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Menopause is associated with adverse changes in vascular health coinciding with an increased risk of stroke and vascular cognitive impairment. However, there is significant variation in the age at menopause. The present study examined how the age at natural menopause impacts cerebrovascular reactivity and structural biomarkers of brain aging. Thirty-five healthy postmenopausal women were classified as early-onset menopause (Early; n = 19, age at menopause: 47 ± 2 yr) or later-onset menopause (Late; n = 16, age at menopause: 55 ± 2 yr). Middle cerebral artery blood velocity (MCAv), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) were recorded during a stepped hypercapnia protocol. Reactivity was calculated as the slope of the relationship between ETCO2 and each variable of interest. Brain volumes and white matter hyperintensities (WMHs) were obtained with 3T MRI. Resting MAP was greater in the Early group (99 ± 9 mmHg) compared with the Late group (90 ± 12 mmHg; P = 0.02). Cerebrovascular reactivity, assessed using MCAv, was blunted in the Early group (1.87 ± 0.92 cm/s/mmHg) compared with the Late group (2.37 ± 0.75 cm/s/mmHg; P = 0.02). Total brain volume did not differ between groups (Early: 1.08 ± 0.07 L vs. Late: 1.07 ± 0.06 L; P = 0.66), but the Early group demonstrated greater WMH fraction compared with the Late group (Early: 0.36 ± 0.14% vs. Late: 0.25 ± 0.14%; P = 0.02). These results suggest that age at natural menopause impacts cerebrovascular function and WMH burden in healthy postmenopausal women.

This research aimed to examine the impact of aerobic exercise intensity on acute post-exercise internal carotid artery (ICA) hemodynamics. This research tested the hypothesis that acute exercise would elicit intensity-dependent effects on ICA cross-sectional area (CSA), shear stress, and blood flow. Ten young, healthy adults (27 ± 4 years of age, 3 males, 7 females) completed a maximal oxygen uptake (VO2max) treadmill test followed by two randomized study visits that involved 30 minutes of treadmill exercise at 30% of VO2max or 70% of VO2max. At each study visit, a venous blood draw and ultrasound imaging of the ICA were completed before and 4 ± 1 min following exercise. During ultrasound imaging, beat-by-beat systemic blood pressure was measured. Vessel diameter and blood velocity were determined using automated edge detection software. ICA blood flow was calculated as: mean blood velocity x CSA x 60. Using measures of blood viscosity from the blood draw, shear stress was calculated as: (4 x viscosity x mean blood velocity)/mean vessel diameter. Mean arterial pressure and blood viscosity were not altered following exercise. ICA CSA was increased following exercise (Time: P = 0.03, Intensity: P = 0.24, Interaction: P = 0.38), but the magnitude of dilation did not differ following exercise at 30% VO2max (Δ0.01 ± 0.03 cm2) and 70% VO2max (Δ0.02 ± 0.04 cm2; P = 0.54). The impact of exercise on ICA shear stress was intensity dependent (Time: P = 0.02, Intensity: P = 0.03, Interaction: P = 0.03), such that shear stress was unaltered following exercise at 30% VO2max (Pre: 10 ± 2 dynes/cm2 vs. Post: 11 ± 3 dynes/cm2; Ppost-hoc = 0.13) but increased following exercise at 70% VO2max (Pre: 12 ± 4 dynes/cm2 vs. Post: 16 ± 4 dynes/cm2; Ppost-hoc = 0.04). ICA blood flow was increased following both exercise intensities (Time: P < 0.01, Intensity: P = 0.02, Interaction: P = 0.03), but a larger increase was observed following exercise at 70% VO2max (Δ257 ± 151 mL/min) compared with 30% VO2max (Δ109 ± 129 mL/min; P = 0.03). Therefore, aerobic exercise produced intensity dependent effects on acute post-exercise ICA hemodynamics. Vigorous intensity exercise increased shear-stress and provoked a larger increase in ICA blood flow compared to light intensity exercise. However, increases in ICA CSA following exercise did not differ between the two exercise intensities. Therefore, the greater increase in ICA blood flow following vigorous intensity exercise may be related to downstream effects in addition to shear-mediated dilation of the ICA. Supported by the Wisconsin Alumni Research Foundation (JNB) and the National Institutes of Health (NS117746; JNB). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

There is a positive association between cardiorespiratory fitness and cognitive health, but the interaction between cardiorespiratory fitness and aging on cerebral hemodynamics is unclear. These potential interactions are further influenced by sex differences. The purpose of this study was to determine the sex-specific relationships between cardiorespiratory fitness, age, and cerebral hemodynamics in humans. Measurements of unilateral middle cerebral artery blood velocity (MCAv) and cerebral pulsatility index obtained using transcranial Doppler ultrasound and cardiorespiratory fitness [maximal oxygen consumption (V̇o(2max))] obtained from maximal incremental exercise tests were retrieved from study records at three institutions. A total of 153 healthy participants were included in the analysis (age = 42 ± 20 yr, range = 18–83 yr). There was no association between V̇o(2max) and MCAv in all participants (P = 0.20). The association between V̇o(2max) and MCAv was positive in women, but no longer significant after age adjustment (univariate: P = 0.01; age-adjusted: P = 0.45). In addition, there was no association between V̇o(2max) and MCAv in men (univariate: P = 0.25, age-adjusted: P = 0.57). For V̇o(2max) and cerebral pulsatility index, there were significant negative associations in all participants (P < 0.001), in men (P < 0.001) and women (P < 0.001). This association remained significant when adjusting for age in women only (P = 0.03). In summary, higher cardiorespiratory fitness was associated with a lower cerebral pulsatility index in all participants, and the significance remained only in women when adjusting for age. Future studies are needed to determine the sex-specific impact of cardiorespiratory fitness improvements on cerebrovascular health. NEW & NOTEWORTHY We present data pooled from three institutions to study the impact of age, sex, and cardiorespiratory fitness on cerebral hemodynamics. Cardiorespiratory fitness was positively associated with middle cerebral artery blood velocity in women, but not in men. Furthermore, cardiorespiratory fitness was inversely associated with cerebral pulsatility index in both men and women, which remained significant in women when adjusting for age. These data suggest a sex-specific impact of cardiorespiratory fitness on resting cerebral hemodynamics.

