Elevated blood pressure (BP) in midlife increases the risk of developing white matter hyperintensities (WMH) in the brain. WMH are associated with increased risk of cognitive decline and dementia. Structural changes of the large central arteries occur prior to changes in brachial BP. We have previously reported positive associations between aortic hemodynamics and WMH in normotensive postmenopausal women. The purpose of this study was to evaluate sex differences in aortic hemodynamics and associations with WMH burden in middle-aged and older adults. Ninety-nine participants (age = 63 ± 4y), including n = 35 men and n = 64 postmenopausal women participated in this study. Aortic hemodynamics were derived from radial artery pressure waveforms measured using applanation tonometry. Aortic systolic blood pressure (aSBP), aortic diastolic blood pressure (aDBP), augmented pressure (AP), aortic augmentation index (AIx), and aortic transit time were calculated. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed to reduce skewness. Age-adjusted multiple linear regressions were used to determine the influence of aortic hemodynamics on WMH fraction. There were no sex differences in aSBP or aDBP. AP was greater in women compared with men (16 ± 5 mmHg vs. 11 ± 5 mmHg; P < 0.001). AIx was also greater in women compared with men (28 ± 6 % vs. 18 ± 9 %; P < 0.001). Aortic transit time was lower in women compared with men (140 ± 11 ms vs. 151 ± 12 ms; P < 0.001). There were no sex differences in WMH fraction. There was a positive association between aSBP and WMH fraction in both men (r = 0.37, P = 0.015) and women (r = 0.36, P = 0.017). In addition, aDBP was positively associated with WMH fraction in men (r = 0.47, P = 0.003) and women (r = 0.36, P = 0.017). AP was positively associated with WMH fraction in men (r = 0.34, P = 0.027), but not women (r = 0.24, P = 0.296). AIx was positively associated with WMH fraction in men (r = 0.46, P = 0.004), but not women (r = 0.22, P = 0.570). There were no significant associations between aortic transit time and WMH fraction. In conclusion, AP and AIx were greater in women compared with men. The positive associations between AP and WMH fraction and AIx and WMH fraction were only apparent in men. These findings suggest a sex-specific association between augmented pressure and augmentation index and WMH burden in middle-aged and older adults.

Mental stress has been shown to elicit increases in arterial blood pressure, heart rate and cerebral blood flow, whereas the degree of sympathoexcitation induced by mental stress has been shown to be inconsistent. Previous studies have examined the relationship between limb vascular responsiveness and muscle sympathetic nerve activity (MSNA) during mental stress; however, this has not been studied in relation to the cerebral vasculature. The purpose of this study was to examine concurrent neural and cerebrovascular responses to mental stress. Thirteen healthy adults (men/women: 7/6; age = 28 ± 5 years; BMI = 25 ± 2 kg/m2) completed the Stroop Color Word Test. Beat‐to‐beat mean arterial pressure (MAP) using finger photoplethysmograpy, heart rate (HR) using a 3‐lead ECG, middle cerebral artery velocity (MCAv) using transcranial doppler ultrasound, and MSNA using microneurography were continuously recorded at baseline and in response to the Stroop Color Word Test. The response to the mental stress was recorded as the change from baseline. Linear regression was used to assess the influence of MSNA on cerebrovascular and hemodynamic variables. As expected, there were increases in HR (baseline = 58 ± 8 bpm vs. Stroop = 66 ± 10 bpm; p = 0.045) and MCAv (baseline = 58 ± 8 cm/s vs. Stroop = 69 ± 13 cm/s; p = 0.016) from baseline during the Stroop test. However, there was no change in MAP (baseline = 96 ± 16 mmHg vs. Stroop = 99 ± 17 mmHg; p > 0.05) or MSNA (baseline = 16 ± 6 bursts/min vs. Stroop = 17 ± 7 bursts/min; p > 0.05) from baseline during the Stroop test. Although the change in MAP was positively associated with the change in MCAv (r = 0.46, p = 0.025), there were no associations between the change in MSNA and the increase in MCAv, MAP, or HR in response to the Stroop test. In conclusion, our results demonstrate a disassociation between the MSNA, MAP and MCAv responses to mental stress. It is also possible that the temporal response to mental stress is different and future studies could examine the time course of the sympathetic and cerebrovascular responses.

