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Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55-80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hypogonadism is a risk factor for cardiovascular disease (CVD) in men related, in part, to increased oxidative stress. Elevated large artery stiffness and central pulsatile hemodynamics (e.g., pulse pressure and wave reflection magnitude) are independent risk factors for CVD. However, whether large artery stiffness and central pulsatile hemodynamics are (1) elevated in hypogonadal men independent of traditional CVD risk factors and (2) related to increased oxidative stress is unknown. Young men (N = 23; 30 ± 4 years) and middle-aged/older (MA/O) men with normal (> 400-1000 ng/dL; n = 57; 59 ± 7 years) or low testosterone (< 300 ng/dL; n = 21; 59 ± 7 years) underwent assessments of large artery stiffness (carotid ß-stiffness via ultrasonography) and central pulsatile hemodynamics (pulse wave analysis; SphygmoCor XCEL) following an infusion of saline or vitamin C to test the tonic suppression of vascular function by oxidative stress. Carotid stiffness differed by age (p < 0.001) and gonadal status within MA/O men (low testosterone vs. normal testosterone: 9.3 ± 0.7 vs. 8.0 ± 0.3U, p = 0.036). Central pulsatile hemodynamics did not differ by age or gonadal status (p > 0.119). Vitamin C did not alter carotid stiffness in any group (p > 0.171). There was a significant group × infusion interaction on aortic reflection magnitude (p = 0.015). Vitamin C treatment reduced aortic reflection magnitude in young and MA/O men with normal testosterone (both p < 0.001) but not MA/O men with low testosterone (p = 0.891). Collectively, hypogonadism may accelerate age-related large artery stiffening in MA/O men with low testosterone, independent of CVD risk factors; however, this is not related to increased reactive oxygen species sensitive to an acute vitamin C infusion., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed "hallmarks" or "pillars" of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex.

Central pulse pressure (PP) is the sum of forward and backward traveling pressure waves that have been associated with cardiovascular disease (CVD) risk. However, previous studies have reported differential findings regarding the importance of the forward versus the backward wave for CVD risk. Therefore, we sought to determine the degree to which the forward and backward pressure waves are associated with subclinical carotid artery wall remodeling and central PP in healthy adults. Using applanation tonometry, carotid pressure waveforms were acquired in 308 healthy individuals (aged 45 ± 17 years, range 19-80 years, 61% women), from which the time integral of the forward (Pf TI ) and backward (Pb TI ) pressure waves were derived via pressure-only wave separation analysis. Common carotid artery intima-media thickness (cIMT), a biomarker of subclinical CVD risk, was derived via B-mode ultrasonography measured ∼2 cm from the carotid bulb. Both Pf TI ( r = 0.31, P < 0.001) and Pb TI ( r = 0.40, P < 0.001) were correlated with cIMT. However, further analysis revealed that Pb TI mediated the relation between Pf TI and cIMT (proportion mediated = 156%, P < 0.001). The association between Pb TI and cIMT remained after adjusting for age, sex, body mass index, blood glucose, low-density lipoprotein cholesterol, heart rate, brachial systolic pressure, and aortic stiffness ( B = 0.02, 95% confidence interval = 0.01, 2.77, P < 0.001). Both Pf TI ( r = -0.58, P < 0.001) and Pb TI ( r = -0.50, P < 0.001) were correlated with central PP, however, Pf TI fully mediated the association between Pb TI and central PP (proportion mediated = 124%, P < 0.001). Although Pf TI is correlated with higher central PP, it is Pb TI that is directly associated with carotid artery wall remodeling. NEW & NOTEWORTHY The present study contributes to the growing body of evidence highlighting the physiological and clinical insight provided by the pulsatile hemodynamic components of central artery pulse pressure. The notable findings of this study are: 1 ) The reflected (backward) pressure wave is associated with carotid intima-media thickness independent of traditional cardiovascular risk factors, including systolic blood pressure and aortic stiffness. 2 ) The incident (forward) pressure wave, and not the reflected pressure wave, is associated with greater central pulse pressure.

