The Cyclical Lower-extremity Exercise for Parkinson's Trial

Current medical and surgical approaches to Parkinson's disease (PD) are expensive and
associated with a variety of side effects that may compromise the patient's quality of life.
Development of a non-drug, non-surgical therapeutic approach to improve motor function would
provide an attractive adjunct to current PD treatment approaches. Promising results from
animal exercise studies have not been translated to patients with PD.

Animal studies suggest forced-exercise produces an endogenous increase in neurotrophic
factors. An increase in these factors is believed to improve the capacity of dopamine neurons
to deliver dopamine and selectively increase dopamine levels within the dorsolateral
striatum. Models of PD provide a theoretical framework for forced-exercise and explain why
voluntary exercise is not associated with global improvements in motor function for PD
patients. Based on model predictions, decreased motor cortical activation limits PD patients'
ability to perform voluntary exercise at the relatively high rate used in animal studies that
demonstrate a therapeutic benefit. Therefore, PD patients may not be able to exercise
(voluntarily) at sufficiently high rates to trigger the endogenous release of neurotrophic
factors thought to underlie global improvements in motor functioning. A safe lower extremity
forced-exercise paradigm that augments PD patients voluntary exercise rates has been
developed for humans in an ongoing R21 project. Similar to our initial study, PD patients
completing an 8-week forced-exercise intervention exhibited nearly a 25% percent improvement
in clinical motor ratings, patients completing a voluntary exercise intervention showed no
improvement in clinical ratings. Our recent fMRI data indicate that an acute bout of
forced-exercise in PD patients produces a similar subcortical and cortical activation pattern
as is seen following administration of levodopa. Global improvements in motor function and
increased neural activity suggest forced-exercise may be altering brain function in PD
patients. The goal of this project is to determine and compare the effects of forced versus
voluntary exercise on PD motor and non-motor function and associated changes in the pattern
of neural activity.

A single-center, parallel-group, rater-blind, study in a 2:2:1 randomization is proposed. A
total of 100 mild to moderate idiopathic PD patients will be randomized to a voluntary,
forced or no-exercise control group. Exercise groups will exercise at identical aerobic
intensities, however those in the forced group will be provided mechanical assistance to
perform exercise 35% faster than their voluntary exercise rate.

Inclusion Criteria:

- Able to provide informed consent.

- Clinical diagnosis of idiopathic PD. The diagnosis of PD will be based on the presence
of at least two of the cardinal signs of this disorder (akine¬sia/bradykinesia, rest
tremor, rigidity, gait and postural instability) with at least one of the signs being
rest tremor or akinesia/bradykinesia.

- Hoehn and Yahr stage II-III when off PD medication.

- UPDRS motor score between 6-45 out of a maximum of 108 when off PD medication.

- Stable anti-parkinsonian medication for one month prior to study enrollment or
consistent in desire to stay off anti-parkinson medication.

- Age between 30 and 75 years.

Exclusion Criteria:

- Clinically significant medical disease that would increase the risk of
exercise-related complications (e.g. cardiac or pulmonary disease, diabetes mellitus,
hypertension, stroke).

- Dementia as evidenced by a score less than 116 on the Mattis Dementia Rating Scale.

- Other medical or musculoskeletal contraindications to exercise.

- Undergone any surgical procedure for treatment of PD, DBS, pallidotomy or thalamotomy