Sedentary Lifestyle
Conditions
Keywords
physical activity, aging, learning and memory, exercise, brain
Brief summary
Given the accelerating growth of older adults worldwide and the decline in cognitive function with aging, therapeutics that remediate age-related cognitive decline are needed more than ever. The proposed research seeks to better understand and enhance the detection of exercise effects on hippocampal network function and learning and memory, which decline with aging and Alzheimer's. Success would lead to new ways to detect benefits of exercise on cognitive aging and would lead to mechanistic insight on how such plasticity is possible while also informing prevention strategies.
Detailed description
Animal models robustly support that exercise protects brain areas vulnerable to aging such as the hippocampus and that these benefits lead to better learning. In contrast, there are mixed findings from human studies on the cognitive benefits of exercise with healthy older adults. This contrast indicates there is still a lack of understanding for how exercise could change the course of cognitive decline in aging adults. However, no human studies have comprehensively tested exercise effects on cognition in older adults with learning tasks inspired from basic exercise neuroscience. The objective in the proposed research is to fill this translational gap by determining if different types of exercise improve the same kinds of learning in older adults that have been shown to improve in animal models by improving hippocampal function. This will bring the investigators closer to a long-term goal of determining how exercise protects the brain from adverse effects of aging in order to develop interventions that minimize age-related cognitive decline. The overall hypothesis is that exercise improves learning when it increases functional hippocampal-cortical communication that otherwise declines with aging. The investigators will test this in a sample of healthy older adults by determining if increases in functional hippocampal-cortical connectivity from exercise training improve learning on an array of tasks that require the hippocampus for acquisition of new relational memories compared to conditions of the same tasks that should not require the hippocampus for learning and memory.
Interventions
BEHAVIORALCardiorespiratory fitness training
Physical exercise of moderate intensity designed to improve cardiorespiratory fitness
BEHAVIORALFunctional fitness training
Physical exercise of light intensity designed to improve functional fitness
Sponsors
National Institute on Aging (NIA)
Michelle W. Voss
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Eligible to participate in an aerobic exercise intervention based on the Physical Activity Readiness Questionnaire, and corrected vision of 20/40. * Approval from a physician that monitored electrocardiography (ECG) response during a maximal aerobic fitness test that is part of the second study visit described below. * Exercising less than 60 minutes a week for the past calendar year
Exclusion criteria
* Not between the ages of 55 and 80 years old * Not fluent in English * Score \< 20 (out of 30) on the Montreal Cognitive Assessment (MoCA) * Inability to comply with experimental instructions * Qualify as high risk for acute cardiovascular event by the published standards of the American College of Sports Medicine * Previous diagnosis of neurological, metabolic, or psychiatric condition, and no previous brain injury associated with loss of consciousness * Inability to complete an MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hippocampal-dependent Learning | Baseline, 24-weeks | Learning rate on constructs that have been examined in animal models including context acquisition, episodic associations, and spatial navigation. The primary outcome is reported for the spatial navigation task that is associated with hippocampal structure and function, which is learning in the wayfinding condition. We report change in slope for wayfinding learning trials. The slope is computed based on the proportion of items correctly recalled on a map, over four learning trials. For each trial, proportion correct can range from 0 to 1, and a higher number represents faster learning, which is better. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hippocampal-cortical Functional Connectivity | Baseline, 30 minutes | The change in strength of the correlation between the spontaneous functional magnetic resonance imaging (fMRI) signal in the hippocampus and cortical regions in a hippocampal-cortical memory system. |
| Change in Cardiorespiratory Fitness | Baseline, 24-weeks | Cardiorespiratory fitness will be measured during a maximal exercise test. Oxygen uptake (VO2) will be measured from expired air samples taken at 30 second intervals until a peak VO2, the highest VO2, is attained at the point of test termination due to symptom limitation and/or volitional exhaustion. Change in maximal VO2 is reported for descriptive results. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cardiorespiratory Fitness Training Cardiorespiratory fitness training will be a 24-week supervised cycling program designed to improve cardiorespiratory fitness, with supervision directly from the research team. All participants will first receive a one-on-one orientation with an exercise training specialist that has been trained by Dr. Gary Pierce in monitoring an exercise program for healthy older adults. Training will start with a 5 minute-warm-up, 20 minutes moderate intensity cycling and 30 minutes light intensity cycling, and 5 minute cool-down per session, for 3 sessions/week. In each additional week, 6 minutes of moderate intensity cycling per session will be added, until the total time for moderate intensity is 50 minutes per session by the start of week 5 (with additional 5 minute warm-up and 5 minute cool-down).
Cardiorespiratory fitness training: Physical exercise of moderate intensity designed to improve cardiorespiratory fitness | 60 |
| Functional Fitness Training Functional fitness training will be a 24-week supervised exercise program designed to focus on functional flexibility and mobility, with supervision directly from our research team. All participants will first receive a one-on-one orientation with an exercise training specialist that has been trained by Dr. Gary Pierce in monitoring an exercise program for healthy older adults. Training will start with a 5 minute-warm-up, 20 minutes of light intensity cycling and 20 minutes of dynamic stretching to increase range of motion and functional fitness, for 3 sessions/week. In each additional week, additional stretches will be added to maintain variety and improve flexibility of all major muscle groups.
