Research ArticlePhysical Activity and the Brain

One-year aerobic exercise altered cerebral vasomotor reactivity in mild cognitive impairment

Abstract

The purpose of this study was to test the hypothesis that changes in cerebral vasomotor reactivity (CVMR) after 1-yr aerobic exercise training (AET) are associated with cognitive performances in individuals with amnestic mild cognitive impairment (MCI). Seventy sedentary patients with amnestic MCI were randomized to 1-yr moderate-to-vigorous intensity AET or stretching and toning (SAT) interventions. Cerebral blood flow velocity (CBFV) with transcranial Doppler, mean arterial pressure (MAP) with finapres plethysmograph, and EtCO2 with capnography were measured during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia) to assess CVMR. Cerebrovascular conductance index (CVCi) was calculated by CBFV/MAP, and CVMR by ΔCBFV/ΔEtCO2 and ΔCVCi/ΔEtCO2. Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Cardiorespiratory fitness was assessed by peak oxygen uptake (V̇o2peak). A total of 37 patients (19 in SAT and 18 in AET) completed 1-yr interventions and CVMR assessments. AET improved V̇o2peak, increased hypocapnic CVMR, but decreased hypercapnic CVMR. The effects of AET on cognitive performance were minimal when compared with SAT. Across both groups, there was a negative correlation between changes in hypocapnic and hypercapnic CVMRs in CBFV% and CVCi% (r = −0.741, r = −0.725, P < 0.001). Attenuated hypercapnic CVMR, but not increased hypocapnic CVMR, was associated with improved cognitive test scores in the AET group. In conclusion, 1-yr AET increased hypocapnic CVMR and attenuated hypercapnic CVMR which is associated cognitive performance in patients with amnestic MCI.

NEW & NOTEWORTHY One-year moderate-to-vigorous intensity aerobic exercise training (AET) improved cardiorespiratory fitness (V̇o2peak), increased hypocapnic cerebral vasomotor reactivity (CVMR), whereas it decreased hypercapnic CVMR when compared with stretching and toning in patients with amnestic mild cognitive impairment (MCI). Furthermore, changes in hypercapnic CVMR with AET were correlated with improved memory and executive function. These findings indicate that AET has an impact on cerebrovascular function which may benefit cognitive performance in older adults who have high risk of Alzheimer’s disease.

INTRODUCTION

Cerebrovascular dysfunction is one of the potential underlying mechanisms of Alzheimer’s disease (AD) and related dementias (13). Cerebral blood flow (CBF) is sensitive to change in arterial partial pressure of carbon dioxide (PaCO2). Elevated PaCO2 (hypercapnia) increases CBF via cerebral vasodilation, whereas reduced PaCO2 (hypocapnia) decreases CBF due to vasoconstriction (4). CBF responses to changes in PaCO2 are referred to as cerebral vasomotor reactivity (CVMR), which can be assessed during either hypercapnia or hypocapnia or both (4, 5). Measurement of CVMR may reflect the capability of brain blood vessel’s responses to neuronal metabolic stimuli, thus neurovascular coupling, and has been used widely to assess cerebrovascular function (3). Altered CVMR has been observed in patients with AD (6) and mild cognitive impairment (MCI) (5, 7), and were associated with impaired cognitive performance. Therefore, interventions to improve CVMR may contribute to prevention or delay of cognitive decline in older adults (1, 3).

Moderate-to-vigorous intensity aerobic exercise training (AET) in a time frame of 3–6 mo may improve peripheral endothelial function in older adults (8, 9). Similarly, some, but not all studies, have shown that moderate-to-vigorous intensity AET improved CVMR assessed with transcranial Doppler measurement of CBF velocity in the middle cerebral artery and cognitive performance in cognitively normal older adults (9). For example, 3-mo moderate-intensity AET increased CVMR during 5% CO2 inhalation (9). However, 6-mo moderate-intensity AET did not alter CVMR during hypercapnia, but showed that increased cerebrovascular resistance during hypercapnia was associated with improvement in verbal fluency (8). In addition, 12-wk moderate-intensity AET did not change CVMR during hypercapnia assessed with magnetic resonance imaging measurement of regional CBF (10). These inconsistent findings suggest that exercise intensity or duration or both may be related to the observed changes in CVMR during hypercapnia, whereas only few studies have measured CVMR during both hypo- and hypercapnia (9). In addition, different methods used to assess CVMR (i.e., CBF measurements, regression of changes in CBF over changes in PaCO2) may have contributed to these discrepancies (810). Furthermore, at present, the effects of AET on CVMR and the relationship between changes in CVMR and cognitive performance in patients with MCI have not been investigated (11).

Understanding the effects of AET on cerebrovascular function is important in that we currently lack effective interventions to treat or delay the onset or progression of AD dementia (12). Patients with MCI have a high risk of developing AD and this may represent a critical time window for implementing lifestyle intervention to prevent further cognitive decline (12, 13). The purpose of this study was to determine the effects of 1-yr AET on CVMR as well as the relationship to cognitive performance in patients with MCI. We hypothesized that AET would improve CVMR and that changes in CVMR would be associated with cognitive performance.

MATERIALS AND METHODS

The present investigation was a substudy of a 1-yr, single-blinded, proof-of-concept, parallel randomized control trial comparing effects of AET versus stretching-and-toning (SAT) programs on neurocognitive function in patients with amnestic MCI (ClinicalTrials.gov, NCT01146717: Aerobic Exercise Training in Mild Cognitive Impairment Study). CVMR assessment was performed at baseline and 1-yr follow-up. The trial design and randomization procedures were described previously (14). Briefly, SAS v9.2 was used to generate the stratified, randomization lists using a blocking factor of 4. Patients were stratified by age (55–70 and 71–80) and sex (men and women). During the study, participants were instructed not to disclose their group assignment or to discuss their interventions during measurements or meeting with blinded investigators or other participants. All data were deidentified before analysis. All data analyses were performed by blinded investigators and unblinding only occurred at the stage of statistical analysis.

