.
      Therefore, patients, physicians, and researchers have developed increased interest in the potential of non-pharmacologic therapies to treat non-motor symptoms in PD.
      • Ekker M.S.
      • Janssen S.
      • Nonnekes J.
      • et al.
      Neurorehabilitation for Parkinson's disease: future perspectives for behavioural adaptation.
      For example, surgical therapies, such as deep brain stimulation (DBS), have been investigated for their influence on non-motor symptoms. An excellent review summarizes available evidence, which suggests that, in general, DBS can worsen performance within some cognitive domains and can improve other non-motor symptoms.
      • Kurtis M.M.
      • Rajah T.
      • Delgado L.F.
      • Dafsari H.S.
      The effect of deep brain stimulation on the non-motor symptoms of Parkinson's disease: a critical review of the current evidence.
      Another non-pharmacologic therapy that has promise for improving non-motor symptoms is exercise. Exercise interventions have established efficacy for treating the motor symptoms of PD, with many different types of exercise activity, including stretching, walking, dance, tai chi, aerobic, resistance, and multimodal exercises showing beneficial effects on motor symptoms in PD.
      • LaHue S.C.
      • Comella C.L.
      • Tanner C.M.
      The best medicine? The influence of physical activity and inactivity on Parkinson's disease.
      From research in the general population, exercise also has the potential to improve autonomic function, attenuate cognitive decline, and improve sleep and daytime sleepiness. In this commentary, we discuss the available evidence that supports the use of exercise for treatment of AutD, cognitive decline, and sleep disorders in patients with PD and suggest areas for future research.

      Autonomic Dysfunction

      AutD in PD

      AutD is common in PD, with reported prevalence ranging from 14% to 80%.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      It may include dysregulation of cardiovascular, gastrointestinal (GI), urinary, pupillary, and thermoregulatory systems.
      • Asahina M.
      • Vichayanrat E.
      • Low D.A.
      • et al.
      Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology.
      AutD can occur at any stage of the disease, with GI, urinary, and orthostatic symptoms increasing over time but notable in early and even premotor stages.
      • Liepelt-Scarfone I.
      • Pilotto A.
      • Muller K.
      • et al.
      Autonomic dysfunction in subjects at high risk for Parkinson's disease.
      As the disease progresses, AutD significantly impairs QoL in patients with PD.
      • Martinez-Martin P.
      • Rodriguez-Blazquez C.
      • Kurtis M.M.
      • Chaudhuri K.R.
      NMSS Validation Group
      The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease.

