Effects of Aerobic Exercise in Parkinson's Disease

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