The aging Veteran population, together with high exposure to Agent Orange or other herbicides during military service, has made diseases such as Parkinson's disease (PD), currently affecting more than 80,000 Veterans, a major health issue in the Veterans' health system. Mobility and cognitive limitations are a common problem in PD and are associated with significant disability, increased fall risk, reduced quality of life, and increased caregiver burden. While less is known about its benefit on cognition, physical therapy has proven to be an effective treatment to mitigate mobility limitations, though the response to rehabilitation interventions is highly variable. The proposed research will inform the investigators' understanding of the impact of certain genetic profiles associated with learning impairments on motor and cognitive benefits in response to gait rehabilitation, and will provide an important foundation for more personalized and improved gait rehabilitation programs for different subgroups of PD patients.

The completion of the Human Genome Project in 2003 marked the beginning of the genomic era and the birth of "personalized" (precision) medicine. In the last decade, genetics have provided a new understanding of predicting, diagnosing, and treating individual health conditions. Indeed, such precision medicine has begun to impact virtually all areas of medicine, with significant potential to influence the timing, dosage, and intensity of physical rehabilitation.

The long-term goals of this research are: (1) to determine if certain genetic variants associated to learning impairments impact the motor and cognitive benefit experienced in response to physical rehabilitation in Veterans with Parkinson's disease (PD), and (2) to use that knowledge to identify subpopulations of patients that may require rehabilitative strategies tailored to their genotype to optimize physical rehabilitation. To achieve these goals the investigators will enroll 30 Veterans with PD in a 10-week moderate intensity gait training program consisting of 2 times per week treadmill training with verbal cues for gait quality. Aim 1 will examine the association between variants in 2 genes known to affect cognition and motor learning (APOE- 4 and BDNF-Met66), and motor improvements after gait training. Specifically, changes in walking from during and after training will be sensitively and objectively assessed using state-of-the-art quantitative gait analysis, and compared between three genotype groups (carriers of BDNF-Met66 (N=10), carriers of APOE- 4 (N=10) and those not carrying either of those variants (N=10)). Aim 2 will examine the effect of APOE- 4 and BDNF-Met66 genetic variants on cognitive changes in response to this training program. In order to do this the investigators will measure cognitive performance pre- and post-training using a brief, targeted battery aimed at assessing attention, processing speed, executive function, and learning/memory, the domains more affected, and more likely to improve with physical exercise in PD. The investigators will test the hypothesis that Veterans with PD who carry an APOE- 4 or BDNF-Met66 allele will demonstrate smaller improvements in gait (Aim 1) and cognition (Aim 2) in response to a 10-week gait training program. Overall the results of this project will enhance the investigators' knowledge regarding the influence of different genetic profiles in the response to physical rehabilitation in Veterans with PD, and will generate supporting data that will translate to more personalized and effective rehabilitation programs for people with PD.

Inclusion Criteria:

• Meet UK Brain Bank (UKBB) criteria for the diagnosis of PD (modified so that having more than one affected relative was not considered an exclusion criteria)
• Have a Hoehn & Yahr score of 3
• Have the ability to walk 400 m without physical assistance from a device or another person
• Do not have other health conditions (e.g., orthopedic, cardiopulmonary) that impact the ability to safely participate in a moderately intense gait training program

Exclusion Criteria:

• The investigators will exclude those patients presenting clinical diagnosis of dementia.
• The investigators will exclude those patients presenting conditions (cardiac, renal, or metabolic) that would pose a risk to their health by exercising.

We will not make individual participant data available.

16 weeks (study duration)

This trial was impacted by local and institutional restrictions on research implemented during the start of the COVID-19 pandemic. Restrictions on research activities impacted recruitment and impacted data collection for some participants.