Resistance Training and Neuroimaging
Condition: Cognitive Decline; Cerebrovascular Function
MeSH terms: Cognitive Dysfunction
Study type: Interventional

Summary: 
      Aging tends to compromise the ability to solve problems, remember details, and process
      information. At the extreme level, this normal cognitive decline can interfere with
      independent living. Because most brain dysfunctions become irreversible before patients show
      clear signs in the clinic, there is a pressing need to prioritize preventative
      countermeasures. Exercise is a promising strategy to slow or reverse these losses. While most
      studies have looked at running or cycling exercise, little is known about the effects of
      weight lifting exercise. In addition, vascular health is intimately linked with cognitive
      abilities and risk of stroke, making it a primary target for intervention. Previous weight
      lifting studies suggest that blood vessels in the brain are a likely site of adaptation.

      The goal of this research is to understand how weight lifting exercise improves cognitive
      function in older adults. Specifically, the contribution of blood vessel changes in the brain
      after 12 weeks of weight lifting exercise 3 days per week. These vascular improvements may
      provide the link between physical and cognitive health, while simultaneously reducing the
      risk of cardiovascular disease and stroke. To determine this, advanced brain imaging
      techniques will be used to measure blood flow/volume changes in the brain non-invasively.
      Physical capacity (i.e. strength), body composition (i.e. lean mass, fat mass), and blood
      markers will also be assessed using standard protocols, and each of these variables will be
      tested for their relationship with cognitive functions.

      Understanding how weight lifting exercise improves cognitive function will support the
      development of comprehensive treatments targeting overall brain health. With no current cures
      for dementia, this information will be vital in prescribing exercise for specific patient
      needs to reducing the risk of dementia and stroke. In addition, the promise of exercise
      therapies extends beyond the target disease, having further benefits to the well-being of
      participants. These types of treatments positively impact fundamental aging processes, and
      thus reduce the risk of all-cause mortality. Even with moderate benefits to a specific
      disease like dementia, the global impact on healthcare would be substantial.
    

Detailed description: 
      Exercise is a promising strategy to slow or prevent the progression of cognitive decline and
      dementia. While resistance training (RT) is a popular form of exercise recommended for older
      adults for its putative role in the protection against sarcopenia, its effects on brain
      health have been less-well studied. Previous RT studies involving traditional protocols
      highlight robust and lasting benefits to fluid cognition. In contrast, little is known about
      the effects of high-intensity RT with advanced periodization techniques. Such protocols may
      produce similar improvements in shorter durations, thus improving clinical utility. In
      addition, the mechanisms of RT-induced cognitive enhancement are not well understood.
      Defining the dominant neural and physiological processes that underlie these protective
      effects is essential to explain the variance in cognitive responses and to design optimal
      treatment strategies for the aging population.

      The effectiveness of RT interventions for cognitive health likely depends on maximizing gains
      in muscular strength. Therefore, the investigators will apply strength and conditioning
      principles and advanced neuroimaging techniques to a 12-week periodized RT intervention to
      determine neuroprotective contributions. Cerebrovascular (CV) function is a major component
      of brain health and a primary mechanism of cognitive enhancement after aerobic training.
      However, the potential for RT to influence these pathways has not been determined. This study
      will test and extend previous cross-sectional evidence linking RT with CV function. In
      addition, RT interventions have been demonstrated to improve systemic vascular function and
      cognition independently. Thus, the investigators hypothesize that RT improves cognitive
      function through muscular strength and CV adaptations. The overall goal of this proposal is
      to investigate changes in cognition and CV function in 23 healthy older adults 60-80 years of
      age, serving as their own controls, and explore the mechanisms that mediate these effects. To
      address this goal, the investigators propose the following aims:

      Aim 1: To determine whether 12 weeks of periodized RT improves fluid cognition in older
      adults. The NIH Toolbox® Cognition Battery will be administered to assess changes in
      executive function, attention, episodic memory, processing speed, working memory, and
      language. Composite scores will be computed for fluid, crystallized, and global cognitive
      function.