Participants

Seventy patients with amnestic MCI were recruited from the University of Texas Southwestern Medical Center Alzheimer’s Disease Center, local newspaper advertisements, and senior centers. Clinical evaluation of amnestic MCI was based on the recommendations from the Alzheimer’s disease Cooperative study Diagnostic Criteria (http://adni-info.org/), and the diagnosis of amnestic MCI was based on Petersen criteria (13, 15) as modified by the Alzheimer’s Disease Neuroimaging Initiative (http://adni-info.org/). Specifically, we used a global Clinical Dementia Rating scale of 0.5 with a score of 0.5 in the memory category, objective memory loss as indicated by education-adjusted scores on the Logical Memory subtest of the Wechsler Memory Scale-Revised immediate and delayed recall, and Mini-Mental State Examination (MMSE) score between 24 and 30 (16).

Inclusion criteria were men and women aged between 55 and 80 yr who were diagnosed with amnestic MCI. Exclusion criteria included major neurological, vascular, or psychiatric disorders, uncontrolled hypertension, clinically diagnosed or self-reported diabetes mellitus, sleep apnea, body mass index (BMI) ≥ 35 kg/m2, and current or history of smoking. Individuals with a physically active lifestyle (defined as participation in moderate-intensity aerobic exercise training over the past 2 yr for 3 times/wk with each session lasting >30 min) were also excluded due to the potential effect of exercise training on CVMR (17). Detailed inclusion and exclusion criteria are presented in our previous study (14).

This study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and Texas Health Presbyterian Hospital Dallas, and was performed in accordance with the guidelines of the Declaration of Helsinki and Belmont Report. All subjects and/or their study partners signed informed written consent before participation.

Interventions

AET program.

The moderate-to-vigorous intensity AET program (brisk walking) was based on each individual’s fitness level evaluated with peak oxygen uptake (V̇o2peak) treadmill testing. Exercise intensity, duration, and frequency were gradually progressed as participants adapted to the previous workload. Each exercise session included a 5-min warm-up and 5-min cool-down and was monitored by changes in the heart rate (HR) (Polar RS400, Polar Electro). The AET program began with 3 exercise sessions/wk for 25–30 min/session at the intensity of 75%–85% of maximal HR which was measured during V̇o2peak treadmill testing at baseline. At week 11, 3, or 4, aerobic exercise sessions/ wk for 30–35 min/session were performed. In the week in which participants performed 3 exercise sessions/wk, a high-intensity exercise session was introduced which consists of 30 min of walking at the intensity of 85%–90% of maximal HR (e.g., brisk uphill walking). After week 26, participants performed 4 or 5 exercise sessions/wk for 30–40 min, including 2 high-intensity sessions. Of note, since the maximal HR is unlikely to changes with exercise training, the absolute exercise intensity for an individual may progress with the targeted HR associated with improvement in cardiovascular fitness (18). The prescribed AET program meets the national physical activity guidelines for older adults (19).

SAT program.

The SAT program was used as an active control group to maintain participants’ attention at a similar level as the AET program. The frequency and duration of the SAT program were the same as that of the AET program. This program focused on the upper and lower limb stretching exercises. During each session, participants were asked to keep their HR below 50% of maximal HR. At week 19, a second set of full-body stretching exercise, more advanced than the previous set, was prescribed. At week 26, a set of low resistance, TheraBand exercise that focuses on strengthening the upper and lower body was prescribed.

In both programs, each participant was closely supervised by an exercise physiologist for the first 4–6 wk to make sure that the participant understood and became familiar with AET or SAT instructions and could perform exercise safely by themselves either at a fitness center or home. During the study period, all participants were asked to perform their assigned interventions on the top of their regular physical activities. To ensure adherence to AET and SAT interventions, participants were required to keep a detailed training log in addition to HR monitoring during each exercise session and to meet with an exercise physiologist monthly or as needed to review and resolve training related issues. The average compliance to exercise training calculated as a ratio of the prescribed exercise sessions over the actually completed exercise sessions in which participants achieved the target heart rate was ∼69% (14).

Measurements

All data were collected in a quiet, environmentally controlled laboratory with an ambient temperature of ∼22°C. The same study protocols were used for baseline and 1-yr follow-up tests. Before measurements, all subjects refrained from high-intensity exercise, caffeinated beverages, or alcohol for at least 24 h.

CVMR assessment.

CVMR was assessed with a procedure previously reported from our laboratory (5, 2022). Cerebral blood flow velocity (CBFV) was measured from the right middle cerebral artery (MCA) using a 2-MHz transcranial Doppler (TCD) probe (Multi-Dop X2, Compumedics/DWL, Singen, Germany) using standard procedures (23). The probe was securely attached to the temporal bone acoustic window by using either an individually created mold to fit the facial bone structure or a probe holder (Spencer Technologies, Seattle, WA) to keep the position and angle of the probe unchanged during the CVMR assessment (24). The individually created probe mold ensured the same probe position and insonation angle during repeated CBFV measurements (24). When a probe holder was used, the probe position where the optimal CBFV signal was obtained was measured carefully perpendicular to and from the eye and ear tragus line at baseline and the same position was used for the repeated visit. End-tidal CO2 (EtCO2), an estimate of PaCO2 (25), and breathing frequency were monitored using capnography (Carpnograd, Novamatrix, Wallingford, CT). Arterial blood oxygen saturation (SaO2) was monitored by a pulse oximeter (Biox 3700, Ohmeda Monitoring Systems, Boulder, CO). Brachial BP was intermittently measured from the right upper arm using an electrosphygmomanometer (Suntech, Morrisville, NC). Beat-to-beat mean arterial pressure (MAP) was continuously recorded from the middle finger of the left hand using a Finapres (Finapres Medical Systems, Amsterdam, The Netherlands). The finger pressure transducer was fixed at the heart level during the study. HR was monitored via a 3-lead ECG system (Hewlett-Packard, Palo Alto, CA). All data were collected simultaneously with a sampling frequency of 1,000 Hz and stored in a computer for off-line analysis using a data acquisition and analysis software (Acknowledge, BIOPAC) systems, Goleta, CA).

