Graded Intensity Aerobic Exercise to Improve Cerebrovascular Function and Performance in Older Veterans: Protocol for a Randomized Controlled Trial
Authors: Bello Medina Oneyi , Mammino Kevin Michael , Vernon Mark Anthony , Wakeman Daniel G , Denmon Chanse Aerius , Krishnamurthy Lisa Crystal , Krishnamurthy Venkatagiri , McGregor Keith Matthew , Novak Thomas Samuel , Nocera Joe Robert 
Published: July 2024

Background
Growing health care challenges resulting from a rapidly expanding aging population necessitate examining effective rehabilitation techniques that mitigate age-related comorbidity and improve quality of life. To date, exercise is one of a few proven interventions known to attenuate age-related declines in cognitive and sensorimotor functions critical to sustained independence.

Objective
This work aims to implement a multimodal imaging approach to better understand the mechanistic underpinnings of the beneficial exercise-induced adaptations to sedentary older adults’ brains and behaviors. Due to the complex cerebral and vascular dynamics that encompass neuroplastic change with aging and exercise, we propose an imaging protocol that will model exercise-induced changes to cerebral perfusion, cerebral vascular reactivity (CVR), and cognitive and sensorimotor task-dependent functional magnetic resonance imaging (fMRI) after prescribed exercise.

Methods
Sedentary older adults (aged 65-80 years) were randomly assigned to either a 12-week aerobic-based interval-based cycling intervention or a 12-week balance and stretching intervention. Assessments of cardiovascular fitness used the YMCA submaximal VO2 test, basal cerebral perfusion using arterial spin labeling (ASL), CVR using hypercapnic fMRI, and cortical activation using fMRI during verbal fluency and motor tapping tasks. A battery of cognitive-executive and motor function tasks outside the scanning environment will be performed before and after the interventions.

Results
Our studies and others show that improved cardiovascular fitness in older adults results in improved outcomes related to physical and cognitive health as well as quality of life. A consistent but unexplained finding in many of these studies is a change in cortical activation patterns during task-based fMRI, which corresponds with improved task performance (cognitive-executive and motor). We hypothesize that the 12-week aerobic exercise intervention will increase basal perfusion and improve CVR through a greater magnitude of reactivity in brain areas susceptible to neural and vascular decline (inferior frontal and motor cortices) in previously sedentary older adults. To differentiate between neural and vascular adaptations in these regions, we will map changes in basal perfusion and CVR over the inferior frontal and the motor cortices—regions we have previously shown to be beneficially altered during fMRI BOLD (blood oxygen level dependent), such as verbal fluency and motor tapping, through improved cardiovascular fitness.

Conclusions
Exercise is one of the most impactful interventions for improving physical and cognitive health in aging. This study aims to better understand the mechanistic underpinnings of improved health and function of the cerebrovascular system. If our hypothesis of improved perfusion and cerebrovascular reactivity following a 12-week aerobic exercise intervention is supported, it would add critically important insights into the potential of exercise to improve brain health in aging and could inform exercise prescription for older adults at risk for neurodegenerative disease brought on by cerebrovascular dysfunction.

Trial Registration
ClinicalTrials.gov NCT05932069; https://clinicaltrials.gov/study/NCT05932069

International Registered Report Identifier (IRRID)
DERR1-10.2196/58316