      Hypothesis: A 12-week periodized RT program designed specifically to maximize strength gains
      improves fluid cognition in healthy older adults.

      Aim 2: To evaluate the effects of periodized RT on CV function in older adults. Arterial spin
      labeling (ASL) MRI techniques will be used to assess changes in CV function by quantifying
      the effects on resting cerebral blood flow, intracranial vascular compliance, and arterial
      transit time. Mediation analyses will be performed to determine the mediating effects of CV
      function on cognition.

      Hypothesis: High-intensity RT can improve CV function in healthy older adults.

      Aim 3: To explore associations between brain adaptations and potential mechanisms of benefit,
      including: 1) physical capacity (e.g. muscular strength), body composition, and functional
      mobility; 2) putative blood markers of exercise-induced brain plasticity; 3) cardiovascular
      risk factors; and 4) brain morphometry and resting state brain activity. Significant changes
      will be analyzed for mediation of cognitive function to identify the major pathways that
      underlie the protective effects of RT.

      For the practicality of this study, participants will serve as their own controls. All
      control periods will take place before the RT intervention to ensure that results are not
      confounded by detraining effects or long-term cognitive benefits of RT. All participants will
      undergo testing at baseline, pre-intervention, and post-intervention. The NIH Toolbox
      Cognition Battery will provide a standard set of comprehensive assessment tools. Three test
      versions will be used to reduce practice effects. During MRI scans, ASL techniques will be
      used to assess CV function and standard sequences will be used for structural MRI (e.g.
      T2-weighted FLAIR and T1-weighted MP-RAGE), resting state function MRI (rfMRI), and diffusion
      tensor imaging (DTI). Physical outcomes will be assessed using standard testing procedures in
      exercise physiology research, including blood pressure, body composition, physical function,
      muscle strength and estimated VO2max. Validated questionnaires for quality-of-life, physical
      activity, sleep quality, and interpersonal support will be administered.

      Participants will perform a periodized and progressive total-body resistance training program
      emphasizing development of lower and upper body strength. All 36 training sessions (3 days
      per week for 12 weeks) will be performed at the CERC, supervised by an exercise specialist.
      Mesocycle I (weeks 1-4) will emphasize muscular hypertrophy to develop a muscular and
      metabolic base for more intense training in later phases. Training bouts will consist of 4-6
      resistance exercises with 2-4 sets per exercise and 8-10 repetitions per set. Mesocycles II
      (weeks 5-8) and III (weeks 9-12) will emphasize strength development. Training bouts will
      consist of 4-6 resistance exercises with 3-5 sets per exercise, 4-6 repetitions per set, and
      linear increases in intensity over time. As in similar RT studies, the training loads used
      will be individually progressed in a safe and effective manner in order to employ a
      progressive overload/challenge to the neuromuscular system and elicit the greatest
      training-induced neuromuscular adaptations possible.
    

Intervention name(s): Periodized Resistance Training
Intervention type(s): Behavioral
Intervention description(s): Mesocycle I (weeks 1-4) will emphasize muscular hypertrophy to develop a muscular and metabolic base for more intense training in later phases. Training bouts will consist of 4-6 resistance exercises with 2-4 sets per exercise and 8-10 repetitions per set. Mesocycles II (weeks 5-8) and III (weeks 9-12) will emphasize strength development. Training bouts will consist of 4-6 resistance exercises with 3-5 sets per exercise, 4-6 repetitions per set, and linear increases in intensity over time. These parameters were chosen to maximize performance on 4-6 repetition maximum (RM) testing post-intervention, according to the principle of specificity - i.e. specific adaptation to imposed demands.The training loads used will be individually progressed in a safe and effective manner, in order to employ a progressive overload/challenge to the neuromuscular system and elicit the greatest training-induced neuromuscular adaptations possible.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: There are two phases in this single-group study: an initial control period and an intervention period. All control periods will take place before the RT intervention to ensure that results are not confounded by detraining effects or long-term cognitive benefits of RT.
Masking: None (Open Label)
Primary purpose: Basic Science