After subjects have rested in the supine position for >10 min, a nose clip was placed and subjects breathed through a mouthpiece with a Y-way valve, with one end connected to the mouthpiece and the other two ends connected to a 5 L rebreathing bag and open to room air (20, 21, 26). Baseline CBFV, HR, MAP, and EtCO2 were recorded simultaneously for 3 min. After the baseline measurement, subjects were coached by an investigator to perform voluntary hyperventilation for 20 s (1 breath/s) which induced a brief period of plateaued hypocapnia and was well tolerated by subjects (21). Following voluntary hyperventilation, a >5-min recovery period was provided to ensure all the hemodynamic variables recovered to the baseline level to minimize potential residual vasoconstrictive effects of hypocapnia on hypercapnic CVMR (20, 27). Then, a modified rebreathing protocol was used to induce hypercapnia (21). Briefly, at the end of one deep inspiration, the Y-way valve of the mouthpiece was switched from room air to an empty rebreathing bag to allow an individual to exhale and inhale his/her own breathing air to induce a progressive increase in EtCO2 for 3 min (21). During rebreathing, a small amount of oxygen was supplied to the rebreathing bag based on each subject’s basal metabolic rate (estimated using the Harris–Benedict formula) to maintain constant SaO2 level (21). The rebreathing protocol was tolerated by all subjects. The modified rebreathing protocol used for assessment of CVMR in this study is simple to apply at bedside and does not require CO2 gas sources such as a gas tank to induce hypercapnia as needed with other CO2 inhalation methods (5, 20, 22, 26). Our previous studies have demonstrated that assessment of CVMR with the modified rebreathing method is similar to that with the method of stepwise increases in inspiratory concentration of CO2 (20).

CVMR analysis.

Baseline hemodynamic data were obtained by averaging 3 min of steady-state data segments under the resting condition before hyperventilation started. Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratio of mean CBFV and MAP. CVCi was calculated to account for the effects of changes in MAP on CBFV during hypocapnia and hypercapnia (21). The magnitude of absolute changes in CBFV, CVCi, MAP, HR, and EtCO2 during hypo- and hypercapnia are presented as ΔCBFV, ΔCVCi, ΔMAP, ΔHR, and ΔEtCO2, respectively. The percentage change in hypo- and hypercapnic ΔCBFV% and ΔCVCi% were calculated relative to their corresponding baseline values. An example of changes in CBFV, BP, and EtCO2 during hyperventilation and rebreathing was shown in Supplemental Fig. S1 (all Supplemental material https://doi.org/10.6084/m9.figshare.14410814).

Hypocapnic CVMR. During hyperventilation, maximal hemodynamic changes were calculated from the average of 3 breath cycles after the reduction of EtCO2 reached nadir. Then, CVMR was calculated as the ratio of maximal reductions in ΔCBFV% to ΔEtCO2 and ΔCVCi% to ΔEtCO2 (21). Cardiovascular reactivity was calculated as the ratio of ΔMAP to the corresponding changes in EtCO2.

Hypercapnic CVMR. Baseline data for hypercapnia were obtained by averaging 1 min of steady-state data segment before the rebreathing protocol started. Breath-by-breath data were extracted for analysis during rebreathing (5, 2022, 26). Linear regression analysis of ΔCBFV% versus ΔEtCO2 and ΔCVCi% versus ΔEtCO2 was performed within each subject, then group averaged for statistical analysis. The slopes of these regression lines were used as the estimates of CVMR during hypercapnia (21). Cardiovascular reactivity was assessed by the slope of a linear regression between ΔMAP and ΔEtCO2. The results of linear fitting were examined by the coefficient of determination (R2). For data visualization, group-averaged bin plots of CBFV%, CVCi%, and MAP were created based on every 4 mmHg increase in EtCO2 from the baseline (Supplemental Fig. S2).

Cardiorespiratory fitness.

The V̇o2peak was assessed by a modified Astrand–Saltin protocol on a treadmill (28). During testing, participants walked or jogged at a fixed speed, which was determined by individual fitness levels. The treadmill grade was increased by 2% every 2 min until exhaustion. V̇o2 was measured during the 2nd minute of each stage using the Douglas bag method. Gas fractions were analyzed by mass spectrometry (Marquette MGA 1100), and ventilatory volume was measured by a Tissot spirometer. The V̇o2peak was defined as the highest V̇o2 measured during the last stage of testing. The criteria to confirm that V̇o2peak was achieved included an increase in V̇o2 < 150 mL despite increasing work rate 2% grade, a relative respiratory exchange ratio > 1.1, and HR < 5 beats/min of age-predicted maximal values (220 - age). In all cases, at least two of these criteria were achieved, confirming the identification of V̇o2peak based on the American College of Sports Medicine guideline (19).

Neuropsychological function.

Standardized total and delayed free recall scores from the California Verbal Learning Test-second edition (CVLT-II) (29), along with scores from the Trail Making, Color-Word inhibition, and Letter and Category Fluency scores from the Delis–Kaplan Executive Function System (D-KEFS) (30) were used to assess episodic memory and executive function. These tests are widely used in aging and dementia research (31) and have good norms in the general population and sensitivity for detecting age-related cognitive decline. These tests have also been used to reveal the effects of AET and cardiorespiratory fitness on neurocognitive function in older adults (31, 32).

