This research examined the impact of aerobic exercise intensity and dose on acute post-exercise cerebral shear stress and blood flow. Fourteen young adults (27 +/- 5 years of age, eight females) completed a maximal oxygen uptake (VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$) treadmill test followed by three randomized study visits: treadmill exercise at 30% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min, 70% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for 30 min and 70% of VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ for a duration that resulted in caloric expenditure equal to that in the 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ visit (EqEE). A venous blood draw and internal carotid artery (ICA) ultrasound were collected before and immediately following exercise. ICA diameter and blood velocity were determined using automated edge detection software, and blood flow was calculated. Using measures of blood viscosity, shear stress was calculated. Aerobic exercise increased ICA shear stress (time: P = 0.005, condition: P = 0.012) and the increase was greater following exercise at 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 4.1 +/- 3.5 dyn/cm2) compared with 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 1.1 +/- 1.9 dyn/cm2; P = 0.041). ICA blood flow remained elevated following exercise (time: P = 0.002, condition: P = 0.010) with greater increases after 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (Delta 268 +/- 150 mL/min) compared with 30% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ (triangle 125 +/- 149 mL/min; P = 0.041) or 70% VO2max${{\dot{V}}_{{{{\mathrm{O}}}_2}\max }}$ EqEE (triangle 127 +/- 177 mL/min; P = 0.004). Therefore, aerobic exercise resulted in both intensity- and dose-dependent effects on acute post-exercise ICA blood flow whereby vigorous intensity exercise provoked a larger increase in ICA blood flow compared to light intensity exercise when performed at a higher dose. What is the central question of this study? What are the independent and combined effects of exercise intensity and dose on post-exercise internal carotid artery (ICA) haemodynamics? What is the main finding and its importance? The combined effects of exercise intensity and dose evoked the greatest haemodynamic response whereby vigorous intensity exercise for a longer duration resulted in the greatest increase in post-exercise ICA blood flow. Therefore, exercise intensity and dose are important considerations for utilizing exercise to improve cerebrovascular function.

Cerebral blood flow at rest declines with age. However, age-related changes in functional measures of cerebrovascular health including cerebrovascular reactivity and neurovascular coupling are not well understood. Additionally, the effect of apolipoprotein E (APOE) ε4, a strong genetic risk factor for Alzheimer’s disease, on cerebral blood flow and cerebrovascular function remains unclear. APOEε4 positive (APOEε4+; n = 37, age = 63±4y) and APOEε4 negative (APOEε4-; n = 50, age = 63±4y) cognitively unimpaired adults participated in this study. Macrovascular cerebral blood flow and microvascular cerebral perfusion were measured using 4D flow MRI and pseudo-continuous arterial spin labeling MRI, respectively. Cerebrovascular reactivity and neurovascular coupling were assessed by measuring middle cerebral artery blood velocity in response to hypercapnia and the n-back test, respectively. Neurovascular coupling was lower in APOEε4+ compared with APOEε4- adults (P<0.05), despite higher cerebral blood flow and cerebrovascular reactivity to hypercapnia. Alterations in neurovascular coupling may occur early, prior to changes in cognition, in aging APOEε4 carriers.

Changes in white matter microstructure of the genu of the corpus callosum are predictive of cognitive decline in patients with mild cognitive impairment. Cardiorespiratory fitness (CRF) is positively associated with brain health; however, the relationship between cardiorespiratory fitness and white matter microstructure of the genu of the corpus callosum is unknown. Further, a novel diffusion method for assessing white matter microstructure, neurite orientation dispersion and density imaging (NODDI), can detect specific microstructural features that are not observed with conventional diffusion tensor imaging (DTI). Young (n=27, age=25±5, m=12, f=15) and older (n=23, age=64±5, m=12, f=11) adults free of underlying disease participated in this study. CRF was assessed using an incremental maximal exercise test on a cycle ergometer. On a separate visit, white matter microstructure of the genu of the corpus callosum was measured using both DTI and NODDI MRI scans. In young adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured using either DTI or NODDI (p>0.05). In older adults, there were no associations between CRF and white matter microstructure of the genu of the corpus callosum measured with DTI. However, in older adults, there was a positive association between CRF and orientation dispersion index of the genu of the corpus callosum measured with NODDI (r=0.47, p=0.02). In conclusion, using conventional DTI, no associations between CRF and white matter microstructure of the genu of the corpus callosum were observed. However, using NODDI, which can detect specific microstructural features, our results suggest that older adults with higher CRF demonstrated enhanced white matter microstructure, specifically orientation dispersion index, of the genu of the corpus callosum. Conventional DTI may underestimate the impact of CRF on age-related changes in white matter microstructure. National Institutes of Health - HL118154 (JNB), HL007936 (KBM). This is the full abstract presented at the American Physiology Summit 2024 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.