Peripheral vascular function is acutely improved, in an intensity dependent manner, following a single session of aerobic exercise. While previous studies have examined the effects of acute exercise on cerebrovascular function, the influence of exercise intensity on post-exercise cerebrovascular function remains unclear. PURPOSE: To determine the influence of aerobic exercise intensity on post-exercise cerebrovascular function. METHODS: Eleven participants (age: 27 ± 4 y; VO2max = 51 ± 8 mL/kg/min; men = 4, women = 7) completed 2 study days, in a randomized order, in which they either walked at 30% VO2max for 30 min (WALK) or ran at 70% VO2max for 30 min (RUN). Cerebrovascular reactivity to hypercapnia (CVR) was measured pre and 30 min post-exercise. Middle cerebral artery velocity (MCAv), mean arterial pressure (MAP), and end-tidal CO2 (ETCO2) were continuously monitored during the hypercapnia protocol. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. CVR was calculated as the slope between the percent changes in MCAv or CVCi and ETCO2. RESULTS: During WALK and RUN, there was no difference in MCAv from pre to post-exercise (p ≥ 0.05 for both), despite a significant post-exercise reduction in ETCO2 (WALK: pre = 42 ± 3 mmHg, post = 40 ± 2 mmHg; RUN: pre = 41 ± 3 mmHg, post = 40 ± 3 mmHg; p < 0.05 for both). While WALK had no significant change in MAP and CVCi from pre to post-exercise (p ≥ 0.05 for both), RUN had a significant decrease in MAP and increase in CVCi (MAP: pre = 95 ± 13 mmHg, post = 85 ± 8 mmHg; CVCi: pre = 0.67 ± 0.14 cm/s/mmHg, post = 0.80 ± 0.12 cm/s/mmHg; p < 0.05 for both). There was no significant change in MCAv CVR or CVCi CVR from pre to post-exercise for WALK (p ≥ 0.05 for both); however, there was a decline in both MCAv CVR and CVCi CVR from pre to post-exercise during RUN (MCAv CVR: pre = 1.7 ± 0.5 AU, post = 1.3 ± 0.4 AU; CVCi CVR: pre = 1.3 ± 0.5 AU, post = 0.9 ± 0.4 AU; p < 0.05 for both). Finally, there was no significant difference in the magnitude of change in MCAv CVR and CVCi CVR from pre to post-exercise between the study days (p ≥ 0.05 for both). CONCLUSION: Exercise intensity influences post-exercise cerebrovascular hemodynamics and function as RUN, but not WALK, had a significant increase in CVCi and a reduced MCAv CVR and CVCi CVR from pre to post-exercise. Supported by UW-Madison’s Fall Research Competition, NHLBI 118154

Vascular dysfunction may occur prior to declines in cognition and accumulation of Alzheimer’s disease (AD) neuropathology. White matter hyperintensities (WMH) develop due to chronic cerebral ischemia and elevated blood pressure in midlife increases risk of developing WMH. PURPOSE: The purpose of this study was to evaluate associations between hemodynamic and cerebrovascular responses to hypertensive stimuli and WMH burden in middle-aged and older adults at elevated risk of AD. METHODS: Sixty-eight adults (age = 63 ± 4y, males = 20, females = 48) participated in this study. Participants completed an isometric handgrip exercise (IHG) exercise protocol at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia (PEI). Mean arterial pressure (MAP), heart rate (HR), middle cerebral artery velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance (CVR) was calculated as MAP/MCAv. Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan on a 3 T MRI scanner. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the influence of hemodynamic and cerebrovascular responses to IHG exercise and PEI on WMH fraction. Regressions were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG. RESULTS: During IHG, there were significant increases from baseline in MAP (27 ± 11%), HR (25 ± 12%), MCAv (5 ± 10%), and CVR (22 ± 17%; P < 0.001 for all). During PEI, MAP (22 ± 9%), HR (8 ± 7%), and CVR (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. In response to IHG, there was a negative association between the percent change in MAP (r = -0.41, P = 0.002), HR (r = -0.42, P = 0.002), and CVR (r = -0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971), and WMH fraction. In response to PEI, there were no associations between hemodynamic or cerebrovascular responses and WMH fraction. CONCLUSION: Blunted cerebrovascular resistance in response to handgrip exercise is associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals with greater WMH burden may have impaired cerebral autoregulatory responses to hypertensive stress.

Cerebral autoregulation (CA) is the process by which the brain maintains adequate blood flow despite sudden changes to perfusion pressure. White matter hyperintensities (WMH) are associated with increased risk of cerebrovascular disease and dementia. This study investigated whether dynamic CA is reduced in cognitively unimpaired middle-aged and older adults. Additionally, we evaluated dynamic CA and cerebrovascular responses at rest and in response to orthostatic tilt. We hypothesized that CA would be impaired during orthostatic tilt and that diminished blood pressure and cerebral artery blood velocity changes would be associated with greater WMH fraction. We studied 33 middle-aged and older adults (age = 63 ± 4 y). Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan, respectively, on a 3T MRI scanner. WMH fraction was calculated as the cube root of (WMH lesion volume/ICV) *100. CA was measured using middle cerebral artery blood velocity (MCAv) from transcranial Doppler ultrasound and beat-to-beat mean arterial pressure (MAP) from a finger cuff. Five minutes of data were collected at rest and during 60º orthostatic tilt. Transfer function analysis was used to quantify dynamic CA and reported as gain and phase at low frequency (LF) (0.07-0.20 Hz). MCAv, MAP and cerebrovascular resistance index (CVRi; calculated as MAP/MCAv) were used to quantify the cerebrovascular response to orthostatic tilt. LF gain was greater at baseline compared to 60º tilt (0.52 cm/s/mmHg vs 0.46 cm/s/mmHg, p < 0.05); however, there were no differences in LF phase between baseline and 60º tilt (29.70 degrees vs 29.42 degrees, p = 0.95). During 60º tilt, MAP and MCAv decreased compared to baseline (MAP: 106 mmHg vs 101 mmHg, p = 0.02; MCAv: 59 cm/s vs 53 cm/s, p < .01). CVRi was higher at 60º tilt compared with baseline (1.90 mmHg/cm/s vs 2.02 mmHg/cm/s, p < 0.01). There were significant inverse associations between the percent change from baseline to 60º tilt in MAP (r = -0.4, p = 0.03), MCAv (r = -0.39, p = 0.03), but not CVRi (r = 0.13, p = 0.50), and WMH fraction. There were no associations at baseline or 60º tilt between gain (Baseline: r = -0.18, p = 0.33; 60º: r = -0.31, p = 0.09) or phase (Baseline: r = 0.07, p = 0.71; 60º: r = -0.29, p = 0.12) and WMH fraction. Our results indicate that dynamic CA is preserved in cognitively unimpaired adults during tilt. However, individuals with diminished MAP and MCAv responses to orthostatic tilt displayed greater WMH fraction. Future studies are needed to investigate the relationship between blood pressure and cerebral blood flow in individuals with cognitive impairment to further understand the role of cerebral blood flow regulation in the development of cognitive decline.