Statistical Analysis

The participant flowchart is presented in Supplemental Fig. S3. Among 70 amnestic patients with MCI enrolled in the trial (39 in SAT and 31 in AET), 48 completed the study interventions (14). Of those who completed, 11 did not have CVMR data because TCD signal at baseline could not be obtained from 8 participants and 3 participants declined to perform the CVMR protocol at 1-yr follow-up visit due to medical reasons (i.e., headache and cardiac arrhythmia). Thus, for the present study, statistical analysis was performed on a total of 37 participants (19 in SAT and 18 in AET) who completed both the baseline and 1-yr hypocapnic and hypercapnic CVMR assessments (Table 1). The participant’s demographic characteristics who completed CVMR tests did not differ from those who participated in the parents study (14). The sample size estimate for CVMR measurement was not performed because it was a secondary outcome of the parent trial (14). The chi-square test was used to examine group differences in categorical variables. Student’s t test was used to examine the group differences between AET and SAT groups at baseline and changes after 1-yr follow-up. Two-way repeated-measures analysis of variance was used to test the main effects of time and group as well as the interaction effect of time-by-group. Partial eta squared (ηp2) was calculated to represent the effect size of the time-by-group interactions. The Bonferroni method was used to correct for multiple pairwise comparisons. Pearson’s product-moment correlation analysis was used to examine the correlations between changes in aerobic capacity, hypocapnic, and hypercapnic CVMR, and cognitive test scores before and after the intervention. Data normality was assessed by the Shapiro–Wilk test and the visual inspection of histogram and Q–Q plots. An α-level of 0.05 was set as the criterion for statistical significance. All statistical analyses were performed using SPSS 20.0 (IBM, Corporation, Armonk, NY).

Table 1. Participants’ demographics by groups

VariablesSATAETP Value
Men/women, n10/910/80.858
Age, yr64.8 (6.6)64.6 (5.9)0.948
Race, White/Black19/016/20.135
Education, yr16.0 (2.2)16.5 (2.4)0.492
Height, cm170.0 (9.1)166.8 (9.5)0.337
Body mass, kg/min79.6 (15.0)75.3 (15.5)0.396
Body mass index, kg/m227.3 (4.0)27.0 (4.8)0.818
o2peak
 mL/min2.08 (0.60)1.71 (0.63)0.110
 mL·kg−1·min−125.8 (4.6)23.0 (6.2)0.188
Heart rate, beats/min66.1 (10.3)62.2 (9.5)0.240
Systolic BP, mmHg121.5 (12.1)119.1 (5.8)0.448
Diastolic BP, mmHg73.9 (7.4)74.9 (5.7)0.651
Mean arterial pressure, mmHg96.4 (12.1)93.7 (8.5)0.426
Clinical dementia rating0.50.5
Mini-Mental State Exam28.7 (1.6)29.0 (1.5)0.540
WMS logical memory immediate recall11.1 (2.6)11.6 (2.5)0.690
WMS logical memory delayed recall8.6 (2.1)9.2 (1.9)0.375
Hypertension, n (%)8 (42%)5 (28%)0.219

Data are presented as means ± SD unless otherwise noted. Group differences in categorical and continuous variables were examined by chi-square test and independent t test. AET, aerobic exercise training; BP, blood pressure; SAT, stretching and toning; V̇o2peak, peak oxygen uptake; WMS, Wechsler memory scale-revised.

RESULTS

Participant characteristics were similar between the SAT and AET groups, including age, sex, education, MMSE, and the Wechsler Memory Scale-Revised Logical Memory recall scores measured during screening for the study enrollment (Table 1).

Intervention Effects on Hemodynamics at Rest, Cognitive Performance, and CVMR

o2peak increased significantly with AET compared with SAT (P < 0.001, ηp2 = 0.305) (Table 2). HR decreased, and brachial BP, MAP, SaO2, EtCO2, mean CBFV, CVCi, and CVRi at rest all remained unchanged in both groups after AET or SAT. CVLT-II long delayed free recall score, D-KEFS trail making test, color-word inhibition, and category fluency scores showed a slight improvement in both groups (Table 2).

Table 2. Systemic and cerebral hemodynamics and cognitive scores under resting conditions pre- and postinterventions by groups

SAT
AET
P Value (ANOVA)
 PrePostPrePostTimeGroupTime×Group
Body mass, kg79.6 (15.0)77.0 (17.8)75.3 (15.5)74.2 (16.1)0.1110.4960.520
BMI, kg/m227.3 (4.0)26.4 (4.4)27.0 (4.8)26.5 (4.7)0.0890.9340.599
o2peak,
 mL/min2.08 (0.60)1.99 (0.61)*1.71 (0.63)1.88 (0.61)*0.1870.246<0.001
 mL·kg−1·min−125.8 (4.6)25.2 (4.8)23.0 (6.2)25.7 (6.5)*0.0240.536<0.001
Heart rate, beats/min66.1 (10.3)62.5 (10.2)*62.2 (9.5)57.3 (6.6)*<0.0010.1210.550
Systolic BP, mmHg121.5 (12.1)122.3 (11.4)119.1 (5.8)120.8 (9.3)0.1240.5390.592
Diastolic BP, mmHg73.9 (7.4)74.6 (5.8)74.9 (5.7)75.2 (9.5)0.5490.7340.786
MAP, mmHg96.4 (12.0)94.3 (12.1)93.7 (8.5)95.2 (11.3)0.8690.7710.306
EtCO2, mmHg37.1 (3.0)36.5 (3.2)36.8 (3.5)36.2 (2.8)0.1390.7450.935
SaO2, %98.1 (1.4)98.3 (1.0)98.3 (1.2)98.3 (0.9)0.7240.6120.724
Cerebral hemodynamics
 Mean CBFV, cm/s49.0 (9.4)46.9 (8.3)48.3 (10.2)49.2 (10.0)0.5810.7800.225
 CVCi, cm/s·mmHg0.52 (0.12)0.50 (0.09)0.52 (0.10)0.52 (0.12)0.8220.7190.638
 CVRi, mmHg·cm−1·s−12.04 (0.48)2.07 (0.44)2.01 (0.44)2.02 (0.50)0.8180.7770.884
Neurocognitive measures
 CVLT-II total45.1 (12.1)45.2 (8.7)45.2 (9.3)48.5 (11.1)0.3070.5810.339
 CVLT-II long delayed free recall8.4 (1.9)10.2 (2.0)9.4 (1.9)10.2 (3.9)0.0050.5160.229
 D-KEFS trail making test10.7 (3.9)12.5 (1.8)11.5 (2.3)12.2 (1.7)0.0040.7870.196
 D-KEFS color-word inhibition10.7 (3.2)11.7 (2.4)11.3 (1.9)12.0 (1.9)0.0040.5880.658
 D-KEFS letter fluency11.1 (3.1)10.9 (3.3)9.7 (3.6)10.8 (3.8)0.2400.4950.116
 D-KEFS category fluency10.9 (3.7)11.4 (3.9)10.4 (3.2)12.5 (3.5)0.0080.8290.073

Data are presented as means ± SD. Total of 37 subjects (19 in SAT and 18 in AET). Two-way repeated ANOVA was performed to test the main effects of time and group as well as the interaction effect of time-by-group. *P < 0.05 compared with pre. Bold values represent P < 0.05.