Cerebral blood flow (CBF) is known to increase in response to both dynamic and isometric exercise. However, middle cerebral artery blood velocity (MCAv) kinetics in response to small-muscle isometric exercise, and sex differences in this kinetic response, require further investigation. Previous work suggests that MCAv response times to stressors may be indicative of cerebrovascular function, so the kinetics of this response to isometric exercise would add to the understanding of cerebrovascular health. The objective of this study was to characterize MCAv kinetics in response to isometric handgrip exercise and investigate potential sex differences in the response. We expected that MCAv at baseline would be higher in females than in males. However, we hypothesized that this sex difference would disappear during isometric handgrip exercise. In addition, we hypothesized that the time constant (τ) would be shorter in females compared with males, with a higher maximum response amplitude in females compared with males. Twenty-six healthy older adults with an average age of 56.8 ± 5.0 years (11 male (M) – aged 59.4 ± 4.8 years; 15 female (F) – aged 54.6 ± 4.1 years) completed an isometric handgrip exercise protocol. The exercise protocol consisted of the following: 1) performing a maximum voluntary contraction (MVC) with a handgrip device in the participants’ left hand (on a separate visit); 2) performing a sustained contraction until failure at 40% of the participant’s MVC. MCAv was continuously measured at rest and during handgrip exercise. The time constant was calculated as 63% of the time until steady-state MCAv during handgrip exercise. There was a trend for higher MCAv at baseline (57.8 ± 11.0 cm/s) in females (61.5 ± 11.2 cm/s) compared with males (53.6 ± 9.6 cm/s) that did not reach significance (p=0.08). There were no significant differences between the sexes for max amplitude of MCAv response to isometric handgrip exercise (M: 20.7 ± 11.1 cm/s; F: 15.4 ± 10.0 cm/s; p = 0.24) or time constant (M: 20.5 ± 9.8 sec; F: 18.6 ± 11.3 sec; p = 0.65). These results suggest no significant differences in MCAv between males and females at baseline. There also appear to be no significant sex differences in the kinetic response of MCAv to handgrip exercise. Future work could model MCAv kinetics in response to isometric handgrip exercise. The relationship between age and MCAv kinetics could also be investigated, along with the effect of menopause on MCAv kinetics in females. American Heart Association (19IPLOI34680015; JNB); American Heart Association COVID Supplement (19IPLOI34680015; JNB). This is the full abstract presented at the American Physiology Summit 2024 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.