Vascular dysfunction may occur prior to declines in cognitive function and accumulation of neuropathology. White matter hyperintensities (WMH) develop due to cerebral ischemia and elevated blood pressure in midlife. The purpose of this study was to evaluate associations between cardiovascular and cerebrovascular responses to sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated in this study. Participants completed isometric handgrip exercise (IHG) exercise at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the association between cardiovascular and cerebrovascular responses to IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG exercise. During IHG exercise, there were significant increases from baseline in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001 for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. There was an inverse association between the percent change in HR (r = −0.42, P = 0.002), MAP (r = −0.41, P = 0.002), and CVRi (r = −0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH fraction. There were no associations between responses to post-exercise ischemia and WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to sympathoexcitatory stress have greater WMH burden.

The central arteries dampen the pulsatile forces from myocardial contraction, limiting the pulsatility that reaches the cerebral vasculature, although there are limited data on this relationship with aging in humans. The purpose of this study was to determine the association between aortic stiffness and cerebral artery pulsatility index in young and older adults. We hypothesized that cerebral pulsatility index would be associated with aortic stiffness in older adults, but not in young adults. We also hypothesized that both age and aortic stiffness would be significant predictors for cerebral pulsatility index. This study included 23 healthy older adults (aged 62 ± 6 years) and 33 healthy young adults (aged 25 ± 4 years). Aortic stiffness was measured using carotid-femoral pulse wave velocity (cfPWV), while cerebral artery pulsatility index in the internal carotid arteries (ICAs), middle cerebral arteries (MCAs), and basilar artery were assessed using 4D Flow MRI. Cerebral pulsatility index was calculated as (maximum flow – minimum flow) / mean flow. In the combined age group, there was a positive association between cfPWV and cerebral pulsatility index in the ICAs (r = 0.487; p < 0.001), MCAs (r = 0.393; p = 0.003), and basilar artery (r = 0.576; p < 0.001). In young adults, there were no associations between cfPWV and cerebral pulsatility index in any of the arteries of interest (ICAs: r = 0.253; p = 0.156, MCAs: r = −0.059; p = 0.743, basilar artery r = 0.171; p = 0.344). In contrast, in older adults there was a positive association between cfPWV and cerebral pulsatility index in the MCAs (r = 0.437; p = 0.037) and basilar artery (r = 0.500; p = 0.015). However, the relationship between cfPWV and cerebral pulsatility index in the ICAs of the older adults did not reach the threshold for significance (r = 0.375; p = 0.078). In conclusion, age and aortic stiffness are significant predictors of cerebral artery pulsatility index in healthy adults. This study highlights the importance of targeting aortic stiffness in our increasingly aging population to reduce the burden of age-related changes in cerebral hemodynamics.

Platelet activation may contribute to age-related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. The purpose of this study was to evaluate the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular function in healthy young and older adults before and after cyclooxygenase inhibition. We hypothesized that higher levels of prostacyclin would be positively associated with cerebrovascular function. Healthy young (n=36; 25 ± 4 yrs; 19 women, 17 men) and older (n=12; 62 ± 2 yrs; 8 women, 4 men) adults who were not taking daily aspirin participated in the study. Prostacyclin was determined by levels of 6-keto-PGF1α in the blood. On a separate study visit, cerebrovascular function was assessed by cerebrovascular reactivity (CVR) to hypercapnia in the middle cerebral artery before (CON) and 90 minutes after cyclooxygenase inhibition with indomethacin (INDO) at 1.2 mg/kg. Participants were instrumented with a transcranial Doppler ultrasound which continuously recorded middle cerebral artery velocity, a nasal cannula to measure end-tidal CO2, a finger blood pressure cuff to measure beat-by-beat blood pressure, and a mask with a one-way valve to prevent rebreathing. CVR was calculated as the slope of the relationship between middle cerebral artery velocity and the change in end-tidal CO2 during stepwise elevations in CO2. The associations between prostacyclin and CVR were analyzed using Pearson's Product-Moment correlations. In young adults, there were no associations between prostacyclin and CVR during CON (r = 0.11, p = 0.54) or INDO (r = 0.15, p = 0.39). In older adults, there was a trend for an association between prostacyclin and CVR during CON (r = 0.52, p = 0.08), but no association during INDO (r = -0.41, p = 0.18). We also evaluated the relationship between prostacyclin and the change in CVR between conditions. We found no association in young adults (r = 0.15, p = 0.37); however, in older adults, those with higher baseline prostacyclin levels demonstrated a greater change in CVR (r = 0.69, p = 0.01). In conclusion, there was a trend for a positive association between platelet inhibition and cerebrovascular function in older adults. Furthermore, older adults may rely more on cyclooxygenase products to mediate CVR. Future studies could evaluate how platelet activation may contribute to age-related changes in cerebrovascular function.