AET, aerobic exercise training; ANOVA, analysis of variance; BMI, body mass index; BP, blood pressure; CBFV, cerebral blood flow velocity; CVCi, cerebrovascular conductance index; CVLT-II, California verbal learning test-second edition; CVRi, cerebrovascular resistance index; D-KEFS, D-KEFS, Delis-Kaplan executive function system (higher scores indicate better cognitive function); EtCO2, end-tidal CO2; MAP, mean arterial pressure; SaO2, arterial blood oxygen saturation; SAT, stretching-and-toning; V̇o2peak, peak oxygen uptake.

During hypocapnia, EtCO2, MAP, CBFV, and CVCi all decreased whereas HR increased from the baseline (Table 3). Despite similar reductions in EtCO2 before and after the intervention in both groups, the magnitude of CBFV and CVCi reductions were increased in the AET group when compared with the SAT group. This resulted in significant elevations of hypocapnic CVMR (i.e., ΔCBFV%/ΔEtCO2 (P < 0.011, ηp2 = 0.169) and ΔCVCi%/ΔEtCO2 (P = 0.004, ηp2 = 0.213) in the AET group when compared with the SAT group. The cardiovascular reactivity calculated by ΔMAP/ΔEtCO2 was similar between the groups after the intervention (P = 0.654, ηp2 = 0.006) (Table 3).

Table 3. Cerebral and cardiovascular reactivity to hypocapnia pre- and postinterventions by groups

 SAT
AET
P Value (ANOVA)
 PrePostPrePostTimeGroupTime×Group
ΔEtCO2, mmHg−19.3 (3.9)−19.0 (3.0)−19.2 (4.0)−18.2 (3.0)0.1650.6650.523
ΔHeart rate, beats/min11.8 (7.2)11.0 (7.9)10.9 (5.7)10.4 (4.4)0.5980.6780.912
ΔMAP, mmHg−12.7 (4.6)−12.5 (4.5)−12.8 (3.1)−12.0 (3.5)0.3330.8410.513
ΔCBFV, cm/s−16.7 (6.0)−15.6 (5.6)−16.6 (6.7)−19.0 (8.1)*0.4230.4170.041
ΔCVCi, cm/s·mmHg−0.13 (0.06)−0.12 (0.05)−0.12 (0.06)−0.15 (0.08)0.2470.3770.051
ΔCBFV, %−33.9 (10.7)−32.8 (8.9)−33.5 (9.3)−37.4 (9.4)0.2830.4780.056
ΔCVCi, %−24.2 (10.4)−22.6 (7.6)−22.9 (9.9)−28.4 (10.3)*0.1590.4450.014
ΔCBFV/ΔEtCO2, cm·s−1·mmHg−10.88 (0.32)0.83 (0.31)0.88 (0.37)1.03 (0.35)*0.2690.3580.029
%/mmHg1.77 (0.49)1.75 (0.48)1.76 (0.41)2.05 (0.34)*†0.0330.2840.011
ΔCVCi/ΔEtCO2, cm/s·mmHg/mmHg0.007 (0.003)0.006 (0.003)0.006 (0.003)0.008 (0.004)*0.1660.3490.038
%/mmHg1.25 (0.47)1.20 (0.42)1.18 (0.45)1.53 (0.44)*†0.0250.3340.004
ΔMAP/ΔEtCO2, mmHg/mmHg0.67 (0.25)0.67 (0.25)0.68 (0.19)0.67 (0.20)0.6510.9400.654

Data are presented as means ± SD. EtCO2, end-tidal CO2. Total of 37 subjects (19 in SAT and 18 in AET). Two-way repeated ANOVA was performed to test the main effects of time and group as well as the interaction effect of time-by-group. *P < 0.05 compared with pre. †P < 0.05 compared with SAT. Bold values represent P < 0.05.

AET, aerobic exercise training; ANOVA, analysis of variance; CBFV, cerebral blood flow velocity; CVCi, cerebrovascular conductance index; CVRi, cerebrovascular resistance index; Δ, changes from baseline during hypocapnia; EtCO2, end-tidal CO2; MAP, mean arterial pressure; SAT, stretching-and-toning.

During rebreathing, EtCO2, HR, MAP, CBFV, and CVCi all increased from the baseline (Table 4). Despite similar increases in EtCO2 before and after the intervention, elevations of CBFV and MAP were attenuated in the AET group compared with the SAT group. Consistently, hypercapnic CVMR measured from the slopes of ΔCBFV% versus ΔEtCO2 was reduced in the AET group (P = 0.001, ηp2 = 0.269). The goodness of line fit for ΔCBFV% with ΔEtCO2 yielded excellent coefficients of determination. The slope of ΔMAP versus ΔEtCO2 decreased in the AET group after intervention (P = 0.005, ηp2 = 0.201) (Supplemental Fig. S2).