Cerebrovascular dysregulation with age contributes to cognitive decline. Age-related changes in intracranial blood flow and cerebral pulsatility are linked with adverse structural changes including white matter hyperintensities. The hippocampus represents a key area for cognition and demonstrates rapid deterioration in the early stages of Alzheimer’s disease. Yet the impact of intracranial blood flow and cerebral pulsatility on hippocampal deterioration in cognitively unimpaired adults remains unclear. Importantly, age-related changes in intracranial blood flow and cerebral pulsatility differ by sex. Therefore, this study tested the hypothesis that intracranial blood flow is positively associated with hippocampal volume, while cerebral pulsatility is negatively associated with hippocampal volume and that the associations would differ by sex. Cognitively unimpaired adults (388 total, 263 females, 64 ± 8 years of age) completed 3T magnetic resonance imaging (MRI). Hippocampal volume (mm3) was normalized to intracranial volume and evaluated from T1-weighted images. Intracranial blood flow (mL/min) and cerebral pulsatility (maximum flow − minimum flow/mean flow; a.u.) were evaluated in the internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery from 4D flow MRI. All data are reported for the left side of the brain. Age was negatively associated with hippocampal volume and similar relationships were observed in males (β = -16 ± 3, P < 0.01) and females (β = -17 ± 2, P < 0.01). As such, age was included as a covariate in all models. Blood flow in the ICA, MCA, and basilar artery was not associated with hippocampal volume (all P > 0.37) and there were no flow-by-sex interactions (all P > 0.19). In contrast, cerebral pulsatility was negatively associated with hippocampal volume in a sex and vessel specific manner. ICA pulsatility was associated with hippocampal volume (P = 0.03, β = -183 ± 83) and the relationship did not differ by sex (pulsatility-by-sex interaction: P = 0.19). Basilar artery pulsatility was associated with hippocampal volume in a sex-specific manner (pulsatility-by-sex interaction: P < 0.01) such that there was an association in females (β = -346 ± 63, P < 0.01) but not males (β = 60 ± 92, P = 0.51). A sex-specific relationship (pulsatility-by-sex interaction: P < 0.01) was also observed between MCA pulsatility and hippocampal volume (females: β = -180 ± 54, P < 0.01; males: β = 1 ± 136, P = 0.99). Therefore, elevated cerebral pulsatility is linked with hippocampal deterioration in a sex and vessel specific manner. These findings may provide insights into sex differences in cognitive decline with age and the development of Alzheimer’s disease. This research was funded by NIH grants (R03 AG070469-01 and R03 AG070469-S1; JNB), a Virginia Horne Henry Research Grant (JNB), and a Wisconsin Alzheimer's Disease Research Center Grant (P30-AG062715). This is the full abstract presented at the American Physiology Summit 2024 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.

Abstract Platelet activation may contribute to age‐related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. This study evaluated the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular reactivity (CVR) in healthy young (n = 35; 25 ± 4 years; 17 women, 18 men) and older (n = 12; 62 ± 2 years; 8 women, 4 men) adults, who were not daily aspirin users, before and after cyclooxygenase inhibition. Prostacyclin was determined by levels of 6‐keto‐prostaglandin F1α (6‐keto PGF1α) in the blood. CVR was assessed by measuring the middle cerebral artery blood velocity response to hypercapnia using transcranial Doppler ultrasound before (CON) and 90 min after cyclooxygenase inhibition with indomethacin (INDO). In young adults, there were no associations between prostacyclin and middle cerebral artery CVR during CON (r = −0.14, P = 0.415) or INDO (r = 0.27, P = 0.118). In older adults, associations between prostacyclin and middle cerebral artery CVR during CON (r = 0.53, P = 0.075) or INDO (r = –0.45, P = 0.136) did not reach the threshold for significance. We also evaluated the relationship between prostacyclin and the change in CVR between conditions (ΔCVR). We found no association between ΔCVR and prostacyclin in young adults (r = 0.27, P = 0.110); however, in older adults, those with higher baseline prostacyclin levels demonstrated significantly greater ΔCVR (r = –0.74, P = 0.005). In conclusion, older adults with higher serum prostacyclin, a platelet inhibitor, may rely more on cyclooxygenase products for cerebrovascular reactivity to hypercapnia.

Age-related changes in cerebral hemodynamics are controversial and discrepancies may be due to experimental techniques. As such, the purpose of this study was to compare cerebral hemodynamics measurements of the middle cerebral artery (MCA) between transcranial Doppler ultrasound (TCD) and four-dimensional flow MRI (4D flow MRI). Twenty young (25 ± 3 years) and 19 older (62 ± 6 years) participants underwent two randomized study visits to evaluate hemodynamics at baseline (normocapnia) and in response to stepped hypercapnia (4% CO 2 , and 6% CO 2 ) using TCD and 4D flow MRI. Cerebral hemodynamics measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity. Cerebrovascular reactivity was calculated as the linear relationship between cerebrovascular conductance (CVC using 4D flow MRI) or cerebrovascular conductance index (CVCi using TCD) and changes in ETCO 2 at rest and during hypercapnia. MCA velocity between the methods was positively correlated across the conditions (r=0.262; p=0.004). Additionally, cerebral PI of the MCA was significantly correlated between TCD and 4D flow MRI across the conditions (r=0.236; p=0.010). However, there was no association between MCA velocity using TCD and MCA flow using 4D flow MRI across the conditions (r=0.079; p=0.397). When age-associated differences in cerebrovascular reactivity were compared using both methodologies, cerebrovascular reactivity was greater in young adults compared to older adults when using 4D flow MRI (2.11±1.68 ml/min/mmHg/mmHg vs. 0.78±1.68 ml/min/mmHg/mmHg; p=0.019), but not with TCD (0.88±1.01 cm/s/mmHg 2 vs. 0.68±0.94 cm/s/mmHg 2 ; p=0.513). In conclusion, our results demonstrated good agreement between the methods measuring MCA velocity at normocapnia and in response to hypercapnia, but MCA velocity with TCD and MCA flow with MRI were not related. In addition, measurements using 4D flow MRI revealed additional effects of aging on cerebral hemodynamics that were not apparent using TCD. This study was funded by the NIH grants (HL118154, NS117746), the NIH, Ruth L. Kirschstein National Research Service Award T32's from the National Institute on Aging to the University of Wisconsin-Madison Biology of Aging & Age-Related Diseases (AG000213) and the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center (HL007936) as well as the Wisconsin Alumni Research Foundation. This study was also supported by Alzheimer's Association Research Fellowship (AARF-22-924325). 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.