Diminished cerebrovascular function is associated with reduced cognitive ability. Habitual exercise may maintain or improve cerebrovascular function; however, limited information exists regarding the optimal exercise prescription for cerebrovascular health. Although aerobic exercise is associated with improved systemic vascular function, the influence of resistance exercise on vascular health is unclear. Therefore, the purpose of this study was to examine the influence of habitual exercise training on cerebrovascular function in healthy young adults. We evaluated 13 untrained (age = 27 ± 5 yr; 11 men, 2 women), 13 aerobic-trained (age = 28 ± 5 yr; 10 men, 3 women), and 13 resistance-trained (age = 24 ± 4 yr; 11 men, 2 women) adults. Middle cerebral artery velocity (MCAv), mean arterial pressure (MAP), and end-tidal carbon dioxide were continuously measured at rest and in response to hypercapnia. At rest, there were no differences between groups for MCAv, however, resistance-trained adults had greater cerebrovascular conductance compared with aerobic-trained adults (0.79 ± 0.26 cm/s/mmHg vs. 0.56 ± 0.17 cm/s/mmHg; P < 0.05). In response to hypercapnia, cerebrovascular reactivity and MAP reactivity were not different between groups. There was no association between aerobic fitness or measures of exercise volume and any variable of cerebrovascular function in the combined or individual groups. Our results suggest that the mode of exercise training does not impact cerebrovascular reactivity in healthy young adults, however, it may influence resting cerebral hemodynamics. Future research could examine the influence of habitual exercise training on cerebrovascular function with aging. NEW & NOTEWORTHY Habitual exercise may influence cerebral hemodynamics, as it affects other variables of vascular health in this population. We report that habitual exercise training does not influence cerebrovascular reactivity in young adults, as there were no significant differences between aerobic-trained, resistance-trained, and untrained individuals. Despite this finding, the mode of habitual exercise training had a moderate influence on resting cerebral hemodynamics such that resistance-trained adults had greater cerebrovascular conductance compared with aerobic-trained adults.

BACKGROUND Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.

Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE ( n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women ( P < 0.05 for all). MCAv increased during IHG in both groups ( P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP −2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) three years after the cessation of the study drug [oral conjugated equine estrogen (oCEE); transdermal 17-β estradiol (tE2); or placebo (PLA)]. RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), mean arterial pressure (MAP) and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated measures modeling, there was a significant upward shift in MCAv responses (p=0.029) in the combined MHT group compared with PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured three years after cessation of hormone treatment.

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.

Reduced middle cerebral artery blood velocity (MCAv) and flow pulsatility are contributors to age-related cerebrovascular disease pathogenesis. It is unknown whether the rate of changes in MCAv and flow pulsatility support the hypothesis of sex-specific trajectories with aging. Therefore, we sought to characterize the rate of changes in MCAv and flow pulsatility across the adult lifespan in females and males as well as within specified age ranges. Participant characteristics, mean arterial pressure, end-tidal carbon dioxide, unilateral MCAv, and flow pulsatility index (PI) were determined from study records compiled from three institutional sites. A total of 524 participants [18-90 yr; females 57 (17) yr

Our purpose was to compare cerebral blood flow in the large intracranial vessels between healthy adults with (VAH+) and without (No VAH) vertebral artery hypoplasia. We also evaluated age-related differences in regional blood flow through the large cerebral arteries. Healthy young (n = 20; age = 25 ± 3 years) and older adults (n = 19; age = 61 ± 5 years) underwent 4D flow MRI scans to evaluate blood flow in the internal carotid arteries (ICA) and basilar artery (BA). VAH was determined retrospectively from 4D flow MRI using both structural (vessel diameter ≤ 2 mm) and flow criteria (flow ≤ 50 mL/min). We identified 5 young and 5 older adults with unilateral VAH (prevalence = 26%). ICA flow was lower in the VAH+ group compared with the No VAH group (367 ± 75 mL/min vs. 432 ± 92 mL/min, respectively; p

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s; P =0.047) and during hypercapnia ( P =0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg; P =0.009). Globally, the association of the 7 identified principal components with preeclampsia ( P =0.107) and with baseline middle cerebral artery velocity ( P =0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR ( P =0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes ( P =0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.

Purpose of Review Risks for developing cardiovascular disease and cognitive decline increase with age. In women, these risks may be influenced by pregnancy history. This review provides an integrated evaluation of associations of pregnancy history with hypertension, brain atrophy, and cognitive decline in postmenopausal women. Recent Findings Atrophy in the occipital lobes of the brain was evident in women who had current hypertension and a history of preeclampsia. Deficits in visual memory in women with a history of preeclampsia are consistent with these brain structural changes. The blood velocity response to chemical and sympathoexcitatory stimuli were altered in women with a history of preeclampsia linking impairments in cerebrovascular regulation to the structural and functional changes in the brain. Summary Having a history of preeclampsia should require close monitoring of blood pressure and initiation of anti-hypertensive treatment in perimenopausal women. Mechanisms by which preeclampsia affects cerebrovascular structure and function require additional study.