Table 4. Cerebral and cardiovascular reactivity to hypercapnia pre- and postinterventions by group

 SAT
AET
P Value (ANOVA)
 PrePostPrePostTimeGroupTime × Group
ΔEtCO2, mmHg18.6 (2.0)19.4 (2.5)18.7 (3.0)18.5 (3.6)0.5260.6270.213
Peak EtCO2, mmHg55.5 (3.4)55.3 (3.9)53.4 (5.7)53.0 (4.4)0.7160.0740.919
ΔSaO2, %0.12 (1.51)0.11 (1.33)0.61 (1.09)0.33 (1.19)0.9490.2100.520
ΔHeart rate, beats/min9.5 (8.7)8.5 (3.1)9.6 (7.4)8.6 (6.0)0.4820.9460.993
ΔMAP, mmHg19.7 (6.0)21.5 (5.4)20.0 (6.0)16.6 (5.0)*†0.2770.1860.001
ΔCBFV, cm/s40.1 (9.2)43.6 (9.2)39.8 (10.7)35.3 (10.4)*†0.7190.1570.004
ΔCVCi, cm/s × mmHg0.26 (0.07)0.28 (0.08)0.26 (0.09)0.24 (0.09)0.9530.4320.092
ΔCBFV, %83.7 (21.2)95.9 (28.1)*85.6 (22.4)79.2 (23.2)0.2320.329<0.001
ΔCVCi, %52.6 (16.2)58.2 (21.0)53.3 (20.4)52.3 (19.6)0.3020.6660.143
ΔCBFV/ΔEtCO2, cm·s−1·mmHg−12.59 (0.53)2.75 (0.66)2.62 (0.74)2.38 (0.64)0.6590.3690.053
%/mmHg5.34 (1.22)5.87 (1.49)*5.66 (1.4)5.21 (1.23)*0.7570.6770.001
R20.94 (0.03)0.95 (0.03)0.94 (0.04)0.94 (0.03)0.2490.9250.809
ΔCVCi/ΔEtCO2, cm/s·mmHg/mmHg0.017 (0.005)0.018 (0.005)0.018 (0.006)0.017 (0.005)0.8350.9230.237
%/mmHg3.33 (1.07)3.60 (1.20)3.63 (1.15)3.50 (1.09)0.5010.7800.054
R20.89 (0.05)0.90 (0.06)0.89 (0.05)0.90 (0.05)0.2970.8220.919
ΔMAP/ΔEtCO2
 Slope, mmHg/mmHg1.26 (0.35)1.35 (0.36)1.18 (0.29)1.07 (0.35)*†0.6910.0970.005
R20.92 (0.08)0.92 (0.06)0.91 (0.06)0.91 (0.04)0.6720.6020.935

Data are presented as means ± SD. Total of 37 subjects (19 in SAT and 18 in AET). Two-way repeated ANOVA was performed to test the main effects of time and group as well as the interaction effect of time-by-group. *P < 0.05 compared with pre. †P < 0.05 compared with SAT. Bold values represent P < 0.05.

AET, aerobic exercise training; ANOVA, analysis of variance; CBFV, cerebral blood flow velocity; CVCi, cerebrovascular conductance index; CVRi, cerebrovascular resistance index; Δ, changes from baseline during hypercapnia; EtCO2, end-tidal CO2; MAP, mean arterial pressure; SaO2, arterial blood oxygen saturation; SAT, stretching-and-toning.

Association between Changes in V̇o2peak, CVMRs, and Cognitive performance

After intervention, elevations in hypocapnic CVMR were negatively correlated with reductions in hypercapnic CVMR across all subjects (Fig. 1). Changes in V̇o2peak, were positively correlated with hypocapnic CVMR, but negatively with hypercapnic CVMR (Fig. 2). Changes in V̇o2peak were also negatively correlated with cardiovascular reactivity during hypercapnia. The reported correlations are moderate in Figs. 1 and 2.

Figure 1.

Figure 1.Linear correlations between changes in hypocapnic and hypercapnic cerebral vasomotor reactivity. Cerebral vasomotor reactivity (CVMR) was calculated from the slope of cerebral blood flow velocity (CBFV%) versus end-tidal CO2 (mmHg) (CBFV/EtCO2) (top) and cerebrovascular conductance index (CVCi%) versus end-tidal CO2 (mmHg) (CVCi/EtCO2) (bottom). Δ represents changes pre- and postinterventions. Solid line, dotted line, and broken line represent those obtained for all subjects, stretching and toning (SAT: 19 subjects) group, and aerobic exercise training (AET: 18 subjects) group, respectively. Bold values represent P < 0.05.


Figure 2.

Figure 2.Linear correlations between changes in peak oxygen uptake (V̇o2peak), cerebral vasomotor, and cardiovascular reactivity. Cerebral vasomotor reactivity weas calculated from the slope of cerebral blood flow velocity (CBFV%) versus end-tidal CO2 (mmHg) (CBFV/EtCO2) (top) and cerebrovascular conductance index (CVCi%) versus end-tidal CO2 (mmHg) (CVCi/EtCO2) (middle). Cardiovascular reactivity was calculated from the slope of MAP versus EtCO2 (mmHg) (MAP/EtCO2) (bottom). Δ represents changes in pre- and postinterventions. Solid line, dotted line, and broken line represent those obtained for all subjects, stretching and toning (SAT: 19 subjects) group, and aerobic exercise training (AET: 18 subjects) group, respectively. Bold values represent P < 0.05. MAP, mean arterial pressure.


Attenuations in hypercapnic CVMR with AET were correlated with improved cognitive performance in CVLT-II total, D-KEFS letter, and category fluency scores (Fig. 3). No correlations were observed between changes in hypocapnic CVMR and cognitive performance (P > 0.200).

Figure 3.

Figure 3.Linear correlations between changes in hypercapnic cerebral vasomotor reactivity and cognitive performance. Δ represents changes in pre- and postinterventions. Positive change in cognitive score indicates improved cognitive function. Solid line, dotted line, and broken line represent those obtain for all subjects, stretching and toning (SAT: 19 subjects) group, and aerobic exercise training (AET: 18 subjects) group, respectively. Bold values represent P < 0.05.


DISCUSSION

The main findings from this study are as follows. First, hypocapnic CVMR increased whereas hypercapnic CVMR decreased in the AET group when compared with the SAT group. Second, changes in hypo- and hypercapnic CVMR were negatively correlated with each other. Third, individual increases in cardiorespiratory fitness as measured by V̇o2peak were correlated with increases in hypocapnic and decreases in hypercapnic CVMR. Finally, changes in hypercapnic CVMR with AET were negatively correlated with improved cognitive performance (memory and executive function). Collectively, these results suggest that 1-yr moderate-to-vigorous intensity AET has an impact on cerebrovascular function which is associated with improved cognitive performance in patients with amnestic MCI.