BACKGROUND: Greater cerebral blood flow pulsatility, measured as pulsatility index (PI), has recently been under investigation as a risk factor for cognitive impairment and neurodegenerative diseases. Furthermore, physical activity (PA), which has been associated with improved cognitive function and holds therapeutic effects for cardiovascular function, may be linked with lower cerebral pulsatility, especially in postmenopausal women (PMW). PURPOSE: To investigate the relationship between PA and PI in PMW and determine if these relationships are maintained in age-matched men. We hypothesized that there would be an inverse relationship between PA and PI in PMW, and that this relationship would diminish in age-matched men. METHODS: Fifty-two healthy PMW (age 63 ± 4 years) and 25 age-matched men (63 ± 4 years) were recruited for this study. PA was self-reported via the Godin Questionnaire (Godin Score) and using the metabolic equivalent to exercise in minutes per week (MET-Min). Cerebral blood flow was measured through the internal carotid arteries (ICAs), middle cerebral arteries (MCAs), and the basilar artery using 4D Flow MRI. PI was calculated as (maximum flow – minimum flow)/mean flow. RESULTS: There were no significant differences in PA between groups via Godin Score (PMW: 37 ± 21 vs. Men 37 ± 13, p = 1.00) or MET-Min (PMW: 1586 ± 901 vs. Men: 1831 ± 901, p = 0.28). When combined, there was a significant inverse association between MET-Min and basilar PI (r = -0.24, p = 0.04). In PMW, there was a trend for greater MET-Min to be associated with lower basilar PI (r = -0.24, p = 0.08), however this trend was not observed in men (r = -0.25, p = 0.25). Interestingly, in men, there was a significant positive association between MET-Min and MCA PI (r = 0.46, p = 0.03). There were no significant associations observed between PA and ICA PI. CONCLUSION: Greater PA may be linked to lower PI in PMW, but not in in age-matched men. The influence of regular physical activity on cerebral PI may be specific to certain cerebral vessels. This study was funded by the Virginia Horn Henry Research Grant, NIH grant (AG070469-01), and the Wisconsin Alzheimer's Disease Research Center (P30-AG062715). 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.

Brain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex-specific. 407 cognitively healthy middle-aged and older adults (45-87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid-attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume. PI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P = 0.01, all male P = 0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P = 0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P = 0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (ß = 0.39±0.09 a.u., R2 = 0.13) compared with females (ß = 0.18±0.05 a.u., R2 = 0.05). These data suggest that, among cognitively healthy middle-aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex- and vessel-specific which may contribute to sex-specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

