Exercise & Sport Sciences Reviews:
Cerebrovascular Reserve: The Link Between Fitness and Cognitive Function?
Davenport, Margie H.1; Hogan, David B.1; Eskes, Gail A.2; Longman, R. Stewart1; Poulin, Marc J.1
1Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta; and 2Life Sciences Research Institute, Dalhousie University, Halifax, Nova Scotia
Address for correspondence: Marc J. Poulin, Ph.D., D.Phil., Department of Physiology and Pharmacology, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Libin Cardiovascular Institute of Alberta, Faculty of Medicine and Faculty of Kinesiology, University of Calgary, Heritage Medical Research Building Room 210, 3330 Hospital Drive NW, Calgary, Alberta, Canada (E-mail: email@example.com).
Accepted for publication: March 12, 2012
Associate Editor: Walter Herzog, Ph.D.
Better physical fitness in later life is associated positively with cognitive functioning. Novel data suggest that this association is mediated, in part, by increases in brain perfusion and the ability of cerebral blood vessels to respond to demand. This review presents evidence on the beneficial effects of exercise on cerebrovascular and cognitive health with aging and explores potential underlying vascular-related mechanisms.
When the 21st century dawned, there were approximately 600 million persons aged 60 yr and older worldwide. By the middle of this century, this will more than triple to 2 billion. Societal aging brings with it important health care, economic, and fiscal challenges. At the level of the individual, aging is associated with a time-dependent but variable decline in exercise capacity and cognitive functioning. These changes are believed to arise from damage caused by the long-term consequences of cellular processes, environmental exposures, and/or age-associated diseases modulated by our genetic makeup and lifestyle.
Recently, we demonstrated that higher levels of aerobic fitness in older individuals are associated with improved cognition, greater cerebrovascular conductance (CVC) at rest (a measure of basal brain perfusion), and increased cerebrovascular reserve (the ability of the cerebral blood vessels to respond to stimuli) (5). Our data suggest that the association between fitness and cognition is mediated, at least in part, by processes that involve the cerebral circulation. In this review, we present current evidence on the beneficial impact of exercise on cognition as we age and explore potential vascular mechanisms by which this occurs.
COGNITIVE CHANGES WITH NORMAL AGING
Age-related cognitive decline refers to the “normal” or expected time-dependent deterioration in certain mental abilities after reproductive maturity (30). Although detectable, and often viewed as an annoyance, these changes normally do not lead to significant problems with everyday functioning. Cognitive domains differ in their aging trajectories. In general, skills that require speed, mental flexibility and organizational processes, or the ability to learn new information show greater declines than those involving simple attention, use of previously acquired knowledge, or that rely on the quality, rather than the speed, of the response. The underlying cause is likely multifactorial.
With dementia, the loss in cognitive function is beyond what would be expected from normal aging and interferes with a person’s ability to live in an autonomous manner (3). The two most common forms of dementia encountered in older individuals are vascular dementia (VaD), where cognition is impaired because of the focal and/or diffuse effects of vascular disease on the brain, and the neurodegenerative condition Alzheimer’s disease (AD). These forms of dementia frequently coexist. Here, clinical manifestations arise from an interplay between the two pathologies. Aging and vascular diseases are risk factors for both AD and VaD. Vascular pathology, including a decrease in cerebrovascular function, is increasingly believed to be part of the underlying etiology of AD as well as VaD.
EFFECT OF NORMAL AGING ON CEREBROVASCULAR FUNCTION
Normal Resting Cerebral Blood Flow
Although the brain makes up only 2% of body weight, it uses 15% of total cardiac output and up to 20% of the oxygen and nutrients supplied by the cardiovascular system (4). A high level of metabolism, coupled with a lack of energy stores within the brain, necessitates that cerebral blood flow (CBF) be constantly maintained. When cerebral perfusion is at risk, blood flow is redirected to the brain at the expense of peripheral vascular beds. With advancing age, blood flow declines in many vascular beds, including the cerebral one. Resting CBF decreases by approximately 4 mL min−1 yr−1 after our third decade (32). This coincides with an increase in oxidative stress with age (35). Mechanoreceptors and chemoreceptors on endothelial cells sense mechanical (shear stress) and chemical stimuli to release signaling molecules, including nitric oxide (NO), endothelin, and prostanoids.
Reactive oxygen species (ROS) are believed to decrease NO bioavailability in the vasculature, leading to endothelial dysfunction. ROS-mediated inhibition of NO production is positively correlated with decreased basal cerebral perfusion (28). Although the decline in resting CBF associated with normal aging is not sufficient to cause major ischemic injury, it might result in hypoperfusion that could prevent sufficient nutrients from reaching areas of high metabolic need and exacerbating age-associated degenerative changes (20).
