The Role of Exercise Induced Cardiovascular.2

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The Role of Exercise-Induced Cardiovascular

Adaptation in Brain HealthTakashi Tarumi 1,2 and Rong Zhang1,2,3

1Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas; and 2Departmentsof Internal Medicine and 3Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center,Dallas, TX

TARUMI, T. and R. ZHANG. The role of exercise-induc ed cardiovascular adaptation in brain health. Exerc. Sport Sci.Rev., Vol. 43, No. 4, pp. 181 Y 189, 2015. Regular aerobic exercise improves brain health; however, a potential dose-response relationshipand the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist betweenthe intensity of exercise and brain health, which needs to be further elucidated. Key Words: age, master athletes, aerobic exercisetraining, cerebral blood flow, cardiovascular function, cognitive function

INTRODUCTION

We are facing an unprecedented aging of population in thehistory of humanity. Life expectancy has nearly doubled duringthe past two centuries, whereas birth rate has steadily declinedin developed countries. Advanced age is a major risk factor for chronic noncommunicable diseases including Alzheimer

disease (AD), the most common type of late-life dementia.In 2010, AD affected about 33.9 million people worldwide,and its prevalence is expected to triple by 2050 if no effectiveprevention or treatments are developed. Currently, there is nocure for AD; however, population-based studies revealed thatapproximately 30% of AD cases may be related to modifiablerisk factors such as physical inactivity and cardiovascular riskfactors (23).

Compelling evidence suggests that habitual aerobic exer-cise attenuates age-related cognitive decline that is linked tothe preservation of brain structure (8,12,38). The mechanismsunderlying exercise-related improvements in brain structure

and function are not well understood and likely to be multi-factorial. One possible mechanism is that cardiovascular adap-tations to endurance exercise ameliorate brain health throughattenuation of age-related arterial stiffness and/or endothelial

dysfunction (30,31). In addition, exercise-related reductions inother cardiovascular risk factors may contribute to the reducedrisk of cognitive impairment and dementia.

Another important question is whether there is a dose-response relationship between the intensity of exercise and brainhealth. We currently do not know whether more exercise wouldnaturally lead to a better brain health or such benefits would

plateau or even have deleterious effects beyond a certain ‘‘dose’’of exercise. The existing evidence suggests the presence of ahormetic relation between the intensity of exercise and brainstructure and function, such that strenuous exercise per-formed without an adequate recovery may be deleterious tobrain health (2,13). To gain insights into these critical ques-tions, we recently investigated master athletes (MA), aunique group of middle-aged and older adults who have par-ticipated in long-term or lifelong endurance exercise training.

COGNITIVE BENEFITS OF AEROBIC EXERCISE TRAININGMounting evidence suggests that regular aerobic exercise

attenuates age-related cognitive decline (8). Cognitive perfor-mance peaks during early adulthood and gradually decreasesafter late 20s to 30s (24). Specifically, the tasks requiringworking memory and attention-executive function such asreasoning, perceptual speed, and spatial visualization experi-ence an earlier loss, whereas performance on tasks involvingthe crystallized intelligence including vocabulary and generalworld knowledge is relatively spared until much later (24).

Investigating two independent samples of MA, we foundhigher cognitive performance in memory and executive func-tion compared with their sedentary peers (31,36). Figure 1shows the result of neurocognitive assessments in middle-agedMA and sedentary adults. In this study (31), besides age, sex,

181

ARTICLE

Address for correspondence: Rong Zhang, Ph.D., Institute for Exercise and Environ-

mental Medicine, Texas Health Presbyterian Hospital Dallas, University of Texas

Southwestern Medical Center, 7232 Greenville Ave., Dallas, TX 75231 (E-mail:

[email protected]). Accepted for publication: June 9, 2015.Associate Editor: Hirofumi Tanaka, Ph.D., FACSM

0091-6331/4304/181 Y 189Exercise and Sport Sciences ReviewsDOI: 10.1249/JES.0000000000000063Copyright * 2015 by the American College of Sports Medicine

Copyright © 2015 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.

