Investigating Gains in Neurocognition in an Intervention Trial of Exercise
Condition: Healthy; Cognitive Function 1, Social
Study type: Interventional
Phase: Phase 3

Summary: 
      This randomized control trial will examine whether a 12 month monitored exercise intervention
      improves brain health in cognitively normal older adults. This trial will also address
      several important unanswered questions: (1) Are the recommended public health guidelines of
      150 minutes/week of exercise sufficient for improving cognitive performance? (2) Does
      exercise influence brain structure and/or function? (3) Is there a dose-response effect of
      exercise on the above variables such that greater amounts of exercise brings about greater
      benefits in cognitive and brain health? (4) What are the mechanisms by which exercise
      influences brain health? and (5) What factors attenuate or magnify the effects of exercise on
      brain and cognitive health and contribute to the individual variability in intervention
      outcomes?
    

Detailed description: 
      The investigators are conducting a 12-month, multi-site, randomized dose-response exercise
      trial (i.e., brisk walking) in 639 cognitively normal adults between 65-80 years of age.
      Participants will be randomized to a (a) moderate intensity aerobic exercise condition at the
      public health recommended dose of 150 minutes/week (N=213), (b) a moderate intensity exercise
      condition at 225 minutes/week (N=213), or (c) a light intensity stretching-and-toning control
      condition for 150 minutes per week (N=213). Participants will meet 3 days/week for site-based
      exercise and do home-based activity on two more days of the week for 12 months. A
      comprehensive state-of-the-science battery of cognitive, MRI, amyloid imaging, physiological
      biomarkers, cardiorespiratory fitness, physical function, and quality of life measures will
      be assessed at baseline and after completion of the intervention.

      Due to Covid-19 pandemic, the exercise intervention was moved to fully home based during the
      months of March 2020 through August 2020. During this time, study participants were mailed
      wrist based heart rate monitors to track intensity. Exercise videos were developed and
      released to study participants to enhance adherence to the prescribed volume of exercise.
      Study participants were contacted weekly to obtain weekly exercise volume, mode and
      intensity. From August 2020 to end of the trial, participants will have flexibility to
      complete randomized goal of exercise. The study recommends three supervised sessions per week
      but will work with study participants who feel unsafe exercising in one of the study
      locations.

      The outcome measures to be collected during March 2020 and July 2020 were delayed in those
      subjects had original intervention end date during this time. For these study participants,
      many signed a study consent extension and continued the intervention until study sites were
      allowed to re-open after careful planning and approved mitigation plans at each respective
      university. Once approved to re-open, participants were scheduled for their post assessment
      outcome collection.

      Specific Aims include:

        1. Cognitive Enhancement: Using a comprehensive neuropsychological battery and the NIH
           Toolbox, the investigators will test (a) whether a 12-month moderate intensity exercise
           intervention improves cognitive performance in older adults and (b) whether the
           improvements occur in a dose-dependent manner. Hypothesis: PA will enhance cognitive
           performance non-uniformly with the greatest effects occurring for executive and
           declarative memory functions. The investigators also predict that these improvements
           will follow a dose-dependent trajectory with 225 minutes/week of PA demonstrating
           greater improvements than 150 minutes/week of PA.

        2. Brain Augmentation: The investigators will test (a) whether a 12-month PA intervention
           augments MRI markers of brain health and (b) whether changes happen in a dose-dependent
           manner. Hypothesis: PA will most profoundly influence the volume, microstructural white
           matter integrity, cerebral blood flow, and connectivity of regions supporting
           declarative memory (e.g., hippocampus) and executive function (e.g., prefrontal cortex;
           PFC). Further, the investigators predict that 225 minutes/week will result in greater
           effects than 150 minutes/week. The investigators predict that these changes in brain
           outcomes will mediate the cognitive improvements in Aim 1.

