Abstract
Objectives:
To (1) investigate effects of aerobic walking on motor function, cognition, and quality of life in Parkinson disease (PD), and (2) compare safety, tolerability, and fitness benefits of different forms of exercise intervention: continuous/moderate intensity vs interval/alternating between low and vigorous intensity, and individual/neighborhood vs group/facility setting.
Methods:
Initial design was a 6-month, 2 × 2 randomized trial of different exercise regimens in independently ambulatory patients with PD. All arms were required to exercise 3 times per week, 45 minutes per session.
Results:
Randomization to group/facility setting was not feasible because of logistical factors. Over the first 2 years, we randomized 43 participants to continuous or interval training. Because preliminary analyses suggested higher musculoskeletal adverse events in the interval group and lack of difference between training methods in improving fitness, the next 17 participants were allocated only to continuous training. Eighty-one percent of 60 participants completed the study with a mean attendance of 83.3% (95% confidence interval: 77.5%–89.0%), exercising at 46.8% (44.0%–49.7%) of their heart rate reserve. There were no serious adverse events. Across all completers, we observed improvements in maximum oxygen consumption, gait speed, Unified Parkinson's Disease Rating Scale sections I and III scores (particularly axial functions and rigidity), fatigue, depression, quality of life (e.g., psychological outlook), and flanker task scores (p < 0.05 to p < 0.001). Increase in maximum oxygen consumption correlated with improvements on the flanker task and quality of life (p < 0.05).
Conclusions:
Our preliminary study suggests that aerobic walking in a community setting is safe, well tolerated, and improves aerobic fitness, motor function, fatigue, mood, executive control, and quality of life in mild to moderate PD.
Classification of evidence:
This study provides Class IV evidence that in patients with PD, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood, and cognition.
Aerobic exercise may be a useful supplemental treatment in Parkinson disease (PD)1,2 because it improves fitness, executive functions,3,4 fatigue,5 depression,6 and quality of life7 in aging and chronic disease, and provides neuroprotective effects in animal models of PD.8,9 Although patients with PD attain fitness benefits from aerobic exercise,10–13 information on its potential benefits on cognition and quality of life is limited.1,14–16 Generalizability of findings from fully11,12 or partially10 laboratory-based aerobic exercise interventions that used special equipment (e.g., treadmill10 with safety harness11,13 or tandem exercise bicycle12) to community setting where walking is the most common aerobic exercise17 is unclear.2
Motivated by reported improvements in aerobic fitness and ability to inhibit conflicting information (a key executive function) on Eriksen flanker task after a 6-month aerobic walking intervention in normal sedentary elderly,3 we conducted a phase I/II study to investigate effects of aerobic exercise on motor function, cognition, and quality of life in patients with mild to moderate PD. To identify the best method to deliver fitness training, we also aimed to compare safety, tolerability, and fitness benefits between different training methods (continuous/moderate intensity vs interval/alternating between low and vigorous intensity) and exercise settings (individual vs group). Interval training reportedly facilitates higher fitness gains than continuous training.18 Group training may promote success through social interaction,3 whereas individual training offers greater flexibility.
METHODS
More details of methods can be found in appendix e-1 on the Neurology® Web site at Neurology.org.
Participants.
The participants were recruited in Spring 2009, 2010, and 2011 through regional newspaper advertisements and solicitations in the Movement Disorders Clinic at the University of Iowa and the Veterans Affairs Medical Center of Iowa City. We phone screened respondents and evaluated eligible candidates in-person using clinical examination, Mini-Mental State Examination, 12-lead ECG, blood count and biochemistry, followed by graded exercise test using cycle ergometry within 1 week of starting the intervention. At each visit, we obtained body weight and height, heart rate, and blood pressure after 5 minutes of supine rest19 and after 3 minutes of standing. Throughout the study, the medications of participants continued to be managed by their treating neurologists.
Inclusion criteria.
Inclusion criteria were as follows: idiopathic PD, Hoehn and Yahr stage 1–3, men or women aged 50–80 years, and stable dopaminergic treatment regimen for at least 4 weeks before baseline not requiring adjustment.
Exclusion criteria.
Exclusion criteria included the following: current participation in an aerobic exercise program; Mini-Mental State Examination score <24; confounding medical, orthopedic, or psychiatric disorders; and cardiac abnormalities during cycle ergometry.
Historical controls.
We compared the baseline cognitive performance of our PD cohort with control participants of similar age from our driving studies.20
Standard protocol approvals, registrations, and patient consents.
