Effects of Aerobic Exercise in Parkinson's Disease
Effects of Aerobic Exercise in Parkinson's Disease
Motivated by reported improvements in aerobic fitness and executive functions after a 6-month
 aerobic walking intervention in normal sedentary elderly, we conducted a Phase I/II study to
 investigate effects of aerobic exercise on motor function, cognition, and quality of life in
 mild-moderate patients with Parkinson's disease (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. Group training may
 promote success through social interaction, whereas individual training offers greater
 flexibility.

 Details of the study can be found in the publication below:

 Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting.

 Uc EY, Doerschug KC, Magnotta V, Dawson JD, Thomsen TR, Kline JN, Rizzo M, Newman SR, Mehta
 S, Grabowski TJ, Bruss J, Blanchette DR, Anderson SW, Voss MW, Kramer AF, Darling WG.

 Neurology. 2014 Jul 29;83(5):413-25. doi: 10.1212/WNL.0000000000000644. Epub 2014 Jul 2.

 PMID: 24991037
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, MMSE, 12-lead ECG, blood
 count and biochemistry, followed by graded exercise test using cycle ergometry within one
 week of starting the intervention. At each visit, we obtained body weight and height, heart
 rate and blood pressure after 5 minutes of supine rest [Goldberg et al. 1988] and after 3
 minutes of standing. Throughout the study, the medications of participants continued to be
 managed by their treating neurologists.

 Inclusion criteria: Idiopathic PD; Hoehn and Yahr Scale I-III; men or women aged 50-80;
 stable dopaminergic treatment regimen for at least 4 weeks prior to baseline not requiring
 adjustment.

 Exclusion criteria: Current participation in an aerobic exercise program; Mini Mental Status
 Exam score <24; confounding medical, orthopedic or psychiatric disorders; cardiac
 abnormalities during cycle ergometry.

 Design:

 Initial design was a 2x2 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 VO2max (estimated improvement=10% /estimated SD of
 change=15%) within each arm at alpha=0.05 and an attrition rate of 25%.

 During the first two years, the participants were randomized in blocks of four 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 afterwards. 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 age [Goldberg,
 Elliot, and Kuehl1988] and reduced by 20% in participants who used beta-blockers [Wonisch et
 al. 2003]. The duration of exercise sessions (3x/week) was advanced from 15 to 45 minutes
 over the first 6 weeks. The goal for continuous training was to remain within 70-80% of HRmax
 throughout the session. Interval trainees alternated every 3 minutes between slower (60-70%
 of HRmax) and faster (80-90% of HRmax) walking[Wisloff et al. 2007]. 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 (VO2) 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 met [Balady et al. 2010]: 1) a plateau in VO2 between two or more workloads, 2)
 respiratory exchange ratio ≥1.10, and 3) HR > 85% of the age predicted HRmax.

 Cognition: Due to sensitivity of the Eriksen's flanker task performance to changes in aerobic
 fitness status [Colcombe et al. 2004;Kluding et al. 2011], 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 two arrow cues that either pointed in the same direction (congruent: <<<<<)
 or a different direction (incongruent: >><>>). Using reaction times (RT) during congruent and
 incongruent trials, the PIS was calculated as =((RT_incongruent - RT_congruent) /
 RT_congruent) * 100.[Colcombe, Kramer, Erickson, Scalf, McAuley, Cohen, Webb, Jerome,
 Marquez, and Elavsky2004] 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),[Uc,
 Rizzo, Johnson, Dastrup, Anderson, and Dawson2009] visual perception using Judgment of Line
 Orientation and Complex Figure Test (CFT)-Copy, verbal memory using Rey Auditory Verbal
 Learning Test, visual memory using CFT-Recall, language using Controlled Oral Word
 Association Test,[Uc, Rizzo, Johnson, Dastrup, Anderson, and Dawson2009] and general
 cognition using Montreal Cognitive Assessment.[Chou et al. 2010] Parkinsonism: Unified
 Parkinson's Disease Rating Scale and timed motor tests (7m Walk and finger tapping),[Defer et
 al. 1999] Functional Reach test for balance,[Uc, Rizzo, Johnson, Dastrup, Anderson, and
 Dawson2009] total daily levodopa equivalents,[Tomlinson et al. 2010] and a patient diary
 [Hauser et al. 2004].