Vertebral artery hypoplasia (VAH) is an anatomical variation that may be associated with lower cerebral blood flow. We demonstrated the prevalence of VAH to be approximately 26% in a pilot study of healthy adults (n = 39). The purpose of this study was to expand on these findings by determining the prevalence of VAH and its impact on cerebral hemodynamics in a larger sample size of middle-aged and older adults. A total of 550 participants (66 ± 9 years; 346 females) underwent 4D flow MRI scans to evaluate the internal carotid arteries (ICA), vertebral arteries, and basilar artery. VAH+ (positive for VAH) was determined from the 4D flow MRI scans using both diameter (<2.5 mm) and flow (<47 mL/min). We identified 152 participants as VAH+ (prevalence of 28%). The prevalence of VAH+ was similar between females (n = 95; 27%) and males (n = 57; 28%). VAH predominantly occurred in the right vertebral artery (n = 102; 67%). As expected within VAH+ participants, the hypoplastic vertebral artery diameter was smaller (2.0±0.2 mm vs. 2.8±0.5 mm; p<0.001), blood flow was lower (29±10 ml/min vs. 100±44 ml/min; p<0.001), and pulsatility index was higher (1.8±0.6 a.u. vs. 1.3±0.3 a.u.; p<0.001) compared to the contralateral artery. There were no differences in ICA diameter (p = 0.875), blood flow (p = 0.553) or pulsatility index (p = 0.984) between VAH+ and no VAH. When evaluating the basilar artery, the diameter was smaller (2.7±0.4 mm vs. 2.8±0.4 mm; p = 0.037) with lower blood flow (105±35 ml/min vs. 116±37 ml/min; p<0.001) in VAH+ compared with no VAH. Males with VAH+ had higher basilar artery pulsatility index compared with males with no VAH (1.4±0.4 a.u. vs. 1.2±0.3 a.u.; p = 0.004), but this was not apparent in females (p = 0.544). When comparing global cerebral blood flow, there was a trend for lower flow in VAH+ compared with no VAH (p = 0.096). We demonstrated VAH prevalence to be around 28%, with similar prevalence in both males and females. VAH was associated with impaired regional flow and with elevated basilar artery cerebral pulsatility in males.

BACKGROUND: Muscle sympathetic nerve activity (MSNA) has been shown to be a predictor of cardiovascular diseases. There are currently disputed findings regarding the effects of exercise training on MSNA at rest. Therefore, this study sought to compare MSNA in young exercise trained and sedentary adults. The purpose of this analysis was to examine associations between MSNA at baseline with VO2max in order to determine if VO2max can be a predictor of MSNA. METHODS: Forty-two young adults were evaluated including 11 resistance trained (RE: age = 24 ± 4 years; BMI = 24 ± 2 kg/m2), 18 aerobically trained (AE: age = 27 ± 5 years; BMI = 24 ± 2 kg/m2), and 13 sedentary controls (CON: age = 28 ± 5 years; BMI = 25 ± 2 kg/m2). Participants underwent a maximal exercise test to exhaustion on a cycle ergometer to measure VO2max. During a separate visit, mean arterial pressure (MAP), heart rate (HR) and MSNA were measured at rest for five minutes. MSNA was assessed using burst frequency, burst incidence, and total activity. One-way ANOVA was performed in order to assess between-group differences in MSNA. Simple linear regression was performed in order to determine the impact of VO2max on MSNA and the relationship between MAP and VO2max. RESULTS: There were significant differences in VO2max across all three groups (RE: 41.4 ± 4.6 ml/kg/min; AE: 46.2 ± 4 ml/kg/min; CON: 35.3 ± 6.7 ml/kg/min; p < 0.01) and between groups (RE vs. AE p < 0.01; RE vs. CON p < 0.02; AE vs. CON p < 0.01). There were no differences in MSNA burst frequency (RE: 15 ± 8 bursts/min; AE: 17 ± 7 bursts/min; CON: 18 ± 5 bursts/min; p = 0.57), MSNA burst incidence (RE: 36 ± 13 bursts/100 cardiac cycles; AE: 34 ± 15 bursts/cardiac cycles; CON: 30 ± 7 bursts/100 cardiac cycles; p = 0.27), and total MSNA (RE: 881 ± 684 B/min; AE: 1361 ± 1092 B/min; CON: 1031 ± 379 B/min; p = 0.29) across the three groups. There were no relationships found between VO2max and MSNA burst frequency (r = 0.23; p = 0.15), VO2max and MSNA incidence (r = 0.06; p = 0.71), or VO2max and total MSNA (r = 0.03; p = 0.89). CONCLUSION: In conclusion, these results demonstrate a disassociation between MSNA and VO2max at rest in young adults. Since this analysis was limited to resting values, future studies could examine the relationship between VO2max and MSNA as a result of an exercise training intervention. Funding: NIH HL118154, Virginia Horne Henry 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.

