Background
Aging is associated with declines in certain cognitive domains and lower levels of physical activity [
1,
2]. The Public Health Agency of Canada [
2] and World Health Organization [
3] report that adults between 65 and 74 years of age are the most sedentary portion of the population. An estimated 60% of older adults lead sedentary lifestyles and do not engage in enough physical activity to achieve favorable health benefits [
4]. Physical inactivity is a recognized modifiable risk factor of cerebrovascular disease and the cognitive decline seen in older adults [
5,
6]. With the projected doubling of the number of older Canadians over the next 25 years [
7], it is anticipated that the personal and societal burden of age-associated conditions like cerebrovascular disease and dementia (e.g., Alzheimer’s disease, AD) will increase substantially [
8].
Post-maturational aging is associated with reduced abilities in a number of cognitive processes, including attention, learning and memory, and executive control [
9]. These age-related changes, while detectable, are generally considered part of the aging process and usually do not interfere with the ability to live independently. Dementia, an acquired decline in multiple cognitive areas causing a significant impairment in social or occupational functioning , occurs in approximately 8% in the older population, with AD and vascular dementia (VaD) either alone or in combination the most common causes [
10,
11]. As both aging and vascular disease are risk factors for both AD and VaD, age-associated declines in cerebrovascular function might contribute to the development of these disorders [
11‐
13].
With normal aging there is an approximately 5% decrease per decade in resting cerebral blood flow (CBF) [
14]. Although the brain represents 2.0 to 2.3% of an adult’s total body weight, in percentage terms it accounts for ten times more of the body’s total resting energy consumption [
15,
16]. Since cerebral tissue does not produce or store sources of energy, its high metabolic need requires constant and adequate blood supply. Age-related hypoperfusion may be associated with sufficient reductions in the delivery of oxygen and nutrients and inadequate removal of metabolic by-products to produce impaired cognitive function and slowly progressive cellular injury [
17]. Neurons, glial and vascular cells are linked together in neurovascular units where neuronal and glial signals control local CBF [
17‐
19]. With aging, neurovascular coupling is disrupted, which could result in the metabolic requirements of the brain tissue not being matched by CBF [
15,
18]. Decreases in CBF have been associated with a number of age-related neurodegenerative changes including a loss of neuropil (i.e., synaptically dense regions of the nervous system mainly composed of unmyelinated axons, dendrites and glial processes) [
20].
There is consistent evidence that regular exercise promotes brain health and is associated with a lower risk for age-related cognitive decline and dementia [
21], however the underlying mechanisms have not been well defined [
22]. Neuroimaging studies of older adults indicate that higher levels of cardiovascular fitness are associated with larger volumes of specific brain regions including the hippocampus, an important region for learning and memory [
23,
24]. This effect may be attributable, in part, to neurogenesis [
25] possibly mediated by increases in vascularization, elevated levels of neurotrophins and growth factors, and/or improved neuronal survival in the aging brain [
26].
Previous studies have focused primarily on neuronal processes that may explain why physical activity promotes healthy brain aging while cerebrovascular mechanisms that might underlie improved cognitive function are relatively poorly understood. Pharmacological manipulation of cerebral blood flow can modify performance on a variety of cognitive tasks in both animal models and humans (for review see [
15,
27]). Cerebrovascular networks are thought to have a high degree of plasticity (i.e., they are changeable or modifiable) [
27]. Exercise appears to stimulate the growth of new capillaries from preexisting vessels in the brain and improve resting CBF [
27,
28]. We recently demonstrated that increased levels of physical fitness were associated with greater cerebrovascular reserve (i.e., the ability of cerebral arteries to dilate in response to a stimulus) and improved cognitive function [
12]. These data suggest that the link between physical fitness and cognition may be mediated, at least in part, by improvements in cerebrovascular function.
We are conducting a quasi-experimental prospective cohort study with two primary aims: 1) to determine the effect of a six-month aerobic exercise intervention on physical fitness, resting CBF, cerebrovascular reserve, and cognitive function in 250 sedentary men and women between the ages of 55 and 80 years; and, 2) to determine the extent to which the changes in cerebrovascular and cognitive function persist six months following the completion of the exercise intervention. We hypothesize the improvement in cognitive function derived from regular aerobic exercise is at least partially mediated by enhanced cerebrovascular reserve. Further, we hypothesize that these beneficial changes will persist in participants who remain physically active as compared to those who revert to a sedentary lifestyle. The purpose of this manuscript is to describe the study design and research methodologies in detail.
Discussion
Current projections suggest that by 2031, approximately 25% of the Canadian population will be over the age of 65 [
7] and in 2050, the estimated world population over the age of 60 will be 2 billion [
3]. With societal aging, a progressive increase in the absolute number of individuals suffering from age-associated health issues like cerebrovascular disease, VaD, and AD will inevitably occur unless we can change the likelihood of these events occurring. If we cannot, population aging will lead to a significantly greater burden on the health and social care system of our country and around the world. Effective prevention of these diseases is of paramount importance. A promising approach is encouraging higher levels of physical activity since exercise may delay or prevent the progression of cognitive decline associated with aging, prevent cerebrovascular disease, and delay the onset of AD and related dementias [
64].