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and education level, lifestyle factors such as daily nutritionalintake and sleep quality were similar between the groups. MAhave participated in vigorous endurance exercise training for more than 1 h d-1. According to an age- and sex-adjusted re-gression analysis established by the American College of SportsMedicine, cardiorespiratory fitness of these MA, as assessed bymaximal oxygen uptake (V̇O2max), was more than 90 percen-tile whereas that of sedentary participants was approximately15 percentile of the general population. In this study, the effectsize of MA, as estimated by the standardized difference between

the two groups (Cohen d ), was 0.75, 0.61, and 0.84 in episodicmemory, attention-executive function, and total cognitive com-posite scores, respectively. This suggests a medium to largeeffect size of vigorous aerobic exercise training on improvingcognitive function, consistent with a previous meta-analysisand systematic review of exercise training and cognition (8).Another study of older MA with similar levels of cardiore-spiratory fitness also exhibited better cognitive performancein global intelligence and executive function when comparedwith age, sex, and education level-matched sedentary older adults (36).

In addition, a systematic review of prospective studies dem-onstrated that efficacy of exercise training on cognitive func-tion increased when performed longer than 6 months, witheach exercise session lasting 30 to 45 min (8). The favorableeffect of exercise training was greater when performed earlier than later in life and when combined with strength exercisecompared with aerobic exercise alone (8).

BRAIN STRUCTURAL ADAPTATIONS TO AEROBICEXERCISE TRAINING

The human brain contains approximately 100 billion neu-rons and consists of the gray (GM) and white (WM) matter.The GM is composed mainly of neuronal cell bodies with

branched projections (dendrites). The dendrites receiveelectrochemical stimuli from the neighboring and remoteneurons via synapse and propagate them to the cell body.Subsequently, the neuronal axons in WM transmit electricalimpulse to the surrounding neurons and function as a relaybetween the adjacent and remote brain areas as well as be-tween the brain and peripheral organs. The axons are cov-ered by myelin, which increases the conduction velocity of electrical impulse and plays a critical role for efficient neu-ronal communications. With advancing age, brain atrophy,

beginning as early as one’s 20s to 30s of age, combined withaxonal demyelination that commensurately slows propaga-tion of electrical impulses, results in a loss of cognitive effi-ciency. In contrast, habitual aerobic exercise may prevent or at least in part attenuate these age-related deteriorations of GM and WM physiological and cellular functions, thereforeimproving cognitive performance.

Brain Volume

Regular aerobic exercise may increase or preserve regionalbrain volume at areas affected by aging and associated with cog-

nitive impairment. Tseng et al. (36) acquired high-resolutionT1 magnetic resonance (MR) images to examine brain volumein MA. Using a voxel-based morphometric approach, MAexhibited greater volume at several cortical areas associatedwith motor control and visuospatial function than sedentaryolder adults (Fig. 2). Specifically, these regions were theBrodmann areas 7 (parietal lobe) and 19 (visual cortex) andthe culmen (anterior portion of the cerebellum). They alsofound a greater concentration of WM at the parietal, occipi-tal, and temporal lobes. Finally, V̇O2max was correlated posi-tively with the precuneus GM volume as well as the subgyralfrontal and occipital WM volume, when analyzed in all studyparticipants (36).

Figure 1. Endurance-trained master athletes demonstrated a higher cognitive performance in episodic memory, attention-executive function, and total

composite scores than age-matched sedentary adults. The sample-specific Z score was calculated for each of the cognitive domains. The numbers inside bargraphs are mean T standard error. (Reprinted from (31). Copyright * 2013 Wolters Kluwer Health. Used with permission.)

182 Exercise and Sport Sciences Reviews www.acsm-essr.org




Regional brain volume may increase after a relatively shortperiod of moderate-intensity aerobic exercise. Sedentary older adults who participated in 6 to 12 months of a walking pro-gram demonstrated greater volume of the hippocampus as well

as several regions of the frontal lobe, including anterior cin-gulate cortex, supplementary motor area, and middle frontalgyrus, when compared with the control group that performedstretching (9,12). In addition, volume of anterior WM tracts,particularly the genu of the corpus callosum, increased in thewalking but not the stretching group (9).