The study was approved by the Institutional Review Boards and Human Subjects Office of the University of Iowa and registered at clinicaltrials.gov as NCT00784563, “Effects of Aerobic Exercise in Parkinson's Disease.” All participants provided written informed consent.
Design.
Initial design was a 2 × 2 randomized trial of different training methods (continuous vs interval) and settings (individual vs group). Sample size was estimated using 80% power to detect an effect size of 0.66 SD in maximum oxygen uptake (V̇o2max) (estimated improvement = 10%/estimated SD of change = 15%) within each arm at α = 0.05 and an attrition rate of 25%.
During the first 2 years, the participants were randomized in blocks of 4 to continuous or interval training. Logistical factors (e.g., rural residence) precluded randomization to group setting, leading to convenience-based assignments in the first year, and dropping of the group setting afterward. In the third year, all participants were assigned to the continuous arm after preliminary analyses of prior data raised safety concerns about interval training.
Intervention.
The maximal heart rate (HRmax) in the exercise prescription was based on age19 and reduced by 20% in participants who used β-blockers.21 The duration of exercise sessions (3×/wk) was advanced from 15 to 45 minutes over the first 6 weeks. The goal for continuous training was to remain within 70% to 80% of HRmax throughout the session (figure e-1A). Interval trainees alternated every 3 minutes between slower (60%–70% of HRmax) and faster (80%–90% of HRmax) walking (figure e-1B).18 We emphasized that these parameters were for guidance only and that the participants should give their best effort without feeling uncomfortable or unsafe.
Participants were asked to wear electronic heart rate and walking speed monitors (Polar RS400, Kempele, Finland) and fill out diaries for each session. A trainer facilitated group training at a track and collected monitor data and exercise diaries. Trainers conducted home visits for the individual arm participants to choose walking routes (a primary outdoor route and an alternative indoor route) and orient the participant about safe exercise procedures, followed by biweekly home visits to monitor safety and compliance.
Efficacy measures.
The participants were tested while on their usual antiparkinsonian regimen, always with adequate symptom control to allow comfortable participation in the protocol, at baseline and at the end of the intervention by evaluators blinded to the treatment arm, but not to pre-post training status.
Aerobic fitness.
Oxygen uptake was measured from expired air samples on a breath-by-breath basis during cycle ergometry. We verified maximal effort when 2 of 3 criteria were met22: (1) a plateau in oxygen uptake between 2 or more workloads, (2) respiratory exchange ratio ≥1.10, and (3) heart rate ≥85% of the age-predicted HRmax.
Cognition.
Because of sensitivity of the Eriksen flanker task performance to changes in aerobic fitness status,3,23 we chose change in percent increase score (PIS) on flanker task as the primary cognitive outcome measure. Participants were asked to identify the orientation of a central arrow cue (“<” or “>”), which was flanked on both sides by 2 arrow cues that either pointed in the same direction (congruent: <<<<<) or a different direction (incongruent: >><>>). Using reaction times (RTs) during congruent and incongruent trials, the PIS was calculated as follows: ([RT_incongruent − RT_congruent]/RT_congruent) × 100.3 The Stroop test was used as another measure of inhibition.
We assessed set shifting using Wisconsin Card Sorting Test and Trail Making Test (B-A),20 visual perception using Judgment of Line Orientation and Complex Figure Test–Copy, verbal memory using Rey Auditory Verbal Learning Test, visual memory using Complex Figure Test–Recall, language using Controlled Oral Word Association Test,20 and general cognition using Montreal Cognitive Assessment.24
Parkinsonism.
Parkinsonism was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests (7-m Walk and finger tapping),25 Functional Reach test for balance,20 total daily levodopa equivalents,26 and a patient diary.27
Quality of life.
The following scales were used to assess quality of life: Fatigue Severity Scale (FSS),28 Geriatric Depression Scale,20 and PD Quality of Life Scale (PDQUALIF).29
Statistical analysis.
Two-sample t tests, Wilcoxon rank-sum, or Fisher exact tests were used to compare baseline features and exercise characteristics and outcomes between different treatment arms, and between the completers and dropouts, and to compare baseline cognitive performance of our PD participants with controls from our driving studies.20 Regression methods were used to adjust these comparisons for age, education, and sex.
