This proposal aims to conduct a 10-week randomized controlled trial comparing walking and resistance training with and without computerized cognitive training in older Veterans with Multiple Sclerosis, followed by 12 months of fall tracking with sensors and fall calendars. The primary objectives of this proposed CDA2 are to provide critical preliminary data on 1) the feasibility of conducting a 10-week RCT, 2) preliminary treatment effects on gait, cognition, and falls, and 3) neuroinflammatory biomarkers. Dr. Katherine Hsieh will receive hands-on training in the design and conduct of clinical trials (Dr. Hackney), mechanisms underlying physical activity, cognitive rehabilitation, and falls (Drs. Twamley, Hackney, & Kesar), fall detection technology (Prof. Sanford), and clinical problems faced by MS participants (Dr. Backus) to achieve her long-term career goal of becoming an independent falls prevention investigator.

Significance to VA: A key aim of this proposal is to equip Dr. Katherine Hsieh with the expertise to become an independent VA investigator leading fall prevention trials for older Veterans with Multiple Sclerosis (MS). MS is a chronic, neurodegenerative disease affecting 55,00-70,000 Veterans. Over 28,000 MS cases are reported annually to the VA, and within the Paralyzed Veterans of America, 1 in 4 members have MS. Gait and cognitive impairments are the two of the most common MS symptoms and two of the most important predictors of falls, which lead to fractures, disability, and even death. Adults 55 years and older are the largest group of people living with MS, and the combination of MS symptoms and aging puts older MS Veterans at a high risk of falls. Preventing falls in older Veterans with MS is needed to improve their independence and quality of life. Innovation and Impact: This proposal seeks to utilize an innovative method of combining walking and resistance training with computerized cognitive training on fall risk outcomes. Falls are associated with slower gait speed and declines in processing speed, attention, executive function, and verbal memory. In people with MS, walking and resistance training improves gait function, and computerized cognitive training improves executive functions, processing speed, and attention. Whether combining computerized cognitive training with walking and resistance training provides additional benefits to gait, cognition, and falls remains unclear. Specific Aims: The objectives of this CDA2 proposal are to: 1) determine the feasibility of conducting a 10-week RCT comparing walking and resistance training with and without computerized cognitive training; 2) obtain estimates of intervention effects on gait, cognitive function, and prospective falls; 3) explore neuroinflammatory mechanisms underlying treatment effects. In addition, the PI has established a team of mentors (Drs. Hackney, Twamley, Sanford, Backus, and Kesar) to achieve five career development goals: 1) advance knowledge in the design and conduct of clinical trials; 2) examine mechanisms underlying physical activity, cognitive rehabilitation, and falls in older MS Veterans; 3) develop expertise in the use and implementation of fall detection technology; 4) acquire basic knowledge of clinical problems faced by people with MS; and 5) enhance professional skills including grant writing, scientific communication, and mentorship. Methodology: This trial will enroll 30 older Veterans with MS aged 55 or older randomized to 10 weeks, 3x/week of walking and resistance exercises with computerized cognitive training (n=15) or computer games (n=15). Participants will complete a battery of physical and cognitive tasks at baseline and 10-week follow-up. Following the intervention, the investigators will track falls for 12 months with an Apple watch and fall calendars. Aim 1, feasibility, will be measured with randomization, adherence, retention, and satisfaction to the 10-week trial. Aim 2 will compare gait and mobility, cognition, and future falls between intervention groups. Aim 3 will explore neuroprotective responses using brain-derived neurotrophic factor, interleukin-6, and tumor necrosis alpha to examine group differences and explore subgroup analyses.

Path to Translation/Implementation: Results of this study will provide critical preliminary data on gait, cognition, and falls to power and inform a full-scale RCT as the investigator's next Parent Merit. The investigators will also possess pilot data on biomarkers to identify responders and non-responders and target specific subgroups. Ultimately, this study aims to implement exercise and cognitive training to maximize functional independence for older Veterans with MS. In addition, leading this RCT and longitudinal study, along with taking didactic coursework and training, will help the investigator accomplish her long-term career goal to become an independent falls prevention investigator. By the conclusion of this CDA2, the investigator will possess the knowledge, skills, abilities, and preliminary data necessary to successfully compete for a Parent Merit award and launch her career as a VA falls prevention scientist.

Inclusion Criteria:

• US Veteran
• Diagnosis of Multiple Sclerosis
• Relapse free in the last 30 days
• Capable of standing unaided for at least 1 minute
• Expanded Disability Status Scale <6.5
• Ability to speak and understand English

Exclusion Criteria:

• Any neurological disorder other than MS
• Modified Telephone Interview for Cognitive Status <20
• Current participation in an exercise or cognitive rehabilitation study

This is a double-blinded randomized controlled trial. (RCT) Outcome assessors and participants will not know which group they are randomized to.