Cerebrovascular reactivity is a measure of cerebrovascular health and attenuated cerebrovascular reactivity is associated with Alzheimer's disease (AD). Gray matter (GM) atrophy occurs with advancing age and is greater in individuals with AD compared to age-matched controls. Normalizing cerebrovascular reactivity to GM to account for individual differences in GM volume may provide a more accurate measure of cerebrovascular reactivity. Therefore, the purpose of this study was to investigate the effects of GM normalization on cerebrovascular reactivity in middle-aged adults with and without a family history of AD. Seventy-five adults with a family history of AD (FH, n = 50, men = 17, women = 33, age = 62 ± 4 yrs) and without a family history of AD (NoFH, n = 25, men = 7, women = 18, age = 63 ± 4 yrs) participated in this study. Family history of AD was determined using a validated Dementia Questionnaire or autopsy report when available. To determine brain volumes, participants underwent a T1-weighted scan on a 3T MRI scanner. GM was segmented in SPM12 and normalized to intracranial volume. Cerebrovascular reactivity to hypercapnia was measured by continuously recording middle cerebral artery velocity (MCAv) with a transcranial Doppler ultrasound, mean arterial pressure (MAP) with a finometer, and end-tidal carbon dioxide (ETCO2) with a nasal cannula during stepwise elevations of CO2. Cerebrovascular conductance index (CVCi) was calculated using the equation (MCAv/MAP)*100. Cerebrovascular reactivity was calculated as the linear relationship between the change in ETCO2 and the change in MCAv or CVCi. GM normalization was performed by dividing reactivity slopes by GM volume. There were no differences in MCAv reactivity (FH: 2.1 ± 0.1 cm/s/mmHg vs. NoFH: 1.9 ± 0.2 cm/s/mmHg; p > 0.05) between groups; however, there was a trend for greater CVCi reactivity in adults with a family history of AD (FH: 1.5 ± 0.1 cm/s/mmHg2 vs. NoFH: 1.2 ± 0.1 cm/s/mmHg2; p = 0.09). There were no differences in GM volume (FH: 0.47 ± 0.03 l vs. NoFH: 0.46 ± 0.03 l; p > 0.05) between groups. After normalizing for GM, there were no differences in normalized MCAv reactivity (FH: 4.4 ± 0.2 cm/s/mmHg/l vs. NoFH: 4.0 ± 0.3 cm/s/mmHg/l; p > 0.05) between groups. The trend for greater CVCi reactivity in adults with a family history of AD persisted after normalizing for GM (FH: 3.2 ± 0.2 cm/s/mmHg2/l vs. NoFH: 2.5 ± 0.3 cm/s/mmHg2/l; p = 0.09). Normalized MCAv and CVCi reactivity were greater than MCAv and CVCi reactivity (p < 0.05). These findings suggest that GM normalization yields greater cerebrovascular reactivity slopes compared to raw slopes; however, GM normalization did not impact the effect of a family history of AD on cerebrovascular reactivity. Normalization of cerebrovascular reactivity values during accelerating GM atrophy with advancing age and AD progression may be important when evaluating cerebrovascular health.

Structural and functional changes in the cerebral vasculature occur with advancing age, which may lead to impaired neurovascular coupling (NVC) and cognitive decline. Cyclooxygenase (COX) inhibition abolishes age-related differences in cerebrovascular reactivity, but it is unclear if COX inhibition impacts NVC. The purpose of this study was to examine the influence of aging on NVC before and after COX inhibition. Twenty-three young (age = 25 ± 4 yr) and 21 older (age = 64 ± 5 yr) adults completed two levels of difficulty of the Stroop and n-back tests before and after COX inhibition. Middle cerebral artery blood velocity (MCAv) was measured using transcranial Doppler ultrasound and mean arterial blood pressure (MAP) was measured using a finger cuff. Hemodynamic variables were measured at rest and in response to cognitive challenges. During the Stroop test, older adults demonstrated a greater increase in MCAv (young: 2.2 ± 6.8% vs. older: 5.9 ± 5.8%; P = 0.030) and MAP (young: 2.0 ± 4.9% vs. older: 4.8 ± 4.9%; P = 0.036) compared with young adults. There were no age-related differences during the n-back test. COX inhibition reduced MCAv by 30% in young and 26% in older adults ( P < 0.001 for both). During COX inhibition, there were no age-related differences in the percent change in MCAv or MAP in response to the cognitive tests. Our results show that older adults require greater increases in MCAv and MAP during a test of executive function compared with young adults and that any age-related differences in NVC were abolished during COX inhibition. Collectively, this suggests that aging is associated with greater NVC necessary to accomplish a cognitive task.