Because all treatment arms were designed to deliver a similar average aerobic intensity, we planned to pool a priori all completers throughout the study to analyze the effects of aerobic exercise with higher statistical power. We used Wilcoxon signed-rank tests or paired t tests to compare final vs baseline outcomes. When a significant change in outcomes was observed, we used regression models to assess and adjust for the effect of different settings and training methods, calendar year, and change in levodopa equivalent. We also used Pearson correlations and regression models to quantify associations of changes in outcomes with changes in aerobic fitness.
Classification of evidence.
The primary research question was whether aerobic exercise could improve aerobic fitness, motor function, quality of life, and cognition in patients with mild to moderate PD. This interventional study presents Class IV level of evidence that aerobic walking improves aerobic fitness, motor function, fatigue, mood, and cognition.
For the other research question on the method of delivery of fitness training, this study provides Class II evidence that varying-intensity interval exercise compared with continuous, moderate exercise does not improve aerobic fitness and gait speed in patients with PD.
RESULTS
Participants.
Of the 104 candidates with PD screened in person (90 community responders to newspaper advertisements and 14 clinic patients), 60 participants started the intervention (table 1). Thirty-six candidates did not meet eligibility criteria and 8 declined participation because of time commitment. Compared with healthy elderly from our past driving studies,20 our PD cohort had mild cognitive deficits in various domains (table e-1). We did not have flanker task results in controls, but the level of interference in our patients with PD appeared to be above that observed in healthy elderly,3 consistent with prior reports in PD.30
Table 1.
Baseline characteristics of the PD participants (n = 60) and comparison of completers (n = 49) vs dropouts (n = 11)
Tolerability and safety.
The randomized segment.
Over the first 2 years, we screened 76 and randomized 43 participants to continuous (n = 21) or interval (n = 22) training arms (figure 1), who did not have demographic, motor, or cognitive differences at baseline except for better depression and quality of life scores in the interval group (table 2). Nine participants (continuous = 4, interval = 5) from an urban region were assigned to group setting.
Figure 1. Flow of participants throughout the study.
The figure includes the CONSORT (Consolidated Standards of Reporting Trials) diagram for the randomized segment (years 1 and 2). All participants in year 3 were assigned to continuous/individual arm. AE = adverse event.
Table 2.
Comparison of the baseline characteristics, exercise characteristics, and fitness effects of the intervention between continuous (n = 21) vs interval (n = 22) arm subjects over the first 2 years (randomized segment of the study)
Thirty-five participants completed the program, indicating a 19% attrition rate (table 2). Three participants in the interval group dropped out because of exercise-related adverse events (knee pain, reversible with rest and conservative measures) whereas no participant in the continuous group dropped out because of exercise-related adverse events. The following reasons for dropping out were deemed not related to exercise: farming accident (n = 1), urinary tract infection (n = 1), depression associated with social circumstances (n = 1), starting a weight-gain program for preexisting weight loss (n = 1), and worsening of neuropathic pain with analgesic adjustment (n = 1).
Heart rate variability was significantly higher in the interval group as expected, but there were no significant differences in attendance, adherence to heart rate goal, or changes in V̇o2max or gait speed on 7-m Walk Test (table 2). Because of potentially increased risk without additional fitness benefits, we eliminated the interval group for the third year.
The third year.
We screened 28 participants and assigned all 17 eligible participants to the continuous/individual arm. Fourteen participants completed the intervention. A participant dropped out because of exercise-related hip pain. Although a participant with preexisting venous circulation problems denied association of increased leg pain during the study with exercise, we recommended discontinuation. The third dropout was due to developing common peroneal neuropathy after prolonged squatting for laying tiles.
Overall.
There were no significant demographic, fitness, motor, or cognitive differences at baseline between completers (n = 49) and dropouts (n = 11) except for better fatigue scores and tendencies for higher use of β-blockers, and better quality of life and depression scores in the dropouts (table 1). The dropouts exercised at significantly higher percentage of heart rate at anaerobic threshold and showed higher heart rate variability (table 1).
There were no serious adverse events throughout the study. Four participants dropped out because of probably/definitely exercise-related musculoskeletal adverse events. Self-limited, exercise-related adverse events of mild to moderate severity included muscle strain (n = 5 participants), shortness of breath (n = 12), dizziness (n = 4), neck pain (n = 2), low back pain (n = 1), and falls with no or minor injury (n = 3).
Attendance and adherence.