Cerebrovascular reserve is the ability of cerebral blood vessels to respond to increased metabolic demand and chemical, mechanical, or neural stimuli. The microvessels of the cerebral circulation are exquisitely sensitive to carbon dioxide (CO2) changes in arterial blood and dilate in response to increased levels of CO2 (i.e., hypercapnia). The cerebrovascular response to hypercapnia is a measure of cerebrovascular reserve and can be used to quantify vascular reactivity and assess cerebrovascular function. There is a general decline in cerebrovascular reactivity to hypercapnia with age (15). It is unclear whether this is related to oxidative stress and endothelial dysfunction or some other mechanism. Studies in nonhuman primates demonstrate that cerebral reactivity to hypercapnia primarily involves NO-mediated endothelial-dependant dilation. When an NO synthase (NOS) blocker is infused into the internal carotid artery, the cerebrovascular response to CO2 is abolished (34). In support of these findings, cerebrovascular reactivity to CO2 also is impaired in humans with peripheral endothelial dysfunction, which also would be expected to be present in the cerebral vasculature (23). In contrast, human studies in young healthy populations examining the influence of the NOS inhibitor L-NMMA on cerebrovascular reactivity found that blocking NOS did not alter CBF reactivity, suggesting that NO may not be required for the cerebrovascular response to hypercapnia (21,38). However, the NO pathway is only one of several pathways that induce vasodilation. Alternative pathways include prostaglandins, the cyclooxygenase pathway, and endothelium-derived hyperpolarizing factor. As the NO and prostanoid pathways are known to be less active with aging, the age-associated decline in cerebral reactivity likely is caused by multiple, possibly overlapping, mechanisms.
Neural activation elicits local increases in CBF to support neural metabolism. Functional hyperemia is critical in the maintenance of the blood flow required for a continuous supply of oxygen and nutrients. This control involves neurons, glial cells (i.e., astrocytes), and vascular cells, which are interrelated structurally and functionally to form the neurovascular unit. As shown in Figure 1, blood vessels are surrounded and supported by astrocyte end-feet that form the blood-brain barrier. Astrocytes also interact directly with neurons. Neurotransmitters and mediators released from neurons activate both vascular smooth muscle cells and astrocytes to alter blood vessel tone (17). Neurotransmitters, in particular glutamate, play a major role in the regulation of CBF. Synaptic release of glutamate leads to upregulation of neuronal NOS, which releases NO from neurons and arachidonic acid from astrocytes, resulting in vasodilation and an increase in CBF (4). Declines in neurovascular coupling with age have been demonstrated in response to both visual (27) and mental stimulation (25). At the same time, an age-associated increase in ROS production promotes vascular inflammation of the systemic and cerebral blood vessels (26,35). This becomes a vicious circle as vascular inflammation further promotes ROS production. In the cerebral circulation, vascular inflammation and ROS disrupt the blood-brain barrier through upregulation of vascular endothelial growth factor (VEGF), causing an increased permeability to proinflammatory cytokines, adhesion molecules, and metalloproteases (26). The resulting vascular and neuronal damage impairs functional hyperemia, which could lead to hypoperfusion, ischemia, and even cell death. Preventing or attenuating vascular inflammation and ROS production could be an important mechanism by which to prevent these outcomes.
EFFECT OF EXERCISE ON CEREBROVASCULAR FUNCTION
Regular aerobic exercise is an effective nonpharmacological method to enhance endothelial function (and thereby arterial compliance) and decrease arterial stiffness, oxidative stress, and vascular inflammation. As previously described, resting CBF declines with age. Recently, Ainslie et al. (1) examined the influence of fitness on basal CBF in men aged 18 to 79 yr. CBF was 17% higher in endurance-trained men compared with healthy but sedentary counterparts after controlling for confounding variables, such as body mass index and mean arterial pressure. Although the mechanism for this was not elucidated, animal work by Endres et al. (12) suggests that increased blood flow with resultant increases in vascular shear stress may upregulate endothelial NOS expression, leading to an increase in NO-dependant vasodilation and an increase in basal CBF. Furthermore, Swain et al. (33) demonstrated that chronic exercise resulted in elevated perfusion of the motor cortex of the rat. This was suggested to be caused by an increase in the recruitment of capillaries as well as the growth of new capillaries (i.e., angiogenesis) (33).
