Aerobic Exercise in Parkinson's Disease

Parkinson's disease (PD) culminates in dementia, immobility, and death at a huge societal
cost. Even early in the course, motor and cognitive dysfunction impairs instrumental
activities of daily living (IADL). Non-motor symptoms due to fatigue, mood, sleep, and
autonomic disorders further reduce quality of life (QoL). DTI shows progressive decline in
brain tissue integrity. Usual care of PD centers on medical and surgical treatments relieve
motor symptoms, but these cause side effects and lose efficacy over time. Usual treatment for
non motor manifestations with pharmaceuticals (e.g., antidepressants) is symptomatic and not
specific for PD. Acetylcholine esterase inhibitors exert modest symptomatic benefits on
dementia, but there is no approved treatment for mild cognitive impairment. Physical Therapy
is usually prescribed in later stages when mobility impairment ensues. There is no approved
standard exercise regimen for PD. There is no cure or disease modifying treatment. Thus,
there is a critical need for treatments that provide broad spectrum of benefits and slow PD.

Preliminary research suggests that aerobic exercise has potential to meet this need. However,
aerobic exercise is demanding and carries some risks. It is unknown if aerobic exercise is
more beneficial than usual care in PD in long term due to gaps in the investigators knowledge
about the effects of cardiorespiratory fitness (CRF) on brain tissue integrity, motor
function, cognition, IADL, QoL, and disease progression. Limitations of current studies
include short duration, small sample size, lack or inadequacy of controls, lack of outcome
measures for cognition and IADL, and lack of biological markers to measure progression. The
objective in this application is to fill the translational gap by determining the biological,
clinical, and functional effects of long term aerobic exercise (LTAE) in PD.

The overall hypothesis is that LTAE improves brain tissue integrity and slows down PD. The
FIRST AIM is to determine the effects of LTAE on clinical features and functional abilities
in PD. The investigators' prior 6-month, uncontrolled trial showed preliminary evidence that
aerobic exercise improves aspects of motor function, cognition, and QoL in PD, but long term
outcomes and implication for functional abilities are unknown. The investigators hypothesize
that LTAE will provide sustained improvement in motor function, cognition, and non-motor
symptoms with translation of benefits to QoL and IADL. The investigators will test this with
a one-year randomized controlled trial (RCT) that compares the effects of moderate aerobic
exercise vs usual care. The investigators will use driving as the outcome for IADL. Driving
represents an important symbol for independence, and depends on integrity of cognitive and
motor systems. The SECOND AIM is to determine the mechanism of LTAE effects in PD. CRF
reflects complex improvements in vascular, cardiac, and metabolic health from aerobic
exercise. There is preliminary evidence that higher CRF is associated with better brain
health and motor/cognitive function, and that aerobic exercise improves these outcomes. For
example, the investigators' preliminary study showed improvement of microtissue integrity in
the striatum and white matter on DTI, but it is unclear how these changes counteract PD
progression over long term. The hypotheses are: 1) LTAE will improve brain tissue integrity
as indexed by DTI, 2) LTAE effects on motor and cognitive function are mediated by changes in
brain tissue integrity on DTI, and 3) physiological processes leading to improved CRF from AE
are critical to the benefits on the brain tissue integrity and motor/cognitive function. The
investigators will test these hypotheses determining the effects of LTAE on CRF and DTI, and
the association between individual differences in training related changes in motor and
cognitive function, DTI, and CRF.

In summary, the investigators' proposal leverages the diverse interdisciplinary team, strong
preliminary data and past work, and unique infrastructure to determine if LTAE slows down
neurodegeneration and clinical disability in PD.

Inclusion Criteria:

- Men or women aged 40 and older with the diagnosis of idiopathic PD per UK Brain Bank
criteria

- Hoehn-Yahr Stage I-III, on stable dopaminergic treatment regimen for equal or greater
than 4 weeks prior to baseline.

- Aerobic Fitness: VO2max below "very good" fitness levels for their age and gender at
baseline cyle ergometry.

To include subjects who have room to improve their aerobic fitness, the investigators will
enroll only those subjects whose VO2max is below "very good" fitness level (about 90% of
the population) using age and gender based VO2max norms based review of 62 studies where
VO2max was measured directly in healthy adult subjects in the USA, Canada and 7 European
countries (Reference: Shvartz, E and Reibold, RC. Aerobic fitness norms for males and
females aged 6 to 75 years: a review.

Aviat Space Environ Med. 1990; 61:3-11).

- Cognitive function: No dementia per Movement Disorder Society Level I criteria
(Reference: Dubois, B, Burn, D, Goetz, C, et al. Diagnostic procedures for Parkinson's
disease dementia: recommendations from the movement disorder society task force. Mov
Disord. 2007; 22:2314-2324).

- Current active drivers with a valid driver's license

- Veteran or non-veteran

Exclusion Criteria:

- Subjects unwilling or unable to give informed consent

- Secondary parkinsonism (e.g., drug induced)

- Parkinson-plus syndromes

- History of brain surgery for PD such as deep brain stimulation

- Corrected visual acuity less than 20/50 (due to effect on driving)

- Contraindications to exercise per ACSM criteria for Exercise Testing and Training
(Reference: American College of Sports Medicine. Cardiorespiratory Exercise
Prescription. In: Ehrman JK, ed. ACSM's Guidelines for Exercise Testing and
Prescription.6th ed. Baltimore: Lippincott Williams & Wilkins, 2010:448-462).

- No confounding acute or unstable medical, psychiatric, orthopedic condition. Subjects
who have hypertension, diabetes mellitus, depression, or other common age related
illness will be included if their disease under control with stable treatment regimen
for at least 30 days.

- Clinically significant TBI or PTSD

- Presence of other known medical or psychiatric comorbidity that in the investigator's
opinion would compromise participation in the study

- Presence of dementia per Movement Disorder Society Level I criteria

- Subjects with clinically significant depression as determined by a Beck Depression
Inventory (BDI) score greater than 15 at the screening visit

- History of exposure to typical or atypical antipsychotics or other dopamine blocking
agents within 6 months prior to the baseline visit

- Use of investigational drugs within 30 days before screening

- Subjects have to be on a stable regimen of central nervous system acting medications
(benzodiazepines, antidepressants, hypnotics) for 30 days prior to the baseline visit

- Contraindication to having a brain MRI