The participants completed a total of 3,658 exercise sessions per diaries (96% captured with electronic heart rate monitors) throughout the study. Across the groups and years, the completers attended 83.3% (95% confidence interval: 77.5%–89.0%) of the required sessions over 187 (183–193) days, with the continuous/individual group showing best attendance at 89.7% (82.0%–97.4%). The mean exercise heart rate was 107.8 (104.3–111.3) beats per minute, which was standardized as 46.8% (44.0%–49.7%) of heart rate reserve (HRR),31 and 69.7% (67.7%–71.8%) of age-predicted HRmax,31 and 101.9% (99.0%–104.9%) of heart rate at anaerobic (ventilatory) threshold during baseline cycle ergometry,19 suggesting that participants gave good effort during the exercise. The mean walking speed was 4.6 (4.3–4.9) km/h. There was no significant difference in the observed heart rates (i.e., exercise intensity) and gait speed between the treatment arms.
Efficacy.
Because there were no significant differences in baseline characteristics (demographics, fitness, motor function, and cognition) and observed mean exercise intensity and adherence between treatment arms, we proceeded with our a priori analysis plan to pool all completers. We observed significant improvements in various outcome categories (table 3): (1) aerobic fitness and motor function: V̇o2max, 7-m Walk time, and UPDRS subscale III (motor) scores, driven by factors32 1 (axial function/gait) and 3 (rigidity); (2) cognition: PIS on the flanker task; and (3) quality of life and other nonmotor functions: scores on various subscales of the PDQUALIF (social role, self-image/sexuality, outlook), FSS, Geriatric Depression Scale, and UPDRS subscale I. The total daily levodopa equivalent stayed the same in 34 of 49 participants, increased in 11, and decreased in 4 (p = 0.057).
Table 3.
Efficacy across all completers in various categories
Table 4 shows unadjusted and adjusted effect sizes in the significantly improved variables. Adjustment for changes in total daily levodopa equivalent did not render the observed improvements insignificant. After simultaneous adjustment for different training methods and settings, calendar year, and change in levodopa equivalent (using the standard covariate pattern as the first year of the study, continuous training, individual setting, and no change in levodopa equivalent), the p values for the changes in these variables still remained significant except change in FSS score (adjusted p = 0.070). However, the p value for the change in the average PDQUALIF score reached significance (adjusted p = 0.006).
Table 4.
Unadjusted and adjusted effect sizes (mean change ± SD) in variables that showed improvement across all completers (n = 49), and n = 42 for V̇o2max and PIS
Associations of exercise intensity and change in fitness.
Increase in V̇o2max correlated with mean exercise intensity expressed as percentage of HRR (r = 0.33, p = 0.034), total exercise dose expressed as mean intensity × time walked across all sessions (r = 0.45, p = 0.003), and mean walking speed (r = 0.31, p = 0.048). Multiple linear regression models showed that improvements on both the flanker task and total quality-of-life score were significantly associated with increase in V̇o2max (for PIS: b = −0.92, p = 0.040; for PDQUALIF: b = −0.476, p = 0.031) and tended to be associated with lower V̇o2max at baseline (for PIS: b = 0.339, p = 0.056; for PDQUALIF: b = 0.176, p = 0.070), but not with change in levodopa equivalent. The changes in gait speed, UPDRS, fatigue, and mood scores were not associated with changes in V̇o2max or baseline V̇o2max.
DISCUSSION
We initiated a 6-month, phase I/II, 2 × 2 randomized trial on aerobic exercise in patients with mild to moderate PD and adapted our design in response to recruitment challenges and safety concerns over the course of the study. We observed improvements in aerobic fitness, motor function, fatigue, mood, and aspects of executive functions and quality of life, which could not be explained by changes in dopaminergic medications during the intervention period. Despite theoretical advantages of interval training18 and group setting,3 continuous training in individual setting provided equivalent fitness gains with better retention, adherence, and safety. Using continuous electronic heart rate and speed monitoring, we were able to show dose-response relationships in improving aerobic fitness. Similar to community-based studies of self-administered aerobic walking exercise in healthy people,33 our intervention was conducted in a real-life environment, and is likely to generalize to community dwelling, independently ambulating patients with PD without significant comorbidities.
The Physical Activity Guidelines for Americans by the US Department of Health and Human Services34 recommend 150 minutes per week of moderate-intensity aerobic physical activity for healthy adults aged 18 to 65 years (Class IA evidence35). The mean exercise intensity observed in our study (46.8% [44.0%–49.7%] of the HRR or 69.7% [67.1%–71.8%] of age-predicted HRmax) is within the limits of moderate-intensity aerobic exercise defined as 40% to 59% of HRR or 64% to 77% of age-predicted HRmax by the American College of Sports Medicine.31 Together with fitness and gait benefits in the “light-intensity aerobic group” (50 minutes per session, 3 times per week, at 40%–50% of HRR) in a recent report,11 our results suggest that patients with mild to moderate PD can safely exercise per the guidelines for the general adult population and experience benefits.