Cardiorespiratory fitness has beneficial effects on the systemic vasculature; however, its influence on the function of the large cerebral vessels is unclear. Recent studies using high field magnetic resonance imaging (MRI) suggest that the middle cerebral artery (MCA) may vasodilate during a vasoactive stimulus such as hypercapnia, but the influence of cardiorespiratory fitness on MCA dilation is unknown. The purpose of this study was to evaluate the association between cardiorespiratory fitness and MCA cross‐sectional area (CSA) before and during hypercapnia. We hypothesized that cardiorespiratory fitness would be positively associated with the percent change in MCA CSA from baseline to hypercapnia. A total of 16 healthy, physically‐active adults (age = 54 ± 17 y, men = 8, women = 8) participated in this pilot study. Left MCA CSA was assessed with a 4D flow MRI scan on a 3T MRI scanner at baseline and during hypercapnia (6% CO2). End‐tidal carbon dioxide and mean arterial pressure were continuously monitored with an anesthesia monitor. CSA analysis was performed offline. On a separate study visit, cardiorespiratory fitness was assessed by a VO2max test on a cycle ergometer. The average absolute VO2max was 2.5 ± 0.9 L/min, the average relative VO2max was 37 ± 8 ml/kg/min and the average maximal workload attained during the VO2max test was 231 ± 77 watts. The MCA CSA was 0.068 ± 0.011 cm2 at baseline and 0.069 ± 0.013 cm2 during hypercapnia. The average percent change in the MCA CSA from baseline to hypercapnia was 2 ± 4 %. The percent change in MCA CSA was positively associated with absolute VO2max (r = 0.52, p = 0.04) and maximal workload (r = 0.58, p = 0.02), but not significantly associated with relative VO2max (r = 0.32, p = 0.22). Because age and body size may impact these results, we also investigated the associations between MCA CSA percent change and cardiorespiratory fitness or workload when adjusted for age and body surface area. With these adjustments, these associations were no longer significant (absolute VO2max: r = 0.16, p = 0.58; workload: r = 0.33, p = 0.25). The results were similar when delta MCA CSA was assessed. In conclusion, absolute cardiorespiratory fitness levels and maximal workload were positively associated with change in MCA CSA during hypercapnia; however, these associations were no longer significant after adjusting for age and body surface area. These results suggest that cardiorespiratory fitness may influence the vasoreactivity of large intracranial vessels in response to vasoactive stimuli. In addition, age and body size may also need to be considered.

Abstract Exercise is associated with higher cognitive function and is a promising intervention to reduce the risk of dementia. With advancing age, there are changes in the vasculature that have important clinical implications for brain health and cognition. Primary aging and vascular risk factors are associated with increases in arterial stiffness and pulse pressure, and reductions in peripheral vascular function. Objective: The purpose is to discuss the epidemiological, observational, and mechanistic evidence regarding the link between age-related changes in vascular health and brain health. Methods: We performed a literature review and integrated with our published data. Results: Epidemiological evidence suggests a link between age-related increases in arterial stiffness and lower cognitive function, which may be mediated by cerebral vascular function, including cerebral vasoreactivity and cerebral pulsatility. Age-associated impairments in central arterial stiffness and peripheral vascular function have been attenuated or reversed through lifestyle behaviors such as exercise. Greater volumes of habitual exercise and higher cardiorespiratory fitness are associated with beneficial effects on both peripheral vascular health and cognition. Yet, the extent to which exercise directly influences cerebral vascular function and brain health, as well as the associated mechanisms remains unclear. Conclusion: Although there is evidence that exercise positively impacts cerebral vascular function, more research is necessary in humans to optimize experimental protocols and address methodological limitations and physiological considerations. Understanding the impact of exercise on cerebral vascular function is important for understanding the association between exercise and brain health and may inform future intervention studies that seek to improve cognition.