      Cardiovascular AutD and Exercise

      Sympathetic dysfunction is the major cause of cardiovascular dysregulation in PD, which occurs in at least 50% of patients.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      Cardiovascular AutD includes orthostatic hypotension (OH), supine hypertension, and increased resting heart rate.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      • Jost W.H.
      • Augustis S.
      Severity of orthostatic hypotension in the course of Parkinson's disease: no correlation with the duration of the disease.
      These symptoms can be exacerbated by medications used to treat PD. Interestingly, the severity of OH does not necessarily increase with the duration of disease.
      • Jost W.H.
      • Augustis S.
      Severity of orthostatic hypotension in the course of Parkinson's disease: no correlation with the duration of the disease.
      In addition to negatively affecting QoL, OH increases fall risk, hospitalizations, and cost of care in PD.
      • Francois C.
      • Biaggioni I.
      • Shibao C.
      • et al.
      Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease.
      Pharmacologic therapies for OH have limited efficacy and can be associated with serious side effects, including exacerbation of supine hypertension and ventricular hypertrophy.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      Therefore, it is important to explore tolerable and effective non-pharmacologic strategies for treatment of AutD. Exercise has potential to enhance autonomic regulation, and this has been investigated in healthy adults. For example, a study of 17 healthy adults showed that regular exercise increases orthostatic tachycardia and cardiovagal baroreceptor sensitivity, which alleviates OH in the early phase after exercise.
      • Sugawara J.
      • Komine H.
      • Miyazawa T.
      • et al.
      Influence of regular exercise training on post-exercise hemodynamic regulation to orthostatic challenge.
      Further, an aerobic training (stationary bike or treadmill) intervention over 1 year improved orthostatic tolerance in elderly participants in a small study (n = 8).
      • Xu D.
      • Wang H.
      • Chen S.
      • et al.
      Aerobic exercise training improves orthostatic tolerance in aging humans.
      In addition, brief exercises can be used to control symptoms of OH. For example, a controlled study, which included 42 older patients, showed that participants who performed leg extension exercises against a resistance band had significantly less reduction in systolic blood pressure compared with a bed rest control group, when given an orthostatic challenge.
      • Galizia G.
      • Abete P.
      • Testa G.
      • et al.
      Counteracting effect of supine leg resistance exercise on systolic orthostatic hypotension in older adults.
      Despite these results, there are also potential risks of exercise on OH. For example, one study of older adults with OH due to various comorbidities failed to show improvement in orthostatic blood pressure in an 8-week home-based resistance training program group,
      • Zion A.S.
      • De Meersman R.
      • Diamond B.E.
      • Bloomfield D.M.
      A home-based resistance-training program using elastic bands for elderly patients with orthostatic hypotension.
      and another study of patients with long-term autonomic failure had exacerbation of OH with short-term exercise.
      • Smith G.D.
      • Mathias C.J.
      Postural hypotension enhanced by exercise in patients with chronic autonomic failure.
      Therefore, studies of the influence of exercise on AutD in patients with PD are needed to determine whether this might be a meaningful treatment option for this patient group.
      Only one randomized controlled trial (RCT) has been published that addressed the effects of exercise on cardiovascular AutD in PD. This study assigned 30 patients with PD to either resistance training or a control group for 12 weeks. PD participants in the training group had improved cardiac sympathetic modulation, as measured by heart rate variability and blood pressure response.
      • Kanegusuku H.
      • Silva-Batista C.
      • Pecanha T.
      • et al.
      Effects of progressive resistance training on cardiovascular autonomic regulation in patients with parkinson disease: a randomized controlled trial.
      No change in parasympathetic modulation was seen. The improvement in sympathetic modulation has potential to help reduce symptoms and rates of cardiovascular morbidity and mortality in patients with PD.
      • Kanegusuku H.
      • Silva-Batista C.
      • Pecanha T.
      • et al.
      Effects of progressive resistance training on cardiovascular autonomic regulation in patients with parkinson disease: a randomized controlled trial.
      Additional studies about the role of exercise in patients with PD are needed to better understand the underlying mechanisms involved in autonomic modulation.

      Urinary Dysfunction and Exercise

      Bladder dysfunction, including nocturia and increased urgency and frequency of micturition, is one of the most commonly reported symptoms of AutD in PD, affecting up to 93% of patients.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      These symptoms can inhibit social activity, disrupt sleep, and impair QoL.
      • Ziemssen T.
      • Fuchs G.
      • Greulich W.
      • et al.
      Treatment of dysautonomia in extrapyramidal disorders.
      To our knowledge, no studies to date have investigated the influence of traditional exercise on bladder dysfunction in PD. However, bladder training exercises have been investigated and shown to reduce urinary incontinence in PD.
      • Vaughan C.P.
      • Juncos J.L.
      • Burgio K.L.
      • et al.
      Behavioral therapy to treat urinary incontinence in Parkinson disease.
      Therefore, more studies are required to establish any role of exercise in treating urinary dysfunction in patients with PD.

      GI Dysfunction and Exercise

      In patients with PD, autonomic impairment can occur along the entire length of the GI tract, resulting in sialorrhea, dysphagia, impaired gastric motility, constipation, and bowel incontinence.
      • Fasano A.
      • Visanji N.P.
      • Liu L.W.
      • et al.
      Gastrointestinal dysfunction in Parkinson's disease.
      These individual symptoms affect up to 70% of patients with PD.
      • Fasano A.
      • Visanji N.P.
      • Liu L.W.
      • et al.
      Gastrointestinal dysfunction in Parkinson's disease.
      In healthy adults, exercise is thought to improve constipation,
      • Peters H.P.
      • De Vries W.R.
      • Vanberge-Henegouwen G.P.
      • Akkermans L.M.
      Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract.
      but questions remain about effects of exercise on constipation in PD. One randomized, controlled pilot study evaluated the effects of Qigong mediation movement exercises on constipation as a secondary outcome and found persistent benefit of the exercise over time in patients with PD.
      • Schmitz-Hubsch T.
      • Pyfer D.
      • Kielwein K.
      • et al.
      Qigong exercise for the symptoms of Parkinson's disease: a randomized, controlled pilot study.
      . Other autonomic symptoms, including urinary and sexual dysfunction, remained unchanged in both groups over time. To our knowledge, no other studies have yet evaluated the influence of exercise or increased physical activity on constipation in patients with PD; therefore, more studies are required to determine the influence of exercise on GI symptoms.