Effects of AET on CBF

There is a growing interest to understand the influence of physical activity on cerebral perfusion (17). Recent studies suggest that habitual physical activity may enhance CBFV measured by TCD (33, 34). For instance, in cross-sectional studies, CBFV measured from the MCA using TCD was elevated in physically fit individuals who were engaging in vigorous intensity AET for more than 2 yr over a lifespan of 18–79 yr (33). Bailey et al. (34) also reported a positive correlation between cardiorespiratory fitness and CBFV in healthy sedentary and aerobically trained young (aged ≤ 30 yr) and old male (≥60 yr). However, findings from exercise training studies are inconsistent. Guadagni et al. (8) observed an increase in CBFV at rest measured by TCD at the MCA in healthy middle-aged and older adults after a 6-mo moderate-intensity AET; however, Murrell et al. (9) showed no change in CBFV measured in the MCA after 3 mo of moderate-intensity AET in previously sedentary young and older adults, although their cardiorespiratory fitness was improved.

In the present study, 1-yr moderate-to-vigorous intensity AET improved V̇o2peak; however, mean CBFV, MAP, CVCi, and CVRi at rest remained unchanged. Of note, measurement of CBFV using TCD does not equal volumetric CBF (35), although we previously reported that CBFV measured at the ipsilateral MCA could reflect ∼31% variance of total CBF (36). Kleinloog et al. (37) assessed CBF using pseudo-continuous arterial spin labeling and found that 8-wk moderate-intensity AET improved CBF by 27% bilaterally in the frontal lobes among sedentary older men. Similarly, our team also reported an increase in global (38) and regional CBF in the anterior cingulate cortex after 1-yr of moderate-to-vigorous intensity AET in patients with MCI (39). In addition to the methodological issues related to CBF measurement, differences in the study design (e.g., single-arm vs. two-arm trial or crossover trial), exercise protocol (e.g., frequency, intensity, and duration), or study population characteristics (e.g., healthy adults, middle-aged, older adults, and patients with MCI) may influence exercise training effects on CBF.

Effects of AET on CVMR

CVMR may reflect capability of brain blood vessel’s responses to neuronal metabolic stimuli, thus may reveal cerebrovascular function which cannot be assessed based on measurements of resting CBF (40). In the present study, hypocapnic CVMR increased whereas hypercapnic CVMR decreased in the AET group when compared with the SAT group. The AET-induced increase in the magnitude of cerebral vasoconstriction during hypocapnia may represent a favorable effect on CBF regulation in that it suggests that cerebral vasoconstriction reserve (i.e., the maximal vasoconstriction from baseline before CO2 stimuli) during hypocapnia is increased in the patients with amnestic MCI (22, 26). In this regard, our previous studies and others have reported a progressive reduction of hypocapnic CVMR with normal aging (22, 41, 42) and a further reduction in hypocapnic CVMR in the patients with amnestic MCI (5). Thus, increases in hypocapnic CVMR suggest an improvement of CBF responses to hypocapnic stimuli.

Previous studies have reported either an increase or unchanged hypercapnic CVMR after AET in healthy adults or stroke survivors in older adults (810, 43). For example, a study of stroke survivors reported that hypercapnic CVMR was increased after 6-mo of moderate-intensity AET (43). A 12-wk moderate intensity AET study in older healthy adults also showed an elevated hypercapnic CVMR with 5% CO2 inhalation (9). On the other hand, a 12-wk moderate-intensity AET study in healthy older adults did not found significant effects of AET on hypercapnic CVMR although cardiorespiratory fitness was improved (10). In contrast to these previous studies, we observed that 1-yr moderate-to-vigorous intensity AET reduced hypercapnic CVMR in patients with amnestic MCI when compared with SAT. The exact reason(s) which may have led to these inconsistent findings is difficult to decipher, particularly the observed increases in hypercapnic CVMR in previous studies versus the attenuated hypercapnic CVMR observed in the present study. The different methods used to assess CVMR, with or without accounting for the effects of changes in arterial pressure during hypercapnia on CBF, as well as differences in study population and/or exercise training protocol all may influence CVMR assessment.

The vascular mechanisms for the observed increase in hypocapnic CVMR (vasoconstriction) and decrease in hypercapnic CVMR (vasodilation) with AET can only be speculated. Moderate-to-vigorous intensity AET may reduce the central and large cerebral artery stiffness, improve cerebral endothelial function (e.g., endothelium-dependent dilation), and decrease cerebral blood vessel wall smooth muscle tone (e.g., arterial stiffness) (38, 44). For example, habitual exercise improved endothelium-dependent vasodilation measured from peripheral arteries, and decreased large elastic artery stiffness in healthy middle-aged and older adults including patients with MCI (38, 44). If AET reduces cerebral arterial stiffness, improves cerebral endothelial function, and reduces the cerebrovascular tone, cerebral vasoconstriction reserve during hypocapnia may increase whereas cerebral vasodilation reserve (i.e., the maximal vasodilation from baseline before CO2 stimuli) during hypercapnia may decrease due to baseline vasodilation before CO2 stimuli, consistent with the observations that AET improved endothelial function at rest (44). Alternatively, AET may attenuate chemoreflex sensitivity and increases in arterial pressure during hypercapnia which may contribute to the observed reduction in hypercapnic CVMR in the AET group (Table 4) (45).

Finally, we observed that there was an inverse relationship between changes in hypo- and hypercapnic CVMR (Fig. 1) and that changes in CVMRs were associated with the magnitude of improved V̇o2peak (Fig. 2). These findings further support the hypothesis that increases in cerebral vascular tone or vasoconstriction at rest with aging or AD pathology may reduce hypocapnic, but augment hypercapnic CVMR, which could be modulated with exercise training (5, 26). However, we caution that CVMR may be influenced by other factors than cerebrovascular tone or vasoconstriction at rest such as the methods used to assess CVMR (5, 22, 26). Morphological changes or damages to cerebral blood vessels also may lead to changes in CVMR (3).