Elevated activity of the sympathetic nervous system at rest and sympathetic hyperreactivity to stress have been shown to be predictors of cardiovascular diseases. The effect of habitual exercise training on muscle sympathetic reactivity to a stressor is unclear, with some studies demonstrating blunted muscle sympathetic nerve activity (MSNA) reactivity following training and others demonstrating no change in MSNA reactivity; however, many of these studies have not been performed in older adults. The purpose of this study was to compare MSNA responses to hypercapnia in older exercise trained and sedentary adults. Twenty-five older healthy adults were evaluated including 14 exercise trained (EX: age = 63 ± 4 years; BMI = 23 ± 3 kg/m2) and 11 sedentary controls (CON: age = 62 ± 6 years; BMI = 23 ± 2 kg/m2). Participants underwent a maximal exercise test to exhaustion on a cycle ergometer to measure VO2max. On a separate day, mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants underwent stepped increases in hypercapnia, stabilizing at 6% CO2. Results are reported as mean ± SE. MAP was not different between groups at baseline (EX: 96 ± 2 mmHg vs. CON: 102 ± 5 mmHg; p>0.05) and during 6% CO2 (EX: 104 ± 4 mmHg vs. CON: 107 ± 5 mmHg; p>0.05). Both the change in MAP (EX: 8 ± 2 mmHg vs. CON: 5 ± 2 mmHg; p>0.05) and % change in MAP (EX: 8 ± 2 % vs. CON: 4 ± 2 %; p>0.05) were not different between groups. HR was not significantly different, but tended to be higher in the CON group at baseline (EX: 53 ± 2 bpm vs. CON: 57 ± 1 mmHg; p=0.09) and during 6% CO2 (EX: 57 ± 2 bpm vs. CON: 62 ± 2 bpm; p=0.09). Both the change in HR (EX: 4 ± 1 bpm vs. CON: 5 ± 1 mmHg; p>0.05) and % change in HR (EX: 8 ± 2 % vs. CON: 8 ± 2 %; p>0.05) were not different between groups. MSNA was not different between groups at baseline (EX: 32 ± 3 bursts/min vs. CON: 34 ± 3 bursts/min; p>0.05) and during 6% CO2 (EX: 35 ± 3 bursts/min vs. CON: 35 ± 3 bursts/min; p>0.05). Similarly, the change in MSNA (EX: 3 ± 1 bursts/min vs. CON: 1 ± 2 bursts/min; p>0.05) and the % change in MSNA (EX: 10 ± 5 % vs. CON: 5 ± 5 %; p>0.05) were not different between groups. The sympathetic response to hypercapnia was not different in older exercise-trained adults compared with sedentary adults. Taken together, these results suggest that hypercapnia-induced sympathoexcitation may not be altered with habitual exercise training in older healthy adults. Future studies could assess sympathoexcitation to other physiological stressors to further explore the effects of exercise on sympathetic reactivity in older adults.

Cyclooxygenase (COX) catalyzes the formation of prostaglandins and influences blood flow regulation. Previous studies have shown that COX inhibition reduces cerebral blood flow velocity and cerebrovascular reactivity to CO2 (CVR), however, the effects of COX inhibition on neurovascular regulation is unknown. Sympathetic nerve activity is an important modulator of blood pressure and blood flow. The purpose of this study was to determine the effect of COX inhibition on the muscle sympathetic nerve activity (MSNA) response to hypercapnia during CVR testing.MethodsFifteen healthy adults were evaluated (M/F = 7/8; age = 40 ± 21 years; BMI = 24 ± 2 kg/m2) before (Pre) and 90 minutes after oral administration of the COX inhibitor indomethacin (Indo), given at 1.2mg/kg. Mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants were evaluated breathing 6% CO2. Results are reported as mean ± SE.ResultsAt baseline, HR was 54 ± 2 bpm, MAP was 100 ± 4 mmHg, MSNA burst frequency was 24 ± 2 bursts/min and MSNA burst incidence was 45 ± 4 bursts/100hb. The change in HR when exposed to hypercapnia was not different after Indo (Pre: 6 ± 2 bpm vs. Indo: 4 ± 1 bpm; p>0.05). The change in MAP (Pre: 0 ± 2 mmHg vs. Indo: 6 ± 1 mmHg; p<0.05), MSNA burst frequency (Pre: 1 ± 1 bursts/min vs. Indo: 4 ± 1 bursts/min; p<0.05), and MSNA burst incidence (Pre: −3 ± 2 bursts/100hb vs. Indo: 4 ± 2 bursts/100hb; p<0.05) was greater after Indo administration.ConclusionThe sympathetic response to hypercapnia was greater following the administration of Indo. Taken together, these results suggest that hypercapnia‐induced sympathoexcitation may be altered following COX inhibition. Future studies could evaluate if the sympathetic responses to hypercapnia vary with age or sex.Support or Funding InformationNIH HL118154

The onset of menopause coincides with a loss of the vasoprotective effects of estrogen. Early menopause is associated with increased cardiovascular risk factors and cardiovascular disease; however, the specific cerebrovascular outcomes regarding the timing at natural menopause are not understood. The purpose of this study was to investigate how the age of natural menopause influences cerebrovascular reactivity, a measure of cerebrovascular function. We studied 37 women with earlier (Early; n = 20; age at onset of menopause = 46 ± 3 y; age at time of study = 61 ± 4 y) and later (Late; n = 17; age at onset of menopause = 55 ± 2 y; age at time of study = 62 ± 3 y) onset of natural menopause. Supine brachial blood pressure was taken in triplicate using a sphygmomanometer before study procedures. Middle cerebral artery velocity (MCAv), mean arterial blood pressure (MAP), and end‐tidal carbon dioxide (ETCO□) were continuously recorded during hypercapnia to measure cerebrovascular reactivity. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the slope of the relationship between ETCO□ and each variable of interest. There were no significant differences in MCAv reactivity (Early: 2.0 ± 0.2 cm/s/mmHg; Late: 2.3 ± 0.2 cm/s/mmHg; p = 0.09), MAP reactivity (Early: 1.0 ± 0.3 mmHg/mmHg; Late: 1.0 ± 0.2 mmHg/mmHg; p = 0.50), or CVCi reactivity (Early: 0.01 ± 0.002 cm/s/mmHg2; Late: 0.02 ± 0.001 cm/s/mmHg2; p = 0.16) between women who experienced an earlier or later onset of menopause. However, the Early and Late groups had a statistically significant difference in supine brachial MAP at rest (Early: 99.5 ± 1.9 mmHg, Late: 91.6 ± 2.9 mmHg; p < 0.05), which may confound cerebrovascular reactivity to hypercapnia. When brachial MAP was added as a covariate, the Early group had a significantly lower MCAv reactivity (p < 0.05) than the Late group. These results suggest that the age at natural menopause may influence cerebrovascular function in postmenopausal women, as women who experience an earlier onset of menopause have lower cerebrovascular reactivity after resting MAP is accounted for. Future studies should examine intervention strategies, such as menopausal hormone therapy, in order to mitigate these discrepancies in cerebral blood flow regulation.Support or Funding InformationResearch funded through a grant from the Alzheimer’s Association.