Brain WM Neuronal Fiber Integrity

The structural integrity of WM neuronal fibers can beassessed by diffusion tensor imaging (DTI). Using the motionof water molecules in the brain tissues as an endogenous probe,DTI provides diffusion metrics that reflect an overall integrityas well as biological characteristic of WM fiber tracts. Specifi-

cally, fractional anisotropy (FA) and mean diffusivity (MD)

provide a measure of water diffusive directionality and magni-tude respectively, in that a higher FA and/or a lower MD gen-erally reflect a better integrity of WM fiber tracts. These DTImetrics have been used to detect early abnormalities which may

precede WM lesions (22).MA demonstrated higher FA and lower MD in the WM tractsassociated with motor control and coordination when comparedwith their sedentary peers (Fig. 3) (35). Specifically, these tractsincluded superior corona radiata, superior longitudinal fasciculus,superior longitudinal fasciculus, inferior fronto-occipital fascicu-lus, and posterior thalamic radiation. In addition, FA mea-sured from the left superior and inferior longitudinal fasciculiwas correlated positively with V̇O2max in all subjects. Further-more, these MA exhibited better WM tract integrity in thecingulum, which carries and integrates memory informationfrom the hippocampus. Damage to this tract is associated withmild cognitive impairment and AD. Finally, subcortical WM

lesion volume was smaller in MA than in the control group.

Figure 2. Master athletes exhibited higher gray matter volume in the (A) SII/SPL, (B) V2/IOG, and (C) higher white matter volume in the O3-WM than age-matched sedentary adults. The color bar illustrates t statistic scores. The neurological coordinates are based on the Montreal Neurological Institute (MNI)space. SII, secondary sensorimotor cortex; SPL, superior parietal lobule; V2, secondary visual cortex; IOG, inferior occipital gyrus; O3-WM, inferior occipitalgyrus white matter; A, anterior; and P, posterior. (Reprinted from (36). Copyright * 2013 Wiley Online Library. Used with permission.)

Figure 3. Master athletes exhibited higher fractional anisotropy (A Y D) and lower mean diffusivity (E Y F) of brain white matter neuronal fiber tracts. Thesetracts are (A) right superior corona radiata, (B) right superior longitudinal fasciculus, (C) left superior longitudinal fasciculus, (D) right inferior fronto-occipitalfasciculus, (E) left posterior thalamic radiation, and (F) left cingulum hippocampus. The white matter tracts are shown by green pixels, whereas the red pixelsshow disruptions of white matter fiber tracks in sedentary elderly compared with master athletes. A scatter plot (G) shows the correlation of maximal oxygenuptake (V̇O2max) with fractional anisotropy (FA) measured from the left superior longitudinal fasciculus (SLF) and left inferior longitudinal fasciculus (ILF). A,anterior; P, posterior; L, left; R, right. [Adapted from (35). Copyright * 2013 Elsevier. Used with permission.]

Volume 43 & Number 4 & October 2015 Exercise and Brain Health 183




To date, there are few studies that investigated the effectof aerobic exercise training on WM structural integrity usingDTI. Voss et al. (38) conducted a randomized controlled trialof 1-yr walking program in sedentary community-dwelling older adults. In this study, the exercise group did not show group-level improvement in WM integrity or cognitive function com-pared with the control subjects who performed stretching.However, within the walking group, there was a positive cor-relation between the individual improvements in V̇O2max

and FA measured from the frontal and temporal lobe WM.More recently, Svatkova et al. (27) conducted a 6-monthinterventional trial of moderate-intensity cycling in the groupof healthy participants as well as patients with schizophrenia.After the program, both groups exhibited elevations in FA atthe areas associated with motor function. Collectively, thesefindings suggest that brain WM integrity is related to cardio-respiratory fitness and those WM areas responsible for motor function likely are sensitive to exercise training.