      Cognitive Dysfunction

      Cognitive Dysfunction in PD

      Cognitive impairment has been recognized as a significant predictor of QoL in PD.
      • Leroi I.
      • McDonald K.
      • Pantula H.
      • Harbishettar V.
      Cognitive impairment in Parkinson disease: impact on quality of life, disability, and caregiver burden.
      In addition, this non-motor symptom increases caregiver burden, leads to loss of productivity, and increases likelihood of institutionalization.
      • Leroi I.
      • McDonald K.
      • Pantula H.
      • Harbishettar V.
      Cognitive impairment in Parkinson disease: impact on quality of life, disability, and caregiver burden.
      • Aarsland D.
      • Larsen J.P.
      • Tandberg E.
      • Laake K.
      Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study.
      Cognitive deficits in PD include executive dysfunction, memory deficits, language impairment, problems with visuospatial and visuoconstructive abilities, and mild cognitive impairment.
      • Litvan I.
      • Goldman J.G.
      • Troster A.I.
      • et al.
      Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
      At the time of diagnosis, up to 20% of patients with PD have some degree of cognitive impairment
      • Weintraub D.
      • Simuni T.
      • Caspell-Garcia C.
      • et al.
      Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease.
      and up to 83% experience dementia within 20 years of motor symptom onset.
      • Hely M.A.
      • Reid W.G.
      • Adena M.A.
      • et al.
      The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.

      Cognitive Dysfunction and Exercise

      Unfortunately, medications that aim to treat cognitive impairment in PD can have associated side effects and are not effective at slowing or stopping progression of cognitive decline.
      • Goldman J.G.
      • Weintraub D.
      Advances in the treatment of cognitive impairment in Parkinson's disease.
      Therefore, it is important to evaluate the potential of different non-pharmacologic therapies to improve cognition in PD. Exercise can improve cognitive function and can attenuate cognitive decline in older adults.
      • Colcombe S.J.
      • Kramer A.F.
      • Erickson K.I.
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      A recent meta-analysis of the effects of exercise on cognition in adults older than 50 years showed significant improvements in multiple cognitive domains due to all modes of exercise reviewed (aerobic, resistance, multimodal, tai chi, yoga).

      Northey JM, Cherbuin N, Pumpa KL, et al. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis [published online ahead of print April 24, 2017]. Br J Sports Med.

      Relevant moderators of this effect were duration of session and intensity of exercise, with best effects for moderate-to-high intensity exercise of a duration of 45 to 60 minutes per session.

      Northey JM, Cherbuin N, Pumpa KL, et al. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis [published online ahead of print April 24, 2017]. Br J Sports Med.