        3. Biomediators: The investigators will test the hypothesis that cardiometabolic,
           inflammatory, and neurotrophic changes mediate improvements in brain and cognition.
           Hypothesis: (1) decreases in pro-inflammatory cytokines, (2) decreases in central
           adiposity, arterial stiffness, and insulin resistance, and (3) increases in
           brain-derived neurotrophic factor (BDNF) levels will statistically mediate changes in
           cognitive performance (Aim 1) and brain health (Aim 2), and that the strength of this
           mediating relationship might vary as a function of certain apriori moderating variables
           of interest

        4. Moderators: To examine subgroups (i.e., individual differences) that attenuate or
           magnify the effect of the intervention on cognitive, brain, and physiological systems to
           better understand the factors that predict 'responders' versus 'non-responders' to the
           intervention. The investigators will examine three categories of variables: (1)
           demographic (e.g., age) (2) genetic (e.g., APOE), and (3) baseline Aβ burden.
           Hypothesis: The favorable effects of PA on brain and cognition will be greatest for
           older individuals with greater Aβ burden, and in those with a genetic susceptibility for
           accelerated cognitive decline.

        5. Amyloid Diminution: We will test (a) assess Amyloid deposition changes in response to
           physical activity and (b) whether changes occur in a dose-dependent manner and (c)
           examine baseline Amyloid as a moderator of intervention effects and (d) examine changes
           in Amyloid as a mediator of changes in brain and cognition. Hypothesis: We predict that
           Aβ burden will be attenuated over the course of the intervention for the aerobic
           exercise groups compared to control group. Further, we predict that 225 minutes/week of
           aerobic exercise will result in a greater effect on Aβ than 150 minutes/week

        6. Exploratory Aims: The investigators will explore (a) whether baseline brain health
           metrics predict adherence and compliance to 12-months of PA, and (b) the utility of
           multi-modal brain imaging analytical approaches to more comprehensively understand the
           effects of PA on the aging brain.
    

Intervention name(s): 150 Minutes Week; 225 Minutes Week; Stretch and Tone
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): This group will complete aerobic based exercise 150 minutes per week. Participants will obtain minutes through supervised on site exercise and home based exercise. An exercise duration of 30 minutes will be achieved by the forth week of the program and be maintained for the duration of the intervention. Heart rate will be monitored to ensure proper intensity levels. Participants will also be instructed to exercise at home for 30 minutes for two other days of the week at a similar intensity. The prescribed intensity will be 50-60% of the maximum heart rate reserve for weeks one to six and 60-75% for the remainder of the program. Participants in the walking conditions will wear heart rate monitors and be encouraged to walk within their target heart rate zone. During the Covid-19 pandemic shutdown, all intervention exercise was been shifted to home based.; This group will complete aerobic based exercise 225 minutes per week. Participants will obtain minutes through supervised on site exercise and home base exercise. A walking duration of 45 minutes will be achieved by the seventh week of the program. This will be maintained for the duration of the intervention and heart rate will be monitored to ensure proper intensity levels. Participants will be instructed to exercise at home for 45 minutes for two other days of the week at a similar intensity. The prescribed intensity will be 50-60% of the maximum heart rate reserve for weeks one to six and 60-75% for the remainder of the program. Participants in the walking conditions will wear heart rate monitors and be encouraged to walk within their target heart rate zone. During the Covid-19 pandemic shutdown, all intervention exercise has been shifted to home based.; The control condition will focus on improving balance, flexibility, and strength. This group will obtain 150 minutes per week via in person sessions, zoom sessions and home based stretching. Resistance bands, balance disks, yoga blocks, and exercise mats will be used to engage in non-cardiorespiratory activities. These are progressive in nature and include modifications to accommodate injuries, physical difficulties, etc. A new set of similar, yet slightly more challenging activities will be introduced every four weeks. During the first two weeks, participants are introduced to the new activities, and, during the second two weeks, they are encouraged to increase intensity by using more weight or more repetitions. During the current Covid-19 pandemic, all intervention exercise has been shifted to home based.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Study participants will be randomly assigned to one of three exercise intervention arms.
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Exercise; Brain Health; Dose Response; Cognition