Improvement in parkinsonism was driven by changes in rigidity and axial functions/gait (accompanied by improvement in gait speed), consistent with the lower extremity predominant nature of the exercise used in the study. The lack of significant improvements in the activities of daily living scores can be partially attributed to ceiling effects in our highly functional participants. The improvement in the motor UPDRS score (mean = 2.8 points) appears to be meaningful because it exceeded the reported mean minimal clinically important difference of 2.5 (2.3–2.7) points.36
The lack of significant changes on most cognitive measures could be attributable to the stability of performance on neuropsychological tests over short time spans in PD with no significant cognitive impairment.37 However, we observed significant improvement on a measure of inhibition in a magnitude similar to that reported in an aerobic exercise study on healthy elderly.3 Potential explanations of this selective cognitive improvement include practice effect, type I error, or sensitivity of the flanker task performance to changes in aerobic fitness status,3,23 as suggested by the significant association of decrease in PIS with the increase in V̇o2max in our study.
Fatigue is a multifactorial, common, and disabling feature in PD with no effective treatment.28 We found an approximately 0.5-point reduction on the FSS, which is considered clinically significant in multiple sclerosis.38 Aerobic walking may represent an accessible, low-risk supplemental treatment for fatigue and depression, and improve quality of life in PD as in aging, primary depression, cancer, and other chronic medical conditions.5–7
Our results suggest that improvement in executive control and average quality-of-life score could be partially explained by increased aerobic fitness, especially in those who tended to have lower fitness at baseline. However, we did not show a direct association of increased aerobic fitness with improvements in parkinsonism, gait speed, mood, and fatigue. Other potential explanations for observed improvements include physical benefits in addition to increased V̇o2max, neuroplasticity,1,9 practice effects, or the Hawthorne effect.
Without a control group, this phase I/II study cannot prove efficacy, but provides guidance on safety, tolerability, feasibility, and motor and nonmotor effect sizes for a future phase III study on aerobic exercise in PD. Studies on resistance training in PD showed improvements in cognition16 and parkinsonism.11,39 Patients with PD also benefit from cognitive training.40 Future directions and challenges for research on exercise in PD include conducting longer-term and controlled studies, using outcome measures with functional and prognostic relevance, and testing the synergy of different physical training modalities (e.g., aerobic and resistance) or of combined physical and cognitive training.
Supplementary Material
ACKNOWLEDGMENT
The authors thank all participants, exercise trainers (Grant Headley, Justin Nicol, Lacey Plathe), and Drs. Robert L. Rodnitzky and Enrique C. Leira for critical review.
GLOSSARY
- CFT
Complex Figure Test
- FSS
Fatigue Severity Scale
- HRmax
maximal heart rate
- HRR
heart rate reserve
- PD
Parkinson disease
- PDQUALIF
Parkinson's Disease Quality of Life Scale
- PIS
percent increase score
- RT
reaction time
- UPDRS
Unified Parkinson's Disease Rating Scale
- V̇o2
maximum oxygen uptake
Footnotes
Supplemental data at Neurology.org
AUTHOR CONTRIBUTIONS
Ergun Y. Uc: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. Kevin C. Doerschug: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. Vincent Magnotta: drafting or revising the manuscript for intellectual content. Jeffrey D. Dawson: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. Teri R. Thomsen: drafting or revising the manuscript for intellectual content. Joel N. Kline: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. Matthew Rizzo, Sara R. Newman, Sonya Mehta, Thomas J. Grabowski, and Joel Bruss: drafting or revising the manuscript for intellectual content. Derek R. Blanchette: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. Steven W. Anderson and Michelle W. Voss: drafting or revising the manuscript for intellectual content. Arthur F. Kramer and Warren G. Darling: design or conceptualization of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content.
STUDY FUNDING
Supported primarily by the Department of Veterans Affairs, Rehabilitation R&D Branch Merit Review Award B6261R (E.Y.U.), and also by National Center for Research Resources grant UL1RR024979 and National Institute of Environmental Health Sciences grant ES005605 (University of Iowa), donations from Charles W. and Harriet J. Seedorff Family (E.Y.U.), R01 AG017177 (M.R.), and R01 NS044930 (E.Y.U.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the granting agencies.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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