      At the structural level, exercise in older adults can increase hippocampal volume,
      • Erickson K.I.
      • Voss M.W.
      • Prakash R.S.
      • et al.
      Exercise training increases size of hippocampus and improves memory.
      suggesting the possibility of neuroprotective effects.
      In PD, clinical trials that investigated different exercise types, durations, and frequencies also found promise for exercise-induced improvements in cognitive function. For example, types of exercise interventions that have shown beneficial effects on cognition in PD include tango, aerobic exercise, combined resistance and aerobic exercise, and resistance training alone.
      • McKee K.E.
      • Hackney M.E.
      The effects of adapted tango on spatial cognition and disease severity in Parkinson's disease.
      • Ridgel A.L.
      • Kim C.H.
      • Fickes E.J.
      • et al.
      Changes in executive function after acute bouts of passive cycling in Parkinson's disease.
      • Picelli A.
      • Varalta V.
      • Melotti C.
      • et al.
      Effects of treadmill training on cognitive and motor features of patients with mild to moderate Parkinson's disease: a pilot, single-blind, randomized controlled trial.
      • Tanaka K.
      • Quadros Jr., A.C.
      • Santos R.F.
      • et al.
      Benefits of physical exercise on executive functions in older people with Parkinson's disease.
      • Cruise K.E.
      • Bucks R.S.
      • Loftus A.M.
      • et al.
      Exercise and Parkinson's: benefits for cognition and quality of life.
      • David F.J.
      • Robichaud J.A.
      • Leurgans S.E.
      • et al.
      Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial.
      Many of these studies included a control comparator group. For example, the effects of adapted tango on visuospatial function were investigated in a study in which 23 patients with PD participated in 30 hours of adapted tango, compared with an educational control group. The patients in the tango group showed improvements in visuospatial function and motor symptom severity, whereas the control group did not improve.
      • McKee K.E.
      • Hackney M.E.
      The effects of adapted tango on spatial cognition and disease severity in Parkinson's disease.
      Another study investigated the effects of a low-intensity passive cycling intervention on cognition in PD. In this intervention, 19 participants with PD sat passively (without providing resistance) on a motorized bicycle that rotated the pedals at different rates. Passive cycling sessions occurred once per week for 4 weeks. Executive function, which was measured with Trail Making test A and B, improved after the intervention.
      • Ridgel A.L.
      • Kim C.H.
      • Fickes E.J.
      • et al.
      Changes in executive function after acute bouts of passive cycling in Parkinson's disease.
      Active aerobic exercise has also been studied in PD. A small study randomly assigned 17 patients to a treadmill training intervention (45 minutes, 3 days per week for 4 weeks) or a control group and showed improvement in executive function in the treadmill group.
      • Picelli A.
      • Varalta V.
      • Melotti C.
      • et al.
      Effects of treadmill training on cognitive and motor features of patients with mild to moderate Parkinson's disease: a pilot, single-blind, randomized controlled trial.
      Tanaka et al
      • Tanaka K.
      • Quadros Jr., A.C.
      • Santos R.F.
      • et al.
      Benefits of physical exercise on executive functions in older people with Parkinson's disease.
      assigned 20 patients with mild-to-moderate PD to a control group or to 6 months of a multimodal exercise program that included moderate intensity aerobic exercise, 3 days per week. Participants in the exercise group showed improvement in executive function, as measured by the Wisconsin Card Sorting Test.
      • Tanaka K.
      • Quadros Jr., A.C.
      • Santos R.F.
      • et al.
      Benefits of physical exercise on executive functions in older people with Parkinson's disease.
      Another study combined resistance and aerobic exercise and measured the effects on cognition in patients with PD. Twenty-eight individuals with PD were assigned to either the exercise group (n = 15) or a control group (n = 13). Participants in the exercise group completed exercise 2 times per week for 12 weeks and showed improvement in executive function.
      • Cruise K.E.
      • Bucks R.S.
      • Loftus A.M.
      • et al.
      Exercise and Parkinson's: benefits for cognition and quality of life.
      A study by David et al
      • David F.J.
      • Robichaud J.A.
      • Leurgans S.E.
      • et al.
      Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial.
      suggests that resistance exercise may also benefit cognition in patients with PD. In this randomized clinical trial, 18 patients with PD participated in modified fitness counts (mFCs) and 20 patients with PD in progressive resistance exercise training (PRET). The mFC group participants underwent stretching, balance, and breathing exercises, and the PRET group participants underwent weight-lifting exercises. This study showed that 24 months of PRET or mFC helps to improve attention and working memory in patients with PD.
      • David F.J.
      • Robichaud J.A.
      • Leurgans S.E.
      • et al.
      Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial.
      This study poses an interesting possibility that the social aspect of an exercise intervention (ie, more social engagement with study staff, trainers, and other participants than if the participant had remained at home) might contribute to cognitive improvement.
      • David F.J.
      • Robichaud J.A.
      • Leurgans S.E.
      • et al.
      Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial.
      Regardless, this compilation of studies provides a good rationale for the use of exercise to improve cognitive function in PD.