 Quality of life: Fatigue Severity Scale,[Friedman et al. 2011] Geriatric Depression
 Scale,[Uc, Rizzo, Johnson, Dastrup, Anderson, and Dawson2009] PD Quality of Life Scale
 (PDQUALIF) [Welsh et al. 2003].

 Statistical analysis Two-sample t-tests, Wilcoxon Rank-Sum, or Fisher's 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.[Uc, Rizzo,
 Johnson, Dastrup, Anderson, and Dawson2009] Regression methods were used to adjust these
 comparisons for age, education, and gender.

 As 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 Ranks 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.

 The analyses of magnetic resonance imaging studies and other biomarkers is continuing and
 will be published in the future.

 Reference List

 Balady GJ, Arena R, Sietsema K et al. Clinician's Guide to cardiopulmonary exercise testing
 in adults: a scientific statement from the American Heart Association. Circulation 2010; 122:
 191-225.

 Chou KL, Amick MM, Brandt J et al. A recommended scale for cognitive screening in clinical
 trials of Parkinson's disease. Mov Disord 2010; 25: 2501-2507.

 Colcombe SJ, Kramer AF, Erickson KI et al. Cardiovascular fitness, cortical plasticity, and
 aging. Proc Natl Acad Sci U S A 2004; 101: 3316-3321.

 Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical
 interventional therapies in Parkinson's disease (CAPSIT-PD). Mov Disord 1999; 14: 572-584.

 Friedman JH, Abrantes A, Sweet LH. Fatigue in Parkinson's disease. Expert Opin Pharmacother
 2011; 12: 1999-2007.

 Goldberg L, Elliot DL, Kuehl KS. Assessment of exercise intensity formulas by use of
 ventilatory threshold. Chest 1988; 94: 95-98.

 Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary: Further validation and
 implications for clinical trials. Mov Disord 2004; 19: 1409-1413.

 Kluding PM, Tseng BY, Billinger SA. Exercise and executive function in individuals with
 chronic stroke: a pilot study. J Neurol Phys Ther 2011; 35: 11-17.

 Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose
 equivalency reporting in Parkinson's disease. Mov Disord 2010; 25: 2649-2653.

 Uc EY, Rizzo M, Johnson AM, Dastrup E, Anderson SW, Dawson JD. Road Safety in Drivers with
 Parkinson Disease. Neurology 2009; 73: 2112-2119.

 Welsh M, McDermott MP, Holloway RG, Plumb S, Pfeiffer R, Hubble J. Development and testing of
 the Parkinson's disease quality of life scale. Mov Disord 2003; 18: 637-645.

 Wisloff U, Stoylen A, Loennechen JP et al. Superior cardiovascular effect of aerobic interval
 training versus moderate continuous training in heart failure patients: a randomized study.
 Circulation 2007; 115: 3086-3094.

 Wonisch M, Hofmann P, Fruhwald FM et al. Influence of beta-blocker use on percentage of
 target heart rate exercise prescription. Eur J Cardiovasc Prev Rehabil 2003; 10: 296-301.
Inclusion Criteria:

 -  Veteran or non-veteran;

 -  Presence of all 3 cardinal features of Parkinson's disease (resting tremor,
 bradykinesia, and rigidity), which have to be asymmetrical;

 -  Hoehn and Yahr Scale stage I-III;

 -  Men or women aged 50-80 capable of performing the planned exercise programs;

 -  Intention to remain in the local area over the study period;

 -  Stable dopaminergic treatment regimen for at least 4 weeks prior to baseline without
 any clinical need for medication adjustment at the time of screening

 Exclusion Criteria:

 -  Secondary parkinsonism;

 -  Parkinson-plus syndromes;

 -  MMSE score <24;

 -  Participating in a aerobic exercise program;

 -  An unstable dosage of drugs active in the central nervous system (e.g., anxiolytics,
 antidepressants) during the 60 days before the baseline visit;

 -  Participation in drug studies or the use of investigational drugs within 30 days
 before screening; structural brain disease;

 -  Active epilepsy;

 -  Acute illness or active, confounding medical, neurological, or musculoskeletal
 conditions; alcoholism or other forms of drug addiction;

 -  Inability to complete the graded exercise test;

 -  Lack of medical clearance from our pulmonologist;

 -  Intention to move or take a >1 month vacation during the study period;

 -  Contraindications to MRI or claustrophobia requiring sedation