The BIM study is designed to add to the literature on whether exercise can be an effective means of decreasing the effects of aging on cognition. This study will combine detailed physiological and cognitive data with sociodemographic, biologic, and lifestyle information obtained from a relatively large and well defined older population. By performing an exercise intervention we are able to investigate the extent to which cerebrovascular physiology might act as a mediating factor between exercise and cognition. If confirmed this raises the possibility of cerebrovascular measures functioning as a surrogate marker of brain health in future studies of exercise interventions.
The BIM study uses state-of-the-art measurements of cerebrovascular function, physical fitness, cognitive function, lifestyle, sleep, biologic, and genetic markers all of which strengthen the study. The Laboratory for Human Cerebrovascular Physiology houses sophisticated equipment to control end-tidal PO
2 and PCO
2 accurately and continuously using our dynamic forcing-function system. The VO
2max testing protocols used in the study are considered the “gold-standard” practice for the assessment of physical fitness, thereby adding strength to the study since we avoid problems associated with predictive tests by measuring VO
2max rather than VO
2peak [
65]. The comprehensive neuropsychological test battery allows us to assess multiple aspects of cognitive function. The battery is administered at multiple time points through the study that will allow the assessment of whether the exercise intervention has an impact on cognitive function, how long it takes to become evident, and its duration. We have included numerous self-administered questionnaires to measure changes in dietary intake, sleep habits, physical activity levels and cognitive abilities at differing time points. Collectively, these data will provide insights regarding the possible mechanisms whereby exercise improves cerebrovascular and cognitive function.
The current study is unique because all the participants of our study attend our supervised and structured exercise program for six-months. Further, the exercise program is individually tailored to each participant as exercise prescriptions are based on each individual’s heart rate reserve. This supervised intervention assesses participants’ progression through the exercise program with modifications to the intervention made as needed. The BIM study uses a quasi-experimental prospective cohort design because it reduces variability over time since each participant is their own control during the repeated baseline assessment over a six-month period. An inherent weakness is the potential carry over or practice effects in repeated cognitive testing. We have attempted to deal with this issue by 1) repeating the baseline cognitive testing to observe the stability of the performance measures over time before the intervention, 2) using alternate forms of tests when possible (i.e., verbal fluency, selective reminding, MCG figure, card sorting), and 3) we will analyze the cognitive data for overall trends at the four time points to examine for a global practice effect over time. The next logical step in our research program will be a randomized controlled trial in first a healthy and then in a diseased population (e.g. individuals with Mild Cognitive Impairment or stroke).
The mechanisms whereby exercise-induced increases in cerebrovascular reserve improve cognitive function are unknown. At this time, we are focused on demonstrating the physiologic mechanisms by which exercise confers its beneficial influence on cognition. The BIM study is the first to examine the influence of an aerobic exercise intervention on cerebrovascular and cognitive function in a healthy aging population. The results from this study may inform the development of new therapies to reduce or prevent the cognitive decline associated with aging.
Acknowledgements
The present study is supported by the Canadian Institutes of Health Research operating grant (735144; MJP (Principal Applicant), GAE, CMF, MDH, DBH, RSL (Co-Applicants), TJA, RL and EES (Collaborators)), Alzheimer Society Research Program doctoral award (AVT), Heart and Stroke Foundation of Canada- Focus on Stroke Postdoctoral fellowship (MHD), Alberta Innovates-Health Solutions (MJP, MDH (Senior Scholar), CMF (Health Senior Scholar), GAE (Visiting Scientist), GAL (Postgraduate Fellowship)), Heart & Stroke Foundation Visiting Scientist (GAE), The Brenda Stafford Foundation Chair in Geriatric Medicine of the University of Calgary (DBH), The Brenda Strafford Foundation (DBH, MJP), Heart & Stroke Foundation of Alberta, NWT and Nunavut (MDH), and the Alberta Cancer Foundation Weekend to End Breast Cancer Chair (CMF). We thank Polar® for their support and contribution of the heart rate monitoring equipment and the Team2 system used during the exercise intervention sessions. We also thank the Dean (Dr. Wayne Giles (2006–2012)) and the Faculty of Kinesiology for the support in facilitating the exercise intervention. We thank Brad Hansen (technical support), Kristin Sabourin (physiological and exercise testing), and Jacqueline Harrison (physiological testing and data analysis) in Dr. Marc Poulin’s Laboratory of Human Cerebrovascular Physiology for their assistance in testing. We also thank Dr. Stephen Wilton and Dr. Billie-Jean Martin for providing medical coverage for exercise testing.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
GAE, CMF, MDH, DBH, RSL, TJA, RL, EES, MJP have made substantial contributions to conception and design of this study. AVT and MHD wrote the draft of the manuscript and all authors were involved in revising the manuscript critically for important intellectual content. BJW provided significant medical coverage for exercise testing. GMB and EH were involved in coordinating the study and recruitment. GAL contributed the social support questionnaire to the study. All authors have given final approval of the version to be published.