Higher levels of fitness are associated with increases in the volume of cerebral gray matter (neurons) and white matter (myelinated axons) in older adults (8). The hippocampus, which is important for long-term memory and spatial abilities, shrinks by 1% to 2% per year after middle age. However, this decline may be attenuated by exercise (13). This neuroplasticity (the ability of the nervous system to change structurally and functionally in response to input from the environment) might arise from exercise-induced increases in brain-derived neurotrophic factor (BDNF) (36). BDNF supports the health and growth of neurons and is believed to regulate neuroplasticity as we age (6). To study the potential role of BDNF in exercise-induced improvements in cognition, Vaynman et al. (36) randomly injected either BDNF blocker or placebo directly into the hippocampus of 3-month-old rats. Subsequently, 50% of the rats in each group were exercised for 1 wk, whereas the rest were sedentary. At the end of the week, the rats were trained to perform a cognitive task. The cognitive abilities of the BDNF-blocked exercising rats were similar to sedentary rats, whereas rats who exercised and received a placebo injection did significantly better on the task. This elegant study demonstrated that BDNF is necessary for at least some of the exercise-induced benefits seen in cognition.
BDNF is regulated by NO and is related to enhanced neurogenesis (6). However, as previously noted, the vascular endothelium that produces NO is highly sensitive to oxidative stress and vascular inflammation. ROS-mediated declines in NO production and increases in proinflammatory cytokines might inhibit the BDNF pathway, but these deleterious effects may be attenuated by exercise. Acute exercise leads to a transient increase in oxidative stress, but chronic aerobic exercise is believed to have an antioxidant effect on the vasculature possibly through improvements in endothelial-dependent vasodilation, arterial remodeling, and decreases in proinflammatory cytokines. In aging mice, exercise restored peripheral endothelial-dependent vasodilation through improvements in the efficiency of antioxidant enzymes and increased NO bioavailability (11). Recently, our group examined the influence of fitness on oxidative stress, NO production, mean arterial pressure (MAP), and CVC at rest in 42 postmenopausal women (28). This study was the first in humans to report that increased levels of fitness were associated with increased antioxidant activity and decreased oxidative stress, suggesting that exercise may attenuate the effects of normal aging on oxidative stress measured in plasma. Furthermore, increased oxidative stress was associated with decreased CVC and NO production as well as higher levels of MAP (Table 1). The negative correlation between measures of oxidative stress and antioxidant enzyme activity combined with the positive correlation between fitness and antioxidants suggests that chronic aerobic exercise may upregulate antioxidants. This may begin to explain the disparate effects of acute and chronic exercise on ROS production. Furthermore, the negative correlation between oxidative stress and CVC suggests that ROS may play a role in the regulation of cerebrovascular tone, potentially through its effects on the endothelium. If this is the case, ROS could play a role in the progression of cerebrovascular diseases and warrants further investigation.
As exercise-induced neurogenesis occurs, there will be an increase in metabolic requirements within the brain. To accommodate this, angiogenesis unfolds. BDNF, insulin-like growth factor 1 (IGF-1), and VEGF are the main growth factors known to mediate the effects of exercise on cerebrovascular function (10). BDNF in concert with IGF-1 increase neurogenesis, which is associated with improved learning and memory. IGF-1 and VEGF synergize to stimulate angiogenesis in the brain. Higher degrees of vascular inflammation as a result of increased levels of ROS, which typically are seen with aging and vascular disease, will increase the permeability of the blood-brain barrier to proinflammatory cytokines and interfere with growth factor signaling within the brain. Exercise attenuates these deleterious effects by decreasing vascular inflammation and circulating cytokines, as well as increasing growth factor concentrations (10,16).
EXERCISE AND COGNITION
Physical activity and exercise are associated with positive effects on the cognitive abilities of older adults. These relationships have been studied using a variety of approaches. In prospective cohort studies, higher levels of physical activity, typically measured by questionnaire, are associated with a reduced risk of cognitive decline, dementia, and AD in later life, even after controlling for potential confounding factors such as age, education, and comorbidities (22). A meta-analysis of 16 prospective observational studies in nondemented individuals at baseline showed that the relative risk for dementia and AD was 0.72 and 0.55, respectively, for individuals in high versus low physical activity categories (18). This reduction in risk has been seen with both short- and long-term follow-up (2–21 yr) (2,29) and in at-risk populations, including women with vascular conditions (37). Physical activity also is related to the rate of cognitive decline in longitudinal studies of healthy seniors. Yaffe et al. (39,40) found that individuals older than 65 yr with higher rates of self-reported exercise and/or walking at baseline were less likely to experience cognitive decline than less active individuals during a 6- to 8-yr period. This relationship has been found in studies using objective measures of activity as well. Middleton et al. (24) reported that higher levels of physical activity, as measured by energy expenditure (determined over 2 wk by the doubly labeled water method), are associated with lower odds of developing cognitive impairment on screening compared with those less active after adjusting for baseline cognition, demographics, and comorbidities (odds ratio, 0.09; 95% confidence interval, 0.01–0.79).
