Exercise Targeting Cognitive Impairment in Parkinson's Disease

The aim of this application is to compare and elucidate the effects of skill-based versus aerobic exercise versus control on mild cognitive impairment (MCI) of the executive function (EF) subtype in Parkinson's disease (PD); we hypothesize that skill-based exercise will result in the greatest improvement in EF and lead to modification of underlying neural substrates.

Mild cognitive impairment (MCI), particularly of the executive function (EF) subtype, is common in Parkinson's disease (PD) and transitions to dementia, increased fall risk, and poor quality of life. EF is a set of processes that include mental flexibility and attention that are needed to learn and optimize performance of complex cognitive and motor skills. Such skills include the ability to generalize task performance under different conditions (context processing) and to perform two tasks simultaneously termed dual-task (DT) performance. Deficits in EF lead to problems in daily functioning and loss of independence and create psychosocial and economic burdens on patients and caregivers and stakeholders including health care providers. There is currently no effective treatment in PD to address EF deficits. Our animal and clinical studies in PD demonstrate that skilled exercise facilitates neuroplasticity of the basal ganglia (BG), a brain region sub-serving EF and supports the hypothesis that exercise will reverse EF deficits in PD. Furthermore, recent studies in healthy aging support that skill-based exercise that specifically promotes motor skill fitness (MSF), compared with aerobic exercise that promotes cardiovascular fitness (CF), has a greater impact on EF and related BG circuits. The aim of this application is to compare and elucidate the effects of skill-based versus aerobic exercise versus control on MCI of the EF subtype in PD; we hypothesize that skill-based exercise will result in the greatest improvement in EF and lead to modification of underlying neural substrates.

The skill-based exercise program is designed to improve skilled function, fine and gross- motor body coordination. The intervention will be focused on acquisition and improvement of complex movements for the whole body and include the following general categories of activities: (1) balance, (2) eye-hand coordination, (3) leg-arm coordination; 4) reaction time to moving objects/persons; (5) dynamic gait and 6) functional activity performance. The treating therapist will direct both general principles of progression and progression specific to each category.

The aerobic cardiovascular exercise will consist of 36 1-hour sessions performed 3 times weekly over 12 weeks. Aerobic exercise will consist of cycling on a recumbent stationary bicycle. Each session will begin and end with gentle stretching. Continuous cycling will be performed for 45-50 minutes, with the first and last 5 minutes designated as warm-up and cool-down periods. The intensity of the middle 30 minutes of cycling will be increased progressively from an initial target of 50% maximum heart rate (HR) during week 1 to 75% of maximum HR by week 12. The initial intensity will be set at 50% of maximum HR. Participants will be encouraged to cycle as fast as they can, with a goal of maintaining 90 revolutions per minute (RPM) throughout the middle 30-minute period. Pedaling resistance will be kept low throughout all sessions. Measures of heart rate via heart rate monitors, blood pressure, RPM, and rate of perceived exertion will be recorded at 5-minute intervals.

The control Social Contact group will consist of an equal amount of social contact as the exercise group. Subjects will have weekly visits at the University of Southern California with the study coordinator. The goal is for 3 hours of social contact every week for a total of 36 hours over 12 weeks. Activities scheduled for the social contact visits will include: (1) support group interactions and (2) social outings such as a trip to a museum, local café for lunch or dinner; (3) book club; (4) sports event. Support group interaction can include discussions among patients and caregivers, presentations from experts in various aspects of PD. They will be instructed to continue with their usual level of activity but refrain from beginning new exercise activities during the study period.

All subjects from each group will undergo a finger sequence motor learning task to determine exercise effects on EF as evaluated through improvement in the transfer of a learned motor task from one contextual setting to another.

A subset of subjects (60 representing 20 per group) will be invited to undergo fMRI studies at University of California, Los Angeles. Patients will perform a learned single finger-sequencing task (a condition of the CDML) with an additional secondary dual task (DT) component during an fMRI scan.

Parkinson Disease Questionnaire-39 (PDQ-39) will be used to indicate overall quality of life and frequency with which patients experience difficulties; high scores for the PDQ-39 reflect poorer quality of life.

Change in Evaluation of PD Motor Symptoms with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)

The MDS-UPDRS is the established gold standard that is currently used for the vast majority of clinical settings and for scientific trials. This scale was developed in 1987 and is the most widely used tool in PD.

Activity Specific Balance Confidence (ABC) Scale is a 16-item self-report in which patients rate their balance confidence in performing several activities; high scores indicate greater balance confidence.

The CONF scale includes nine items, which assesses how sure subjects are that they would do exercise under different conditions or constraints, including when they are tired.

The EFFIC scale is a self-efficacy barriers to exercise measure, a 13-item instrument that focuses on self-efficacy expectations related to the ability to continue exercising in the face of barriers to exercise.

The FrSBe assesses changes in behavior dysfunction and disturbances associated with frontal-subcortical damage, which is the circuitry involved with executive functioning

An individual's Motor skill fitness will be a composite score of their Physical Performance Test (PPT) and their Timed Up and Go (TUG).

Subjects will participate in testing designed to determine their level of cardiovascular fitness by estimating maximal oxygen uptake (V02max) known as the Balke treadmill submaximal fitness test and has been optimized for use in samples of elderly adults.

The Mattis Dementia Rating Scale will be used to differentiate between study subjects with mild cognitive impairment and dementia

The D-KEFS Color Word Interference Test will be used to evaluate attention, working memory and executive function

Inclusion Criteria: willing and able to provide informed consent confirmed diagnosis of idiopathic PD based on the United Kingdom Brain Bank criteria Mild cognitive impairment (Level II criteria Movement Disorder Task Force) medically eligible for MRI imaging able to provide a written medical clearance from their primary physician to participate in exercise stable PD medications for 3 months Exclusion Criteria: a Hoehn & Yahr staging greater than 2.5 at screening severe cardiac disease (New York Heart Association classification IIIV) history of an abnormal stress test clinically significant medical or psychiatric illness electrically, magnetically, or mechanically activated implant (such as cardiac pacemakers or intracerebral vascular clip) metal in any part of the body including metal injury to the eye past history of brain lesions (such as stroke) seizures or unexplained spells of loss of consciousness family history of epilepsy physical therapy within 6 months of the study symptomatic orthostatic hypotension at the screening visit orthopedic and other movement-influencing diseases such as arthritis or total hip joint replacement requirement for central nervous system active therapies (e.g. hypnotics, antidepressants, anxiolytics) moderate or severe depression or apathy using the Geriatric depression scale and Apathy scale taking anticholinesterase inhibitors taking anticholinergic medication PD dementia Colorblindness