THE ROLE OF CARDIOVASCULAR FUNCTION INBRAIN HEALTH

The voluntary contractions of skeletal muscle during dy-namic exercise dramatically increase the metabolic demandand challenge whole-body homeostasis. In response, the bodymust coordinate its compensatory mechanisms that deliver adequate oxygen and nutrients to the working muscles. Suchcompensatory responses take place in multiple organs, par-ticularly the cardiovascular system, and minimize the disrup-tions of homeostasis. During exercise, heart rate and cardiaccontractility increase to augment cardiac output, which is thesystemic source of blood flow distributed to all organs. For

efficient substrate delivery, blood flow is redistributed to theworking muscles during dynamic exercise via an integrativemechanism of nervous, hormonal, and humoral systems. Con-sequently, dynamic exercise performed at moderate to highintensity can increase cardiac output and skeletal muscle bloodflow by eightfold and 100-fold, respectively, whereas brainblood flow may increase by approximately 10% to 20% abovethe resting values during moderate-intensity exercise (16,25).

Repeated bouts of aerobic exercise during a prolonged pe-

riod improve the cardiovascular control of systemic perfusionand counteract the degenerative processes of aging and/or disease (16). Because the brain lacks intracellular energy stor-age and heavily relies on the vascular supply of oxygen andnutrients, exercise-related improvements in cardiovascular con-trol of cerebral blood flow (CBF) may play a crucial role inmaintaining normal brain function and structure. Although CBFis coupled closely with the metabolic demand of neurons, hypo-perfusion and/or impaired regulation of CBF attributed tovascular disease or dysfunction can cause neuronal dysfunction(17). Below, we discuss the key components of cardiovascular system that may benefit from aerobic exercise training and confer the favorable effects on brain structure and function (Fig. 4).

The Ventricular-Central Arterial Coupling

Regular aerobic exercise alters chronotropic and inotropiccontrol of cardiac output. Specifically, endurance training de-creases heart rate at rest by shifting autonomic balance of sympathetic and parasympathetic innervations to the heart.This is accompanied by an eccentric remodeling of cardiacchambers, which increases left ventricular end-diastolic fillingand stroke volume. Because of a close coupling with metabolism,

Figure 4. A hypothetical diagram illustrating the effect of aerobic exercise training on cerebral blood flow (CBF) regulations. ‘‘Normal’’ CBF is maintainedby the hierarchical layers of hemodynamic support extending from the systemic circulation to the local capillary levels. Although not shown in this diagram,there are overlaps and interactions between each of the layers. For example, cerebral autoregulation and vasomotor reactivity may also take place atthe level of large conduit arteries (e.g., internal carotid and vertebral arteries). Arterial baroreflex may interact with cerebral autoregulation. Please seethe text for detailed explanations. Arrows next to vascular phenotype represent the change that may occur after aerobic exercise training. Currently,potential effects of aerobic exercise training on the cerebral vasculature, such as cerebral autoregulation, vasomotor reactivity, and microcirculatoryfunction, remain largely unknown.





cardiac output at rest may not change in healthy individualsafter exercise training.

In contrast, patients with heart failure may benefit fromaerobic exercise training by improving cardiac function atrest. According to the Framingham Heart Study, systemichypoperfusion resulting from depressed cardiac index (i.e.,cardiac output divided by body surface area) is associated withan elevated risk of incident dementia and AD (19). Con-versely, an 18-wk treadmill program improved cognitive per-

formance in attention and psychomotor speed, accompaniedby increased cardiac index at rest, in patients with severecongestive heart failure (28).

Habitual aerobic exercise attenuates age-related stiffeningof central elastic arteries (e.g., aorta and carotid arteries) (26),which may improve the efficiency of left ventricular ejectionof stroke volume. The left ventricle generates systolic bloodpressure (SBP) by ejecting a stroke volume against a hydraulicload (i.e., aortic impedance). Aortic impedance is determinedby its morphological characteristics such as diameter and wallelasticity. With age and/or presence of cardiovascular riskfactors, the aorta stiffens; arterial wave reflections returningfrom the peripheral vascular beds arrive prematurely to the heart;and consequently aortic impedance rises. These changes neces-sitate the left ventricle to increase contractility and maintainstroke volume and cardiac output. With endurance training,reductions in central arterial stiffness and cardiac afterload de-crease the contractile energy required to generate the equivalentstroke volume, accompanied by a lower SBP. Importantly, SBPis an established risk factor for stroke and cognitive impairment.

