A Precision Rehabilitation Approach to Counteract Age-Related Cognitive Declines

Physical activity is increasingly recognized to play a role in maintenance of brain health
and attenuation of physical decline associated with aging. While physical activity has been
shown to gradually decline with increasing age, initiation of an exercise protocol attenuates
declines in cognition associated with advancing age, including impaired neurogenesis as well
as decreased attention and learning. These benefits may be attributed, at least in part, to
physical activity's role in maintaining an anti-inflammatory phenotype, and several clinical
observational studies performed in older adults have shown an inverse relationship between
self-reported physical activity and inflammatory biomarkers. Pre-clinical studies have also
revealed that exposing aged animals to circulating factors derived from young animal
counterparts significantly improves cognitive function and promotes neurogenesis.

A major limitation of clinical studies investigating the effect of physical activity on
cognitive function is that subjects display considerable variability in their responses to
the intervention. There are likely to be multiple biological pathways by which physical
activity influences brain structure and function, and the type of physical activity that may
be effective for influencing these pathways is likely to vary greatly. A better mechanistic
understanding of how different modes of physical activity may target varying regions of the
brain and other aspects of aging is therefore warranted.

This study examines the behavioral, molecular, and structural biomarkers of brain health that
will allow for the stratification of individuals according to their "cognitive signature" and
function. This study will randomize older adults into one of four interventions for a period
of 12 months: 1) Aerobic Exercise, 2) Resistance Exercise, 3) Yoga Exercise, 4) Health
Education (involves stretching and range of motion activities).

This aims of this study will examine whether and how these different types of training
interventions exert differential effects on potential pathways of cognition and function in
aged individuals, and the role of baseline subject characteristics in mediating these
responses. The specific aims are:

1. To compare changes in cognitive function in response to three different types of
physical activity (aerobic activity, resistance training activity, yoga) versus health
education control.

2. To compare changes in brain structure in response to three different types of physical
activity (aerobic activity, resistance training activity, yoga) versus health education
control.

3. To compare biomarkers of brain health and cognition in response to three different types
of physical activity (aerobic activity, resistance training activity, yoga) versus
health education control.

4. To examine changes in physical function in response to three different types of physical
activity (aerobic activity, resistance training activity, yoga) versus health education
control.

5. To conduct post-hoc analyses to examine whether baseline measures of cognitive function,
brain structure, biomarkers, or physical function influence responsiveness to any of the
three different types of physical activity (aerobic activity, resistance training
activity, yoga) versus health education control.

Inclusion Criteria:

1. Age 65-80 years.

2. Sedentary, which is defined as regular participation over the past 3 months in <60
minutes per week of moderate-to-vigorous leisure-time or transportation-related
physical activity performed in bouts of >10 minutes.

3. Independent ambulation without or with an cane or walking stick.

4. Able to walk (with or without assistive device such as a cane or walking stick) a
distance of at least 400 meters based on self-report.

5. The ability to provide clearance from a physician for participation in the assessments
and intervention aspects of this study.

6. Ability to provide informed consent.

Exclusion Criteria:

1. Reporting engaging in regular aerobic exercise, resistance exercise, or yoga exercise
over the prior 3 months.

2. History of stroke, uncontrolled resting hypertension (systolic blood pressure ≥150
mmHg or diastolic blood pressure ≥100 mmHg), congestive heart failure, recent
myocardial infarction, or other contraindications to engagement in moderate-intensity
physical activity for at least 10 continuous minutes.

3. Incompatibility with the MRI environment (e.g. claustrophobia, metal implants, or body
size, etc.)

4. Inability to attend the sessions as prescribed.

5. Consuming >1 alcoholic drink per day on >4 days per week, or current treatment for
substance use disorder.

6. Report plans to relocate to a location not accessible to the study site or having
employment, personal, or travel commitments that prohibit attendance to at least 80
percent of the scheduled intervention sessions and all of the scheduled assessments.

7. Use of a walker or rolling walker for ambulation.

8. SPPB score of <6 or unable to perform any of the 3 components of the total score [item
score = 0].

9. Inability to complete the 400m walk test; or an unhealthy response to test [e.g.,
Systolic blood pressure >240 or diastolic blood pressure >115; or a drop in diastolic
blood pressure > 10mm].

10. Depressive symptoms not controlled or treated.

11. List the medications that will exclude a participant (e.g., those that may complicate
brain imaging, cognitive test, or biomarker testing or interpretation).

12. Degenerative neurological condition [e.g., Parkinson's Disease, multiple sclerosis].

13. Severe respiratory disease [eg COPD with shortness of breath], or use of supplemental
oxygen.

14. Lower limb below or above knee amputation / prosthesis.

15. Score of <85 of the 3MS (Modified Mini-Mental State Exam).