Increased central arterial stiffness is associated with downstream vascular dysfunction. Despite this relationship, our lab has previously demonstrated no association between central arterial stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), and cerebrovascular or mean arterial pressure (MAP) reactivity in habitually active adults. Physical activity level may affect the relationship between cfPWV and cerebrovascular or MAP reactivity, yet these associations have not been evaluated in aerobically trained young adults. Further, the relationship between baseline cfPWV and post-exercise cerebrovascular and MAP reactivity is unknown. PURPOSE: To examine the relationship between baseline cfPWV and pre- and post-exercise cerebrovascular reactivity and MAP reactivity in aerobically trained young adults. METHODS: Thirteen trained runners (age: 27 ± 5 y; VO2max = 54 ± 10 mL/kg/min; men = 6, women = 7) completed a study visit in which they walked for 30 min at 30% VO2max. cfPWV was measured prior to exercise. Cerebrovascular and MAP reactivity to hypercapnia were measured pre- and 30 min post-exercise. Middle cerebral artery velocity (MCAv), MAP, and end-tidal CO2 (ETCO2) were continuously monitored during hypercapnia. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the slope between MCAv, CVCi, or MAP and ETCO2. RESULTS: While cfPWV was not associated with pre-exercise MCAv and CVCi reactivity (p ≥ 0.05 for both), it was associated with MAP reactivity (r = 0.65, p = 0.02). There was no association between cfPWV and post-exercise MCAv, CVCi, or MAP reactivity (p ≥ 0.05 for all). Finally, there was no association between cfPWV and the pre-to-post exercise change in MCAv and CVCi reactivity (p ≥ 0.05 for both), but there was an association between cfPWV and the pre-to-post exercise change in MAP reactivity (r = -0.78, p < 0.01). CONCLUSION: While cfPWV was not associated with pre- or post-exercise cerebrovascular reactivity, it was associated with pre-exercise MAP reactivity and the change from pre-to-post exercise MAP reactivity. These results suggest that in aerobically trained individuals, central arterial stiffness may influence blood pressure reactivity to a vasoactive stimulus. Supported by the Wisconsin Alumni Research Foundation.

Apolipoprotein (APOE) is the strongest genetic risk factor for Alzheimer’s disease (AD). Individuals with at least one copy of the APOE ε4 allele are at increased risk of age-related diseases such as AD. Cerebrovascular reactivity (CVR) to hypercapnia is a commonly used measure of brain health and we have previously shown age-related reductions in CVR. However, the influence of APOE ε4 on CVR in middle-aged adults is unclear. PURPOSE: The purpose of this study was to evaluate the influence of APOE ε4 on CVR to hypercapnia in middle-aged adults. We hypothesized that APOE ε4 positive adults would demonstrate reduced CVR to hypercapnia. METHODS: 87 cognitively unimpaired adults participated in this study and were separated into groups based on APOE ε4 status. Participants with at least one copy of the APOE ε4 allele were considered APOE ε4 positive (APOE ε4+, age = 63 ± 4 y, males = 13, females = 25). Participants without a copy of the APOE ε4 allele were considered APOE ε4 negative (APOE ε4-, age = 63 ± 4 y, males = 14, females = 35). CVR to hypercapnia was measured by recording middle cerebral artery blood velocity (MCAv) using transcranial Doppler ultrasound, end-tidal CO2 (ETCO2), and mean arterial blood pressure (MAP). Participants breathed normocapnic room air for 5 min followed by stepwise elevations in inspired CO2 at 2%, 4%, and 6% for 5 min each. Cerebrovascular conductance index (CVCi) was calculated as (MCAv/MAP)*100. CVR was calculated as the linear relationship between the change in ETCO2 and the change in MCAv or CVCi. CVR to hypercapnia was compared between groups using Student’s t-tests. RESULTS: There were no differences in MCAv, CVCi, MAP, or ETCO2 at rest or during 6% CO2 between groups. MCAv reactivity was greater in APOE ε4+ compared with APOE ε4- adults (APOE ε4+: 2.4 ± 0.8 cm/s/mmHg vs. APOE ε4-: 1.9 ± 0.8 cm/s/mmHg; p = 0.007). There were no differences in CVCi reactivity between groups (APOE ε4+: 1.5 ± 0.7 cm/s/mmHg vs. APOE ε4-: 1.3 ± 0.8 cm/s/mmHg; p = 0.264). CONCLUSION: In contrast to our hypothesis, these findings suggest that cognitively unimpaired middle-aged adults at greater genetic predisposition to develop cognitive decline and AD have greater MCAv CVR to hypercapnia. Supported by Alzheimer’s Association Research Grant #17-499398 and Wisconsin Alzheimer’s Disease Research Center Grant: P30-AG062715.