Exercise-related reductions in central arterial stiffness mayattenuate the transmission of excessive blood pressure pulsatil-ity into the brain (32). Cerebral circulation has low vascular resistance/impedance and, thus, may be vulnerable to exces-sive hemodynamic pulsatility transmitted into the microcir-

culations. In young healthy adults, SBP generated by the leftventricle is dampened effectively by the Windkessel functionof central arteries that expand and recoil with cardiac pulsa-tions. With arterial stiffening and chronic exposure to highblood pressure pulsatility, cerebral resistance vessels may adaptby increasing vascular resistance. This maladaptation has beenshown in animal studies where higher pulse pressure is associ-ated with hypertrophic remodeling of cerebral arterioles (4).Elevated cerebrovascular resistance may not only increase therisk of ischemia (7,33) but also impair a clearance of neuronalwaste products (e.g., amyloid-A) (18). Consistent with thesenotions, MA demonstrated greater distensibility of the carotidartery that was correlated positively with a higher cerebral

perfusion in the occipitoparietal area (31).Regular aerobic exercise may improve blood pressure con-

trol via enhanced arterial baroreflex function (1). Arterialbaroreceptors, a type of mechanoreceptor located in the aorticarch and carotid sinus, monitor changes in blood pressure viamechanical distortion of the vessel walls. The baroreceptor afferents are relayed to the brainstem, which in turn sends outautonomic efferent to the heart and blood vessels to controlblood pressure. The brain is particularly sensitive to changes inblood pressure because of its low resistant vascular bed. There-fore, baroreflex-mediated control of blood pressure is likelyimportant for maintaining stable CBF, possibly working to-gether with cerebral autoregulation (discussed below) (37).

Regular aerobic exercise decreases stiffness of the barosensoryarteries and thereby restores baroreflex sensitivity (1,26,31).Our recent study exhibited that baroreflex sensitivity is asso-ciated with the structural integrity of WM neuronal fibers,as assessed by DTI, and cognitive performance in executivefunction (i.e., Trail Making Test B minus A) in older adults(Fig. 5) (29).

Collectively, exercise-related increase in central arterial elas-ticity may have favorable effects on CBF regulations, including

attenuation in the transmissions of excessive blood pressurepulsatility, reduction in cerebrovascular resistance, and stableblood pressure control and CBF homeostasis. These datafurther suggest that central elastic arteries function as a keyvascular component that bridges the heart to the brain.

Large Conduit Artery: Endothelial Functionand Atherosclerosis

The main function of conduit arteries is the delivery andregulation of blood flow to the peripheral organs. In the brain,a large portion of vascular resistance is located outside of theparenchyma including the pial arterioles as well as the largeextracranial (i.e., internal carotid and vertebral arteries) andintracranial arteries, whereas cerebral penetrating arteriolesand capillaries account for the remaining (21,39). This neces-sitates a coordinated regulation of cerebrovascular resistanceboth inside and outside of the parenchyma to maintain ade-quate blood supply to the active neurons ( i.e., neurovascular coupling). In this regard, vascular endothelial cells are situ-ated ideally at the intima of the arterial wall, release vasoactivesubstances in response to blood shear stimuli as well as neu-ronal and blood-borne chemicals, and protect the vesselwalls from atherogenesis.

Regular aerobic exercise improves vascular endothelial func-tion via an upregulation of nitric oxide bioavailability (26). The

nitric oxide regulates vasomotor tone during rest and func-tional activations and also inhibits atherogenesis by reducingoxidative modification of low-density lipoprotein cholesteroland preventing the proliferation of vascular smooth musclecells. Atherosclerosis, a pathological condition characterizedby the buildup of cholesterol and inflammatory substances inthe arterial walls, occludes blood flow and is associated withAD pathology (6). Thus, exercise-related ameliorations inendothelial function as well as a reduced risk of atheroscle-rosis may facilitate cerebral perfusion.

