Aerobic Exercise in Parkinson's Disease
Aerobic Exercise in Parkinson's Disease
Parkinson's disease (PD) is an incurable brain illness that afflicts more than one million
 Americans, including many aging Veterans. PD places an unbearable burden on the individual
 due to progressive impairment of movement and mental function. As a result, patients lose
 critical abilities such as driving and can become isolated. Although drugs and surgery help
 movement problems, their benefits are temporary and may cause side effects. Drugs provide
 limited and temporary benefit for cognition and do not prevent dementia. Animal and
 preliminary human studies on aerobic exercise show promising results in helping a broad
 spectrum of symptoms. However, due to limited and inconsistent research results, the long
 term effects of aerobic exercise on brain health and clinical features in PD is unknown. The
 investigators will conduct a clinical trial to test the long term effects of aerobic exercise
 on the brain tissue, movement, mental functions, and driving in PD. If effective, aerobic
 exercise can be implemented immediately as a low cost, easily accessible treatment in PD.
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