Functional fitness training: Physical exercise of light intensity designed to improve functional fitness | 56 |
| Total | 116 |
Baseline characteristics
| Characteristic | Cardiorespiratory Fitness Training | Functional Fitness Training | Total |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 6 | 63.4 years STANDARD_DEVIATION 5 | 63.3 years STANDARD_DEVIATION 6 |
| Cardiorespiratory fitness (VO2 max as ml/kg/min) | 20.1 VO2 max (ml/kg/min) STANDARD_DEVIATION 5.2 | 21.1 VO2 max (ml/kg/min) STANDARD_DEVIATION 5.8 | 20.6 VO2 max (ml/kg/min) STANDARD_DEVIATION 5.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 57 Participants | 52 Participants | 109 Participants |
| Region of Enrollment United States | 60 participants | 56 participants | 116 participants |
| Sex: Female, Male Female | 41 Participants | 35 Participants | 76 Participants |
| Sex: Female, Male Male | 19 Participants | 21 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 119 | 0 / 122 | 0 / 60 | 0 / 56 |
| other Total, other adverse events | 0 / 119 | 0 / 122 | 22 / 60 | 8 / 56 |
| serious Total, serious adverse events | 0 / 119 | 0 / 122 | 0 / 60 | 0 / 56 |
Outcome results
Primary
Change in Hippocampal-dependent Learning
Learning rate on constructs that have been examined in animal models including context acquisition, episodic associations, and spatial navigation. The primary outcome is reported for the spatial navigation task that is associated with hippocampal structure and function, which is learning in the wayfinding condition. We report change in slope for wayfinding learning trials. The slope is computed based on the proportion of items correctly recalled on a map, over four learning trials. For each trial, proportion correct can range from 0 to 1, and a higher number represents faster learning, which is better.
Time frame: Baseline, 24-weeks
Population: Participants with both pre- and post-intervention measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiorespiratory Fitness Training | Change in Hippocampal-dependent Learning | -.00369 learning rate (proportion correct/trial) | Standard Deviation 0.03 |
| Functional Fitness Training | Change in Hippocampal-dependent Learning | .00404 learning rate (proportion correct/trial) | Standard Deviation 0.04 |
Comparison: We tested the prediction that learning rate would increase more so for the moderate-to-vigorous training group compared to the light intensity training group. This prediction was tested with a linear mixed model, according to our statistical analysis plan.p-value: <0.0595% CI: [-0.04, 0.01]Mixed Models Analysis
Secondary
Change in Cardiorespiratory Fitness
Cardiorespiratory fitness will be measured during a maximal exercise test. Oxygen uptake (VO2) will be measured from expired air samples taken at 30 second intervals until a peak VO2, the highest VO2, is attained at the point of test termination due to symptom limitation and/or volitional exhaustion. Change in maximal VO2 is reported for descriptive results.
Time frame: Baseline, 24-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiorespiratory Fitness Training | Change in Cardiorespiratory Fitness | 2.33 ml/kg/min | Standard Deviation 2.26 |
| Functional Fitness Training | Change in Cardiorespiratory Fitness | .53 ml/kg/min | Standard Deviation 2.4 |
Comparison: We tested the prediction that cardiorespiratory fitness would increase more so for the moderate-to-vigorous training group compared to the light intensity training group. This prediction was tested with a linear mixed model, as reported in our protocol paper.p-value: <0.0595% CI: [0.27, 2.59]Mixed Models Analysis
Secondary
Change in Hippocampal-cortical Functional Connectivity
The change in strength of the correlation between the spontaneous functional magnetic resonance imaging (fMRI) signal in the hippocampus and cortical regions in a hippocampal-cortical memory system.
Time frame: Baseline, 30 minutes
Population: Before randomization in the parallel assignment intervention study, all participants completed an acute exercise manipulation that had a repeated measures, within-subject cross-over design for exposure to exercise intensity. Participants completed this acute exercise manipulation before randomization so participants are not yet in their chronic intervention arm. The N for each arm therefore corresponds to the n that was exposed to each of the acute exercise conditions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiorespiratory Fitness Training | Change in Hippocampal-cortical Functional Connectivity | .001 functional connectivity (correlation) | Standard Error 0.005 |
| Functional Fitness Training | Change in Hippocampal-cortical Functional Connectivity | -.005 functional connectivity (correlation) | Standard Error 0.005 |
Comparison: We tested the prediction that hippocampal-cortical functional connectivity would change more for the moderate-to-vigorous acute condition compared to the light intensity condition. This prediction was tested with a linear mixed model, according to our statistical analysis plan.p-value: <0.0595% CI: [-0.01, 0.02]Mixed Models Analysis
Secondary
Change in Hippocampal-cortical Functional Connectivity
The change in strength of the correlation between the spontaneous functional magnetic resonance imaging (fMRI) signal in the hippocampus and cortical regions in a hippocampal-cortical memory system.
Time frame: Baseline, 24-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiorespiratory Fitness Training | Change in Hippocampal-cortical Functional Connectivity | -.007 functional connectivity (correlation) | Standard Deviation 0.07 |
| Functional Fitness Training | Change in Hippocampal-cortical Functional Connectivity | -.005 functional connectivity (correlation) | Standard Deviation 0.06 |
Comparison: We tested the prediction that functional connectivity strength would increase more so for the moderate-to-vigorous training group compared to the light intensity training group. This prediction was tested with a linear mixed model, according to our statistical analysis plan.p-value: <0.0595% CI: [-0.03, 0.02]Mixed Models Analysis