Cerebral Resistance Vessel: Cerebral Autoregulationand Vasomotor Reactivity

Cerebral autoregulation (CA) and vasomotor reactivity(CVMR) provide a local control of CBF. CA is a protectivefunction of cerebral resistance vessels that keep CBF rela-tively constant in the face of changes in cerebral perfusionpressure. Although uncertain, age and endurance trainingseem to have fewer effects on the CA compared with theperipheral vascular beds (5). For example, MA demonstratedthe presence of similar dynamic CA compared with seden-tary adults, as assessed by transfer function analysis of arterialpressure and CBF velocity measured in the middle cerebralartery during a repeated sit-stand maneuver (1). Currently, wedo not know whether steady-state CA also is less influencedby age or exercise training.





There are inconsistent findings on the effects of age andregular aerobic exercise on CVMR. In our study of MA (40),CVMR was assessed by transcranial Doppler using a modi-fied rebreathing technique that induces incremental ele-vations in end-tidal CO2, a proxy of arterial pCO2. Wefound a higher CVMR during hypercapnia in sedentary andendurance-trained older adults than in younger subjects,whereas no difference was observed between the older groups. Testing a similar sample using functional MR imag-ing, blood oxygen level-dependent (BOLD) responses tosteady-state hypercapnia were attenuated in MA comparedwith that observed in sedentary older adults (34) (Fig. 6).

In contrast, other studies reported higher CVMR in exercise-trained adults than in sedentary subjects, as assessed bytranscranial Doppler during steady-state hypercapnia (3).Therefore, these inconclusive findings necessitate the stan-dardization of techniques to assess CVMR. Of note, neither transcranial Doppler nor BOLD measures CBF per se, andrebreathing and steady-state hypercapnia may have differenteffects on cerebrovascular beds and brain tissues. A recentstudy using multimodal methods to quantify CBF (i.e., arterialspin labeling and BOLD) revealed a significant contributionof basal cerebrovascular tension to CVMR (15). As such,elevated cerebrovascular tension under resting conditions mayincrease hypercapnic vasodilatory reserve while decreasing

hypocapnic vasoconstrictor capacity, consistent with our previous observations (40).

Cerebral Microcirculation: Substrate Exchange andWaste Clearance

CBF ultimately perfuses neuronal tissues at the level of thecapillary where substrate exchange and waste product clear-ance occur across the blood-brain barrier. Regional cerebralperfusion is coupled tightly with metabolic demand of neu-ronal tissues (neurovascular coupling), which presents a highlevel of temporal and spatial heterogeneity. Among the im-portant areas of brain that are highly active during rest and

also involved in AD pathology are the prefrontal lobe, medialtemporal lobe including the hippocampus, posterior cingulatecortex (PCC), and precuneus. These brain areas function as aneural network hub in mediating and processing informationflow and also serve as the main components of the Default-Mode-Network that contributes to learning and memoryconsolidations (14).

MA demonstrated an enhancement of CBF at the PCCand precuneus compared with sedentary older adults (34)(Fig. 7). Using the arterial spin labeling technique, whole-brain and regional CBF were measured. Our initial anal-ysis of whole-brain CBF showed similar levels between thesedentary and endurance-trained older subjects, whereas

Figure 5. Associations among cardiovagal baroreflex sensitivity (BRS), fractional anisotropy measured from brain white matter neuronal fiber tracts, andTrail Making Test BjA performance in older adults. The BRS was assessed during acute changes in arterial blood pressure using the established phar-macological method (modified Oxford technique). The brain images on the top (A) exhibit the area of neuronal fiber tracts that were significantly associatedwith BRS based on voxelwise statistics. The color bar illustrates P value of the association. At the bottom (B), scatter plots show the correlations of BRS (left)and Trail Making Test BjA performance (right) with individual FA values that were extracted from the significant white matter tracts highlighted byvoxelwise analysis (A). [Adapted from (29). Copyright * 2015 Elsevier. Used with permission.]





younger subjects demonstrated higher levels of CBF than theolder groups. Next, we calculated relative CBF, which repre-sents a ratio of regional CBF to the whole-brain value andnormalizes the effect of interindividual differences in globalCBF. This analysis revealed that MA have significant elevationsin relative CBF at the PCC and precuneus compared with youngand older sedentary subjects. Therefore, these findings sug-gested that aerobic exercise training selectively preserve bloodsupply in the PCC and precuneus by attenuating the age effect.