Elevated activity of the sympathetic nervous system at rest and sympathetic hyperreactivity to stress have been shown to be predictors for the development of cardiovascular diseases, such as hypertension. Previous studies have shown that there is no difference in resting muscle sympathetic nerve activity (MSNA) with exercise in young adults; however, the effects of exercise on the sympathoexcitatory response to chemical stimuli, such as hypercapnia, have not been studied. The purpose of this study was to compare MSNA responses to hypercapnia in young exercise trained and sedentary adults. Twenty‐nine young healthy adults were evaluated including 16 exercise trained (EX: M/F = 7/9; age = 27 ± 5 years; BMI = 23 ± 2 kg/m 2 ) and 13 sedentary controls (CON: M/F = 7/6; age = 28 ± 4 years; BMI = 25 ± 2 kg/m 2 ). Mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants underwent a stepped hypercapnic protocol increasing to 6% CO 2 . Results are reported as mean ± SE. MAP was not different between groups at baseline (EX: 95 ± 4 mmHg vs. CON: 91 ± 5 mmHg; p>0.05) and during 6% CO 2 (EX: 96 ± 4 mmHg vs. CON: 101 ± 5 mmHg; p>0.05). Both the change in MAP (EX: 1 ± 4 mmHg vs. CON: 11 ± 5 mmHg; p<0.05) and % change in MAP (EX: 2 ± 4 % vs. CON: 13 ± 5 %; p<0.05) were greater in the CON group compared with the EX group. HR was greater in the CON group compared with the EX group at baseline (EX: 50 ± 1 bpm vs. CON: 59 ± 3 mmHg; p<0.05) and during 6% CO 2 (EX: 57 ± 2 bpm vs. CON: 68 ± 3 bpm; p<0.05). Both the change in HR (EX: 8 ± 1 bpm vs. CON: 9 ± 2 mmHg; p>0.05) and % change in HR (EX: 16 ± 3 % vs. CON: 16 ± 4 %; p>0.05) were not different between groups. MSNA was not different at baseline (EX: 16 ± 1 bursts/min vs. CON: 18 ± 2 bursts/min; p>0.05) and during 6% CO 2 (EX: 17 ± 2 bursts/min vs. CON: 20 ± 2 bursts/min; p>0.05). The change in MSNA was greater in the CON group compared with the EX group (EX: 0.5 ± 0.4 bursts/min vs. CON: 2.4 ± 0.9 bursts/min; p<0.05) and the percent change in MSNA was non‐significant but tended to be higher in the CON group compared with the EX group (EX: 4 ± 2 % vs. CON: 16 ± 6 %; p=0.057). The sympathetic response to hypercapnia was lower in young exercise‐trained adults compared with sedentary adults. Taken together, these results suggest that hypercapnia‐induced sympathoexcitation may be altered with exercise training status, even in young healthy adults. Support or Funding Information NIH HL118154 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