      Sleep Disorders

      Sleep Dysfunction in PD

      Sleep dysfunction is another common non-motor symptom in PD, affecting up to 98% of patients.
      • Lees A.J.
      • Blackburn N.A.
      • Campbell V.L.
      The nighttime problems of Parkinson's disease.
      Sleep disorders in PD include sleep fragmentation, insomnia, rapid eye movement (REM) sleep behavior disorder, excessive daytime sleepiness (EDS), periodic limb movements of sleep, and circadian rhythm dysregulation.
      • Chahine L.M.
      • Amara A.W.
      • Videnovic A.
      A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005 to 2015.
      • Simuni T.
      • Sethi K.
      Nonmotor manifestations of Parkinson's disease.
      Patients with PD also have alterations in sleep architecture, including reduced time spent in REM and slow wave sleep, which is important for memory consolidation and intellectual performance.
      • Rye D.B.
      • Bliwise D.L.
      Movement disorders specific to sleep and the nocturnal manifestations of waking movement disorders.
      Sleep symptoms negatively influence QoL, and EDS has the potential to impair safety and reduce independence.
      • Gomez-Esteban J.C.
      • Tijero B.
      • Somme J.
      • et al.
      Impact of psychiatric symptoms and sleep disorders on the quality of life of patients with Parkinson's disease.
      • Uc E.Y.
      • Rizzo M.
      • Anderson S.W.
      • et al.
      Driving with distraction in Parkinson disease.
      Pharmacologic therapies are available for some sleep complaints in PD, they but have potential for side effects.
      • Amara A.W.
      • Chahine L.M.
      • Videnovic A.
      Treatment of sleep dysfunction in Parkinson's disease.
      For example, soporific agents can impair balance and cognition and cause residual grogginess the next morning.
      • Schroeck J.L.
      • Ford J.
      • Conway E.L.
      • et al.
      Review of safety and efficacy of sleep medicines in older adults.
      Alerting agents can lead to tachycardia and weight loss.
      • Moreau C.
      • Delval A.
      • Defebvre L.
      • et al.
      Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial.
      Therefore, non-pharmacologic therapy such as exercise is an attractive alternative for treatment of sleep dysfunction in PD.