The sympathetic nervous system is an important regulator of blood pressure and blood flow. There is conflicting evidence on the effects of exercise training on muscle sympathetic nerve activity (MSNA). Furthermore, the effects of exercise modality on the sympathoexcitatory response to chemical stimuli, such as hypercapnia, have not been studied. PURPOSE: The purpose of this study was to evaluate the MSNA response to hypercapnia in resistance trained (RT), aerobic trained (AT) and untrained (UT) adults. METHODS: Forty-one young healthy adults were evaluated including 11 RT (M/F = 9/2; age = 24 ± 4 years; BMI = 24 ± 2 kg/m2), 17 AT (M/F = 9/8; age = 27 ± 5 years; BMI = 24 ± 2 kg/m2) and 13 UT (M/F = 7/6; age = 28 ± 5 years; BMI = 25 ± 2 kg/m2). 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% CO2. A one-way ANCOVA with age as a covariate was used to determine statistical differences between groups. RESULTS: MAP at baseline (RT: 91 ± 11 mmHg; AT: 92 ± 10 mmHg ;UT: 90 ± 17 mmHg; p > 0.05) and the change in MAP in response to 6% CO2 (RT: 6 ± 15 mmHg; AT: 4 ± 7 mmHg ;UT: 8 ± 7 mmHg; p > 0.05) were not different between groups. HR was lower at baseline in AT compared with UT only (RT: 55 ± 9 bpm; AT: 50 ± 6 bpm; UT: 59 ± 9 bpm; p < 0.05 AT vs UT). The change in HR in response to 6% CO2 was not different between groups (RT: 6 ± 8 bpm; AT: 8 ± 5 bpm; UT: 9 ± 7 bpm; p > 0.05). MSNA burst frequency (RT: 12 ± 4 bursts/min; AT: 17 ± 7 bursts/min; UT: 18 ± 5 bursts/min; p > 0.05) and burst incidence (RT: 23 ± 8 bursts/100hb; AT: 35 ± 15 bursts/100hb; UT: 30 ± 7 bursts/100hb; p > 0.05) were not different between groups at baseline. In response to 6% CO2 the change in MSNA burst frequency was greater in RT compared with AT (RT: 5 ± 7 bursts/min; AT: 1 ± 3 bursts/min; UT: 2 ± 3 bursts/min; p < 0.05 RT vs AT); however, there were no differences in the change in MSNA burst incidence between groups (RT: 6 ± 10 bursts/100hb; AT: -3 ± 4 bursts/100hb; UT: 0 ± 7 bursts/100hb; p > 0.05). CONCLUSIONS: While exercise modality did not influence baseline MSNA, exercise modality did influence the response to hypercapnia, such that RT individuals had a greater MSNA burst frequency response to 6% CO2 compared with AT individuals. Supported by NIH HL118154, Virginia Horne Henry Fund

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 (VO 2max ) treadmill test followed by two randomized study visits that involved 30 minutes of treadmill exercise at 30% of VO 2max or 70% of VO 2max . 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% VO 2max (Δ0.01 ± 0.03 cm 2 ) and 70% VO 2max (Δ0.02 ± 0.04 cm 2 ; 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% VO 2max (Pre: 10 ± 2 dynes/cm 2 vs. Post: 11 ± 3 dynes/cm 2 ; P post-hoc = 0.13) but increased following exercise at 70% VO 2max (Pre: 12 ± 4 dynes/cm 2 vs. Post: 16 ± 4 dynes/cm 2 ; P post-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% VO 2max (Δ257 ± 151 mL/min) compared with 30% VO 2max (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.