In a healthy brain, the cerebral microvessels respond to increased metabolic demand by vasodilating to increase blood flow. Reduced cerebrovascular responses to stimuli are indicative of impaired cerebrovascular functioning, and this mismatch may be a mechanism underlying age‐related reductions in cognition. The purpose of this study was to investigate how the cerebral blood flow (CBF) response to a metabolic stimulus differs between young and older participants. It has been shown that older adults have lower CBF response to chemical stimuli compared to young adults, and we hypothesized there would also be age‐associated differences in the CBF response to metabolic stimuli. We evaluated 15 young (25±1 y) and 11 older (64±1 y) habitual exercisers. Participants were instrumented with a transcranial Doppler ultrasound to measure middle cerebral artery velocity (MCAv) and a Finometer to measure beat‐to‐beat mean arterial pressure (MAP) at baseline and during two difficulty levels of the n‐back memory test. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. There were no group differences in BMI or resting heart rate. The older adults had a significantly higher MAP at rest compared with young adults (96±4 mmHg vs. 86±2 mmHg, respectively; p<0.05). There were no differences in MCAv at baseline. However, baseline CVCi was lower in the older adults compared with young adults (0.55±0.04 cm/s/mmHg vs. 0.70±0.06 cm/s/mmHg respectively; p<0.05). There were no differences in MCAv during either level of the test. During the level 1 test, older adults had higher MAP compared with young adults (111±6 mmHg vs. 96±3 mmHg respectively; p<0.05). During the level 2 test, the older adults again demonstrated augmented MAP compared with young adults (108±5 mmHg vs. 94±3 mmHg; p<0.05). Interestingly, older adults had a greater percent increase in CVCi compared with young adults during the level 2 test (13±3% vs. 7±2% respectively; p<0.05). Thus, while older adults had lower baseline CVCi and lower CVCi during the test, they had a greater increase in CVCi during the higher difficulty test. In summary, there were no age‐associated differences in baseline MCAv or change in MCAv during the cognitive tests, yet MAP was higher in the older adults. Therefore, our results suggest that the CBF response to an acute cognitive challenge is similar in young and older adults, but the regulatory mechanism may be different. Support or Funding Information Supported by National Institute of Health grant HL118154, and the American Physiological Society Undergraduate Research Excellence Fellowship. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The ability of the cerebral microvessels to respond to chemical or metabolic stimuli declines with age and this change may be one mechanism through which age‐related cognitive decline occurs. Prostaglandins play an important role in the control of vascular tone, therefore changes in prostaglandin synthesis or expression may be underlying the age‐related alterations in cerebral microvascular function. Additionally, we have previously shown that aerobic fitness was associated with a decrease in cerebral microvascular function after cyclooxygenase (COX) blockade; yet this was in a small sample size of healthy older adults who were not exercise trained. Thus, the purpose of our study was to evaluate the effect of age on cerebral microvascular reactivity to hypercapnia (CVR) and to determine if habitual exercise modifies the response to COX blockade. We recruited 45 younger (YA; age = 26±1 y) and 31 older (OA; age = 63±1 y) healthy adults, including 21 sedentary YA, 24 exercising YA, 12 sedentary OA, and 19 exercising OA. Aerobic fitness (VO2 max) was measured during an incremental cycle ergometer test. Middle cerebral artery blood flow velocity (MCAv) and end‐tidal CO2 (ETCO2) were continuously recorded. CVR was calculated as the linear slope of the relationship between ETCO2 and MCAv and was assessed before and after the administration of the COX inhibitor indomethacin (INDO). The change in CVR was calculated as pre INDO CVR – post INDO CVR. There were no group differences in MCAv pre INDO (YA: 65±3 cm/s vs. OA: 59±3 cm/s; p>0.05); however, YA had higher MCAv post INDO (YA: 45±1 cm/s vs. OA: 40±2 cm/s; p<0.05). OA had significantly greater change in CVR compared with YA (2.0±0.1 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). There was also a significant effect of habitual exercise, such that sedentary adults had a greater change in CVR compared with exercising adults (2.0±0.2 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). In addition, there was an inverse association between VO2 max and the change in CVR in OA (r=0.42, p<0.05), but not in YA (p>0.05). Our results indicate that older adults, regardless of exercise status, rely more on COX‐derived products for cerebral microvascular responses to hypercapnia. Our results also suggest that habitual exercise may alter the contribution of COX‐derived products to cerebral blood flow regulation.Support or Funding InformationSupported by National Institute of Health grant HL118154This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Menopausal hormone therapy (MHT) is used for management of menopausal symptoms; however, the long-term effects of MHT on the cardiovascular and cerebrovascular system are controversial. Previous studies have shown that pulsatility index (a measure of the variability of blood velocity in a vessel) of the middle cerebral artery (MCA) decreases during the use of MHT, but increases again within months after suspension of MHT; however, these effects have not been studied long term. PURPOSE: The purpose of this study was to evaluate the long term effects of prior use of MHT on MCA pulsatility index (PI). METHODS: Fifty-four postmenopausal women were evaluated 3 years after cessation of use of MHT or placebo (as part of a 4 year randomized, placebo-controlled clinical trial). Women had received either a placebo (PLA: n=19; age=59±3 y; BMI=28±3 kg/m2) or MHT (MHT: n=35; age=60±3 y; BMI=27±5 kg/m2). MCA velocity (MCAv), mean arterial pressure (MAP), and end-tidal CO2 were continuously measured throughout the study. Baseline measurements were recorded then women underwent a stepped hypercapnic protocol inhaling 2%, 4%, then 6% CO2 at each stage for three minutes. PI was calculated as (systolic MCAv-diastolic MCAv)/mean MCAv. RESULTS: Baseline MAP and MCAv were similar between groups (PLA: MAP=90±2 mmHg; MCAv=60±3 cm/s; MHT: MAP=91±1 mmHg; MCAv=69±3 cm/s; p>0.05 for both). PI was greater in the MHT group compared to the placebo group at baseline (MHT: PI=0.86±0.02 vs. PLA: PI=0.77±0.02; p<0.05), during 2% CO2 (MHT: PI=0.85±0.02 vs. PLA: PI=0.76±0.02; p<0.05), and during 4% CO2 (MHT: PI=0.82±0.02 vs. PLA: PI=0.73±0.02; p<0.05). PI was not different between groups during 6% CO2 (MHT: PI=0.75±0.02; PLA: PI=0.71±0.02; p=0.28). CONCLUSIONS: Cerebral PI was higher in women who had taken MHT compared to women who had not taken MHT. The differences between groups persisted until the CO2 vasodilatory stimulus increased to 6%. Taken together, these results suggest that previous use of MHT alters regulation of the cerebral circulation that has effects at least up to three years after cessation. Supported by NIH grant AG44170, HL118154