      Sleep Disorders and Exercise

      In healthy older adults, both short- and long-term exercise interventions improve sleep. For example, meta-analyses have found that long-term exercise training increases sleep efficiency and total sleep time, reduces latency to sleep onset, and, in some studies, increases slow wave sleep.
      • Uchida S.
      • Shioda K.
      • Morita Y.
      • et al.
      Exercise effects on sleep physiology.
      • Kredlow M.A.
      • Capozzoli M.C.
      • Hearon B.A.
      • et al.
      The effects of physical activity on sleep: a meta-analytic review.
      Short-term exercise reduces REM sleep, delays REM latency, and increases total sleep time and slow wave sleep.
      • Youngstedt S.D.
      Effects of exercise on sleep.
      In addition, healthy older adults who undergo aerobic or resistance training report improved subjective sleep quality.
      • Yang P.Y.
      • Ho K.H.
      • Chen H.C.
      • Chien M.Y.
      Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review.
      • Rubio-Arias J.A.
      • Marin-Cascales E.
      • Ramos-Campo D.J.
      • et al.
      Effect of exercise on sleep quality and insomnia in middle-aged women: a systematic review and meta-analysis of randomized controlled trials.
      Exercise has shown promise for improving sleep in patients with PD as well. Only a few RCTs have evaluated sleep as an outcome due to an exercise intervention in PD. In one such study, Nascimento et al
      • Nascimento C.M.
      • Ayan C.
      • Cancela J.M.
      • et al.
      Effect of a multimodal exercise program on sleep disturbances and instrumental activities of daily living performance on Parkinson's and Alzheimer's disease patients.
      evaluated 42 patients with PD (23 in the exercise group and 19 in the control group) with the Mini-Sleep Questionnaire before and after a 6-month, multimodal exercise intervention, which included aspects of resistance, aerobic, and balance training.
      • Nascimento C.M.
      • Ayan C.
      • Cancela J.M.
      • et al.
      Effect of a multimodal exercise program on sleep disturbances and instrumental activities of daily living performance on Parkinson's and Alzheimer's disease patients.
      The investigators found a significant improvement in sleep quality in the exercise group relative to the control group.
      • Nascimento C.M.
      • Ayan C.
      • Cancela J.M.
      • et al.
      Effect of a multimodal exercise program on sleep disturbances and instrumental activities of daily living performance on Parkinson's and Alzheimer's disease patients.
      In another RCT, Silva-Batista et al
      • Silva-Batista C.
      • de Brito L.C.
      • Corcos D.M.
      • et al.
      Resistance training improves sleep quality in subjects with moderate Parkinson's disease.
      randomly assigned 22 patients to resistance training or a no-exercise control for 12 weeks, with 2 sessions per week. They used the Pittsburgh Sleep Quality Index to assess sleep quality before and after the intervention between the groups and also compared participants with PD with healthy control participants who did not exercise. Although at baseline the participants with PD had worse sleep quality than healthy control participants, the resistance training PD group reported improvement in sleep quality and at the end of the intervention had better sleep quality scores than control participants. This improvement was correlated with improvement in muscle strength. The control PD group did not show any change in sleep quality.
      • Silva-Batista C.
      • de Brito L.C.
      • Corcos D.M.
      • et al.
      Resistance training improves sleep quality in subjects with moderate Parkinson's disease.
      Another RCT used a Baduanjin Qigong meditative movement intervention and randomly assigned 100 patients with PD to Qigong and walking or a walking-only control. The Qigong group had improvement in sleep quality, as measured by the Parkinson’s Disease Sleep Scale (PDSS)-2, whereas the control group did not improve.
      • Xiao C.M.
      • Zhuang Y.C.
      Effect of health Baduanjin Qigong for mild to moderate Parkinson's disease.
      A recent study compared individual (n = 15) versus group (n = 15) exercise plus chronic disease self-management in a group of patients with PD with depression. In this study, depression was the primary outcome and improved equally in both groups. Sleep quality and daytime sleepiness were measured as secondary outcomes in the combined groups (n = 30) with the Scales for Outcomes in Parkinson’s Disease sleep and did not show improvement.
      • Sajatovic M.
      • Ridgel A.L.
      • Walter E.M.
      • et al.
      A randomized trial of individual versus group-format exercise and self-management in individuals with Parkinson's disease and comorbid depression.
      A small study evaluated the influence of physiotherapy compared with active theater on motor and non-motor symptoms in PD with a 3-year intervention. The sleep-related outcome was daytime sleepiness, as measured by the Epworth Sleepiness Scale, which showed more improvement in the active theater group than in the physiotherapy group.
      • Modugno N.
      • Iaconelli S.
      • Fiorlli M.
      • et al.
      Active theater as a complementary therapy for Parkinson's disease rehabilitation: a pilot study.
      Non-randomized studies and uncontrolled studies have also been performed to investigate the influence of exercise on sleep in PD. One retrospective study investigated the PDSS before and after a rehabilitation program. Eighty-nine patients completed the program 3 times a day, 5 days per week for 28 days and were compared with a control group of 49 patients who did not receive the intervention. The rehabilitation group showed significant improvement in sleep quality, whereas the control group did not improve.
      • Frazzitta G.
      • Maestri R.
      • Ferrazzoli D.
      • et al.
      Multidisciplinary intensive rehabilitation treatment improves sleep quality in Parkinson's disease.
      A pilot study investigated the influence of exercise on QoL in 20 patients with PD. The intervention used a combined strength training/aerobic protocol 3 days per week over 12 weeks. QoL was measured with the Nottingham Health Profile, which includes some questions about sleep. Participants with PD showed a trend toward improvement in sleep quality after this exercise intervention.
      • Rodrigues de Paula F.
      • Teixeira-Salmela L.F.
      • Coelho de Morais Faria C.D.
      • et al.
      Impact of an exercise program on physical, emotional, and social aspects of quality of life of individuals with Parkinson's disease.
      Finally, Wassom et al
      • Wassom D.J.
      • Lyons K.E.
      • Pahwa R.
      • Liu W.
      Qigong exercise may improve sleep quality and gait performance in Parkinson's disease: a pilot study.
      investigated the influence of 6 weeks of Qigong exercises on sleep and gait in 7 patients with PD. After the intervention, participants had a trend toward improvement in the PDSS-2.
      • Wassom D.J.
      • Lyons K.E.
      • Pahwa R.
      • Liu W.
      Qigong exercise may improve sleep quality and gait performance in Parkinson's disease: a pilot study.
      Taken together, these studies indicate that many different types of exercise can improve subjective sleep quality in PD.

      Discussion

      Exercise is a beneficial, cost-effective, low-risk intervention that improves overall health and provides promise for improving both motor and non-motor symptoms in PD. In this commentary, we discuss that, although additional study is needed, exercise interventions of several different modalities and durations demonstrate potential for improvement of cognitive dysfunction and sleep disorders. To delineate the impact of exercise on autonomic function, more RCTs are needed.
      Several factors specific to patients with PD should be considered when recommending an increase in physical activity. For example, certain symptoms experienced by patients with PD might prevent active engagement in physical exercise. These factors include motor symptoms and risk of falls; EDS; depression, which decreases self-esteem and self-efficacy
      • DiMatteo M.R.
      • Lepper H.S.
      • Croghan T.W.
      Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence.
      ; apathy; and cardiac sympathetic denervation, which can be associated with fatigue.
      • Nakamura T.
      • Hirayama M.
      • Hara T.
      • et al.
      Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease?.
      Any of these symptoms can reduce participation in physical activity and can contribute to a more sedentary lifestyle among patients with PD.
      • van Nimwegen M.
      • Speelman A.D.
      Hofman-van Rossum EJ, Overeem S, Deeg DJ, Borm GF, et al. Physical inactivity in Parkinson's disease.
      Strategies to improve participation include development of community-based programs; identifying and treating symptoms, such as depression, that might affect compliance to an exercise program; adapted interventions (ie, seated exercises) to accommodate motor symptoms; and discussing barriers to exercise with the patient and caregiver. Further, an increased understanding of the beneficial effects of exercise on both motor and non-motor symptoms has the potential to increase enthusiasm for participation.