EXERCISE INTENSITY AND BRAIN HEALTHMA as well as sedentary adults who have undergone aero-

bic exercise training even for a short period of 6 months toa year demonstrated a similar magnitude of improvements in

cognitive performance when compared with their control groups(8,31,36). These improvements appeared mainly in the memoryand executive function. On the other hand, brain structuraladaptations to exercise training seemed somewhat differentbetween the cross-sectional and longitudinal studies. For exam-ple, those sedentary adults who completed a short-term exercisetraining program demonstrated increases in hippocampal andprefrontal volume as well as frontal and temporal WM integrity(9,12,38). In contrast, MA exhibited preservations of the pari-etal lobe volume and WM integrity, which is not only limited tothe frontal or temporal areas (35,36). Although it is importantto acknowledge the limitations of different study designs andMA may differ from the general population in terms of geneticand/or lifestyle factors, these findings collectively suggest that

Figure 7. In panel A, voxelwise analysis revealed a higher level of relative cerebral blood flow (rCBF) in master athletes (MA) than in sedentary elderly (SE)subjects (cluster size, 250). The cluster was located in the posterior cingulate cortex (PCC) and precuneus of the Default-Mode-Network. No clusters showedMA G SE. Results are shown in glass brain view. Panel B shows group-averaged rCBF in the area highlighted by panel A. The rCBF values in MA were higherthan those in the SE and young control (YC) groups. In panel C, absolute CBF in the same area showed a significant reduction in SE compared with YC;however, MA and YC showed similar levels. These data suggest that aerobic exercise training selectively preserves CBF in the PCC/precuneus region byattenuating the age effect. The rCBF was calculated as a ratio of regional CBF to the whole-brain value. CBF was measured by arterial spin labelingtechnique.*P G 0.05, **P G 0.005. Error bars represent standard error. (Reprinted from (34). Copyright * 2013 Wiley Online Library. Used with permission.)

Figure 6. Panel A shows cerebrovascular reactivity (CVR) to steady-state hypercapnia at regions of interest (ROI), as assessed by blood oxygen leveldependence (BOLD) using functional magnetic resonance imaging. Master athletes (MA) demonstrated lower levels of CVR in all of the ROI than thesedentary elderly (SE) and young control (YC) groups. The CVR was calculated as a percentage change in BOLD divided by an absolute change in end-tidalCO2 (in millimeters mercury) relative to the baseline level. Panel B shows the result of voxelwise comparison of CVR between the MA and SE groups.Consistent with the ROI analysis, MA showed a lower CVR throughout the cortex (red), and there was no cluster in which CVR was greater in MA than in SEsubjects. Fro, frontal lobe; Tem, temporal lobe; Par, parietal lobe; Occ, occipital lobe; Cer, cerebellum; Ins, insula; Sub, subcortical gray matter. Error bars

represent standard error. (Reprinted from (34). Copyright * 2013 Wiley Online Library. Used with permission.)





aerobic exercise training for both a short and a longer durationhas favorable effects on brain structure and function. Prospectivetrials that investigate the lifelong effects of exercise training aredifficult to conduct; however, future studies combining cross-sectional and interventional study design may elucidate further the relation between the duration of exercise training and brainstructure and function.

How is exercise intensity linked with brain health in gen-eral and cerebrovascular health in particular? A meta-analysis

of cohort and case-control studies reported a dose-dependentinverse linear relation between physical activity intensity andstroke incidence or mortality (11). Specifically, moderatelyactive individuals had a 20% lower risk and highly active in-dividuals had a 27% lower risk of stroke incidence or mortalitythan the low-active individuals (11). However, this meta-analysis was limited by different definitions of physical activ-ity intensity used in individual studies, and a few prospectivestudies reported a curvilinear relation between exercise inten-sity and stroke risk. For example, Harvard University alumnistudy showed a U-shape relation between relative risks of strokeand the estimated weekly energy expenditure accounted for by physical activity (20). Particularly, the effect of physicalactivity on reducing stroke risk steadily increased up to theenergy expenditure of 3000 kcal wk-1 but attenuated there-after. In addition, physical activity performed with moderateintensity such as walking 20 km wk-1 or more or stair climbing(Q4.5 metabolic equivalents) was associated with the nadir of the U-shape relation.