Cross-sectional studies have reported protective effects of fitness on brain structure and function. For example, in our study of older women, cognition was measured by an 11-test neuropsychological battery, covering the cognitive domains of processing speed, perception, verbal ability, verbal memory, visual memory, attention, and executive function, as well as a global score for each individual. Global cognitive function was correlated with physical fitness, as measured by V˙O2max (r = 0.41), and was higher in the active compared with the sedentary group (as defined by participation in regular aerobic exercise). Scores in the domains of cognitive speed, verbal ability, perception, and executive function also were significantly higher in the active compared with the sedentary group after controlling for age and education (5).
Randomized intervention trials of older subjects have confirmed the positive benefits of aerobic training on cognitive function (31), particularly with executive processes (7), and brain volume and function as measured by magnetic resonance imaging, electroencephalography, and evoked response potential (19). A meta-analysis of the impact of fitness on cognition highlighted some of the important factors linking the two variables, such as the length and intensity of training, gender, and the cognitive domain tested (7).
Other factors such as intellectual stimulation may play a modifying role on the maintenance of cognitive functioning with aging. They may lead to the development of neural structures that synergize with exercise-induced brain changes (22). Work by our group highlights the relationship of cognitive stimulation, physical fitness, and cognitive abilities (5). Multiple hierarchical regression analyses showed that both physical fitness (V˙O2max) and the number of cognitive activities (i.e., leisure pursuits judged to be cognitively stimulating, such as board games, reading, drawing, puzzles) were independent predictors of cognitive function, particularly global and executive function (Table 2). Of interest was the finding that the number of cognitive activities (i.e., diversity of stimulation) and not the overall time spent on them (duration) was associated significantly with cognitive function (14). We currently are studying the modifying effect of intellectually stimulating activities on the cognitive benefits seen with exercising in a prospective cohort study.
EVIDENCE LINKING FITNESS, CEREBROVASCULAR RESERVE, AND COGNITION
Based on the preceding evidence, we hypothesize that the positive relationship seen between increased levels of fitness and improved cognitive functioning is mediated, at least in part, by vascular mechanisms, including an increase in cerebrovascular reserve. We acknowledge that there likely are other mechanisms by which exercise has its beneficial impact. In our cross-sectional study, we demonstrated that cardiovascular fitness was associated with increased CVC at rest and improved cognitive functioning. Furthermore, assessment of cerebrovascular reserve during exercise and hypercapnia found that physically active women had a greater vascular responsiveness to stimuli compared with sedentary women (Fig. 2). This improved responsiveness was related positively to better overall cognitive functioning, which suggests that the link between fitness and cognition is mediated, at least in part, by cerebrovascular reserve. Based on the results of our studies, we suggest that regular exercise leads to a number of favorable adaptations in the vascular system, including decreases in blood pressure and oxidative stress and increases in antioxidant activity, which all contribute to improved cerebrovascular function (Fig. 3). The elevated levels of BDNF and NO as a result of improved cerebrovascular reserve serve to promote neurogenesis, angiogenesis, and synaptogenesis, thereby potentially providing a substrate for preserving, or even improving, cognitive function (36). In an ongoing prospective study, our group is exploring further what we feel is a causal relationship between fitness, cerebrovascular reserve, and cognition.
Intervention studies will be required to determine the extent to which cerebrovascular reserve might explain the association between increased fitness and improved cognition. If confirmed in efficacy studies, the potential for physical fitness to prevent and/or delay age-related cognitive decline and dementia through vascular-mediated mechanisms has huge implications for both preventive and therapeutic strategies.
Despite the other demonstrated benefits of exercise, less than 5% of North Americans older than 60 yr achieve the recommended 30 min of moderate to vigorous physical activity 5 d wk−1 (9). Exercise could well turn out to be the most convenient, practical, and cost-effective way to ameliorate age-related declines in cognition while mitigating other age-related diseases. These benefits have the potential to improve health with advancing age and to significantly reduce the anticipated and rapidly escalating costs associated with age-related cognitive impairment and dementia facing our aging society.
This work was supported by the Canadian Institutes of Health Research (grant to Drs. Poulin, Eskes, Hogan, and Longman), Heart and Stroke Foundation of Canada-Focus on Stroke Postdoctoral Fellowship (Dr. Davenport), Alberta Innovates-Health Solutions (senior scholar Dr. Poulin; visiting scientist Dr. Eskes), Brenda Strafford Foundation Chair in Geriatric Medicine, University of Calgary (Dr. Hogan), and the Brenda Strafford Foundation (Dr. Poulin).
The authors declare no conflicts of interest.
The authors thank Richard Rawling for his graphic design contributions to Figures 1 and 3.
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©2012 The American College of Sports Medicine
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