      Areas In Need of Future Research

      Although most studies suggest that exercise promotes improvements in non-motor symptoms in PD, many questions remain unanswered. For example, the ideal modality, session duration, and frequency of exercise for the best improvement in each non-motor symptom, or even for motor symptoms, are not known. Although head-to-head comparisons of different exercise variables may be difficult, it is possible that biomarkers for improvement in non-motor symptoms can be identified that will allow for monitoring of efficacy of different exercise interventions in smaller groups of patients. Whether such biomarkers will be derived from body fluids (ie, blood, cerebrospinal fluid, saliva, urine), neuroimaging, or clinical measures or a combination of markers has yet to be determined. These measures could also be used to investigate longitudinally whether physical activity might alter the course of PD or its symptoms.
      Other potential areas of investigation include determination of factors that may predict responsiveness to exercise and its effects on non-motor symptoms. These features could include baseline levels of fitness; comorbid conditions; underlying motor symptoms of PD; baseline cognitive function, sleep quality, mood, or autonomic function; premorbid activity levels; trophic factors; degree of inflammation; and as yet unknown factors. In addition, potential mechanisms underlying exercise-induced changes in non-motor symptoms need to be investigated. Another important consideration is that there are possible factors relevant to PD that may not be as important in the general population that could make patients with PD more susceptible to improvements due to exercise. For example, exercise can alter dopamine receptor availability in humans and in animal models of PD, which could have downstream effects on motor and non-motor symptoms.
      • Ouchi Y.
      • Kanno T.
      • Okada H.
      • et al.
      Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease.
      • Hattori S.
      • Naoi M.
      • Nishino H.
      Striatal dopamine turnover during treadmill running in the rat: relation to the speed of running.
      Structural and functional imaging studies to investigate changes due to exercise interventions could provide additional insight to these underlying mechanisms.
      To better address knowledge gaps related to the effects of exercise on cognition, research studies that explore the impact of different exercise modalities on specific cognitive domains may ultimately help to tailor exercise prescriptions to individual patient needs. Regarding autonomic dysfunction, more and larger studies are needed to delineate the beneficial effects and the potential risks of exercise on orthostatic hypotension, urinary dysfunction, and GI symptoms. Specific to sleep disorders, although evidence finds efficacy of exercise to improve subjective sleep quality, to our knowledge there are no published studies on how exercise influences objective sleep outcomes, as measured by polysomnography or even actigraphy monitoring, in PD. These outcomes need to be investigated to develop a complete understanding of exercise-induced effects on sleep and vigilance. Further, the influence of exercise on circadian rhythms and the influence of time of day of exercise on sleep in PD are not known. These and other unanswered questions in combination with the promise of therapeutic efficacy of exercise on multiple different aspects of motor and non-motor symptoms in PD make exercise interventions an exciting area of research.

      Conflict of Interest

      Dr. Amara has no conflicts of interest related to this manuscript. She receives grant funding from the National Institutes of Health, National Institute of Neurological Disorders and Stroke (K23 NS080912), Parkinson’s Disease Foundation, the Rehabilitation Research Resource to Enhance Clinical Trials (1P2CHD086851), National Institute on Aging (P30 AG022838), and the Center for Clinical and Translational Science (UL1 TR00141), and is an investigator for studies sponsored by the Michael J. Fox Foundation for Parkinson’s Research, Roche, Jazz Pharmaceuticals, Axovant Sciences, Ltd., and Abbvie. She served on an advisory board for Jazz Pharmaceuticals. Dr. Memon has no conflicts of interest related to this manuscript and has no disclosures.
      The authors have indicated that they have no other conflicts of interest regarding the content of this article.

      Acknowledgments

      This work is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke grant K23NS080912 (A.W. Amara) and the Parkinson’s Disease Foundation.

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