Emerging evidence suggests that strenuous endurance exer-cise leads to brain injury when performed without adequaterecovery (2,13). Freund et al. (13) measured global GM volumeof ultramarathon runners before, twice during, and 8 monthsafter the race using MR imaging. The race took over 4487 km(2788 miles) in 64 days without a rest day. During the race,

those runners experienced an average of approximately 6%reduction in global GM volume accompanied by a significantweight loss. The authors estimated that this magnitude of the volume reductions equates to approximately 30 yr of age-related atrophy, which normally progresses at an annual rateof approximately 0.2%. After 8 months of the race, the reduc-tion in GM volume recovered back to the baseline level. Other studies also reported the link between prolonged enduranceexercise and an elevated risk of cerebral lesions or edema (2).

The mechanism underlying the adverse effects of strenuousexercise on the brain is not clear. Strenuous exercise sub-stantially increases systemic catabolic burden, inflammatoryresponses, and risks of cardiovascular injury, which may affect

brain structure and function. Under normal physiologicalconditions, the brain secures its energy intake to support thehigh metabolic demand of neuronal tissues via neurovascular coupling and a relatively constant blood supply. Conversely,a prolonged high-intensity exercise can deplete intracellular energy storage of active skeletal muscles (e.g., phosphocrea-tine and glycogen). Thereafter, those working muscles needto rely on oxidative phosphorylation of adenosine triphosphate,which may not be able to sustain a high exercise intensity(16). These elevations in metabolic demand can lead tosystemic catabolic conditions, which may compromise brainstructure and function via elevated stress hormone levels (e.g.,cortisol), changes in electrolyte balance (e.g., hyponatremia),

inflammation and edema, hypoxia, and oxidative stress (2). Nevertheless, this apparent hormetic relation between the in-tensity of exercise and brain health needs to be investigatedfurther.

Currently, there is no clear evidence of a dose-responserelation or any consensus on the optimal dose of exercise train-ing that may prevent or slow the age-related functional andstructural deteriorations of the brain. It is likely that such an‘‘optimal’’ dose is individually based and determined by the

environmental and genetic factors, including age, sex, car-diovascular disease risk, and presence or absence of brain-derived neurotrophic factor Val66Met or apolipoprotein Epolymorphisms (10). Furthermore, most studies to date focusedon older subjects and there are not enough data to supportwhether exercise training in middle age, for example, wouldmodify the trajectory of cognitive aging, although midlife vas-cular risk factors (e.g., hypertension, obesity) elevate an inci-dence of late-life dementia (23). For future work, muchresearch is needed to identify and design a personalized‘‘optimal program’’ of exercise training for heterogeneouspopulations, including the individuals who have comorbid-ities or chronic diseases.

CONCLUSIONS

Current evidence suggests that regular aerobic exercise per-formed at moderate to high intensity attenuates an age-relatedreduction in regional brain volume, deterioration of WM in-tegrity, and cognitive decline. Cardiovascular adaptations toaerobic exercise training represented by reductions in arterialstiffness and improvements in endothelial function make a fa-vorable systemic and cerebral hemodynamic environment(milieu) where the brain may benefit from the improvements inarterial pressure regulation, blood flow homeostasis, and met-abolic waste clearance. However, strenuous exercise performed

without adequate recovery may have deleterious effects asmanifested by GM atrophy and WM lesions, which suggeststhe presence of a hormetic relation between the intensity of exercise and brain health. Currently, there are no effectiveprevention and treatment modalities for dementia; however,improvement of cardiovascular health, particularly via regular aerobic exercise, may prevent or slow age-related cognitivedecline and delay the onset of dementia, thus improvingquality of life and extending a healthy life span.

Acknowledgments

This work was supported by the National Institutes of Health (R01AG033106,R01HL102457, and P30AG012300) and the American Heart Association(14POST20140013). The authors thank Jonathan Riley and Erin Howden for editing and revising the manuscript.

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The Role of Exercise Induced Cardiovascular.2

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