Association of CVMR with Cognitive Performance

Altered CVMR has been associated with cognitive performance in cross-sectional studies. Richiardi et al. (27) and Cantin et al. (46) assessed hypercapnic CVMR in AD, amnestic MCI, and cognitively normal controls using BOLD MRI and inhalation of CO2. They observed that lower hypercapnic CVMR in multiple brain regions was correlated with lower MMSE score. Furthermore, Shim et al. (47), using TCD and a breath-hold method, demonstrated that decreased CVMR was associated with lower MMSE score. In our previous study, lower hypercapnic CVMR and higher hypocapnic CVMR were associated with better cognitive performances (CVLT-II scores and D-KEFS Trail Making Test), but not with the total MMSE score (5). Consistently, Tarumi et al. (48) reported that endurance trained middle-age adults demonstrated better cognitive performance (CVLT-II scores and Attention-executive function) than sedentary control, and the better cognitive performance was associated with greater CVMR. Recently, Guadagni et al. (8) demonstrated that 6 mo of moderate-intensity AET were associated with improvement in cognitive performance and that increased cerebrovascular resistance during hypercapnia was associated with improvement in verbal fluency. In the present study, decreased hypercapnic CVMR were correlated with improvement of cognitive performance (Fig. 3, CVLT-II total score and D-KEFS letter and category fluency scores) in the AET group. These findings suggest that AET-induced change in cerebrovascular function may lead to improvement in cognitive performance in patients with amnestic MCI. We speculate that AET induced reduction in hypercapnic CVMR may reflect reduced cerebrovascular tone or cerebral vasoconstriction which may lead to improvement in brain perfusion and cognitive performance. However, we did not observe associations between changes in hypocapnic CVMR and cognitive performance which suggests that hypercapnic CVMR, compared with hypocapnic CVMR, may be related more closely to the hyperemia responses associated with cognitive activity (3). Further studies are needed to investigate the mechanisms by which alternations in CVMR lead to change in cognitive performance.

Study Strength and Limitations

There are several notable strengths of our study. First, this is the first randomized controlled study in patients with amnestic MCI that investigated the effects of 1-yr AET on hypocapnic and hypercapnic CVMR and their potential relationship with cardiorespiratory fitness and cognitive performance. Second, both hypocapnic and hypercapnic stimuli were used with simultaneous BP measurements to reveal potential asymmetrical CBF responses to changes in CO2 after accounting for changes in BP (26).

The major limitations are the relatively small sample size, technical challenges related to the acquirement of a proper TCD signal in some older adult, as well as a relatively high drop rate of this proof-of-concept study which may bias our results. In addition, the majority of participants of this study were well educated white Caucasians which limited the study generalizability. We also did not collect the information whether the participants in the SAT group performed structured aerobic exercise by themselves during the study period although we had encouraged them to continue and remain their physical activity level unchanged during the study. Therefore, our findings need to be confirmed in future studies with a large sample size. Second, changes in CBFV reflect changes in CBF only if the insonated MCA diameter stays relatively constant. Recent studies using high-resolution MR angiography showed MCA dilation during moderate hypercapnia (∼15 mmHg) which suggests a potential underestimation of CVMR assessed by TCD during hypercapnia (49). However, in this study, the magnitude of EtCO2 changes during both hyperventilation and rebreathing were similar before and after the intervention; therefore, the hypo- and hypercapnic effects on the MCA are also likely to be similar between the groups. Third, assessment of CVMR may be influenced by the protocol employed for CO2 stimuli and regional differences in CVMR, for example, transient versus steady-state; anterior versus posterior cerebral circulation, as well as potential effects of residual vasoconstrictions of hypocapnia on the follow up hypercapnic CVMR (27, 50). In this regard, we previously observed that assessments of CVMR during transient and steady-state changes in respiratory CO2 were similar (20). In addition, a time period of  >5 min after hyperventilation was provided to allow the peripheral and cerebral hemodynamic variables to recover to the baseline level to minimize potential residual vasoconstrictive effects of hypocapnia on hypercapnic CVMR. Finally, although we observed that cognitive performance improved in both groups, these changes were minimal, which may limit clinical relevance of our findings.

Conclusions

This study demonstrated that 1-yr moderate-to-vigorous intensity AET enhanced hypocapnic CVMR while reduced hypercapnic CVMR in patients with amnestic MCI. Notably, we also observed negative correlations between hypo- and hypercapnic CVMR and that changes in hypocapnic CVMR were positively and changes in hypocapnic CVMR were negatively associated with improvements of cardiorespiratory fitness as measured with V̇o2peak. Furthermore, the attenuation of hypercapnic CVMR were associated with improved cognitive performance in the AET group. Taken together, these findings provide evidence that aerobic exercise training has an impact on cerebrovascular function in patients with amnestic MCI which may contribute to improvements in cognition.

GRANTS

This study was supported in part by the National Institutes of Health Grants R01AG033106 and R01HL102457.

DISCLAIMERS

The results of the present study do not constitute endorsement by American College of Sports Medicine.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.S.H., C.M.C., and R.Z. conceived and designed research; T. Tarumi, C.M.C., and R.Z. performed experiments; T. Tomoto and J.N.C. analyzed data; T. Tomoto, T. Tarumi, J.N.C., L.S.H., C.M.C., and R.Z. interpreted results of experiments; T. Tomoto prepared figures; T. Tomoto drafted manuscript; T. Tomoto, T. Tarumi, J.N.C., L.S.H., C.M.C., and R.Z. edited and revised manuscript; T. Tomoto, T. Tarumi, J.N.C., L.S.H., C.M.C., and R.Z. approved final version of manuscript.

ACKNOWLEDGMENTS

The authors thank the study participants for willingness, time, and effort devoted to this study.

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