Objective: Central artery reservoir pressure and excess pressure (XSP) are associated with cardiovascular disease (CVD) events and mortality. However, sex differences in the trajectory of central reservoir pressure and XSP with advancing age and their relations with vascular markers of subclinical CVD risk are incompletely understood. Therefore, we tested the hypothesis that central reservoir pressure and XSP would be positively associated with advancing age and vascular markers of subclinical CVD risk in men and women., Method: Healthy adults ( n  = 398; aged 18-80 years, 60% female individuals) had central (carotid) artery pressure waveforms acquired by applanation tonometry. Reservoir pressure and XSP peaks and integrals were derived retrospectively from carotid pressure waveforms using custom written software. Carotid artery intimal-medial thickness (IMT) was measured by ultrasonography, and aortic stiffness was determined from carotid-femoral pulse wave velocity (cfPWV)., Results: Reservoir pressure peak, reservoir pressure integral and XSP integral were higher with age in both men and women ( P  < 0.05), whereas XSP peak was lower with age in men ( P  < 0.05). In women, both reservoir pressure peak ( β  = 0.231, P  < 0.01) and reservoir pressure integral ( β  = 0.254, P  < 0.01) were associated with carotid artery IMT, and reservoir pressure peak was associated with cfPWV ( β  = 0.120, P  = 0.02) after adjusting for CVD risk factors., Conclusion: Central artery reservoir pressure and XSP were higher with advancing age in men and women, and reservoir pressure peak was associated with both carotid artery wall thickness and aortic stiffness in women but not men. Central reservoir pressure peak may provide some insight into sex differences in vascular remodeling and subclinical CVD risk with advancing age in healthy adults., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Endothelial function (brachial artery flow-mediated dilation [FMD]) is reduced in estrogen-deficient postmenopausal women, mediated, in part, by reduced nitric oxide (NO) bioavailability, secondary to tetrahydrobiopterin (BH 4 ) deficiency and oxidative stress. FMD is increased, but not fully restored, in postmenopausal women after acute intravenous vitamin C (VITC; superoxide scavenger) or oral BH 4 supplementation. In vitro studies demonstrate that coadministration of VITC with BH 4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite. To investigate mechanisms of endothelial dysfunction in women, we assessed the separate and combined effects of VITC and BH 4 to determine whether coadministration of VITC + BH 4 improves FMD in healthy postmenopausal women ( n = 19, 58 ± 5 yr) to premenopausal ( n = 14, 36 ± 9 yr) levels, with exploratory testing in perimenopausal women ( n = 8, 51 ± 3 yr). FMD was measured during acute intravenous infusions of saline (control) and VITC (∼2-3 g) ∼3 h after a single dose of oral BH 4 (KUVAN, 10 mg/kg body wt) or placebo (randomized crossover, separated by ∼1 mo). Under the placebo condition, FMD was reduced in postmenopausal compared with premenopausal women during the saline infusion (5.6 ± 0.7 vs. 11.6 ± 0.9%, P < 0.001) and increased in postmenopausal women during VITC (+3.5 [1.4, 5.6]%, P = 0.001) and acute BH 4 (+1.8 [0.37, 3.2]%, P = 0.01) alone. Coadministration of VITC + BH 4 increased FMD in postmenopausal women (+3.0 [1.7, 4.3]%, P < 0.001), but FMD remained reduced compared with premenopausal women ( P = 0.02). Exploratory analyses revealed that VITC + BH 4 did not restore FMD in perimenopausal women to premenopausal levels ( P = 0.045). Coadministration of VITC + BH 4 does not restore FMD in menopausal women, suggesting that additional mechanisms may be involved. NEW & NOTEWORTHY Endothelial function is reduced across the menopausal stages related to increased oxidative stress associated with estrogen deficiency. In vitro studies demonstrate that coadministration of VITC with BH 4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite; however, this remains untested in humans. We demonstrate that the coadministration of BH 4 + VITC does not restore endothelial function in perimenopausal and postmenopausal women to the level of premenopausal women, suggesting that other mechanisms contribute.

Aging is associated with reductions in cardiovagal baroreflex sensitivity (cBRS), which increases cardiovascular disease risk. Preclinical data indicate that low testosterone reduces cBRS. We determined whether low testosterone is associated with greater age-associated reductions in cBRS in healthy men. Twenty-six men categorized as young ( N = 6; age = 31 ± 4 yr; testosterone = 535 ± 60 ng/dL), middle-aged/older with normal ( N = 10; aged 56 ± 3 yr; testosterone = 493 ± 85 ng/dL) or low ( N = 10; age = 57 ± 6 yr; testosterone = 262 ± 31 ng/dL) testosterone underwent recordings of beat-by-beat blood pressure and R-R interval during rest and two Valsalva maneuvers, and measures of carotid artery compliance. IL-6, C-reactive protein (CRP), oxidized LDL cholesterol, and total antioxidant status (TAS) were also measured in blood. Middle-aged/older men had lower cBRS compared with young men (17.0 ± 6.5 ms/mmHg; P = 0.028); middle-age/older men with low testosterone had lower cBRS (5.5 ± 3.2 ms/mmHg; P = 0.039) compared with age-matched men with normal testosterone (10.7 ± 4.0 ms/mmHg). No differences existed between groups during Phase II of the Valsalva maneuver; middle-aged/older men with low testosterone had reduced cBRS (4.7 ± 2.6 ms/mmHg) compared with both young (12.8 ± 2.8 ms/mmHg; P < 0.001) and middle-aged/older men with normal testosterone (8.6 ± 4.4 ms/mmHg; P = 0.046). There were no differences in oxidized LDL ( P = 0.882) or TAS across groups ( P = 0.633). IL-6 was significantly higher in middle-aged/older men with low testosterone compared with the other groups ( P < 0.05 for all) and inversely correlated with cBRS ( r = -0.594, P = 0.007). Middle-aged/older men had reduced carotid artery compliance compared with young, regardless of testosterone status ( P < 0.001). These observations indicate that low testosterone in middle-aged/older men may contribute to reductions in cBRS. These data suggest that increased inflammation may contribute to reductions in cBRS. NEW & NOTEWORTHY Middle-aged/older men with low testosterone have accelerated reductions in cardiovagal BRS compared with middle-aged/older men with normal testosterone. Increased concentrations of the proinflammatory cytokine IL-6 appear to contribute to the reductions in cardiovagal BRS in men with low testosterone.

Cerebrovascular reactivity (CVR) to a physiological stimulus is a commonly used surrogate of cerebrovascular health. Cross-sectional studies using blood oxygen level dependent (BOLD) neuroimaging demonstrated lower BOLD-CVR to hypercapnia among adults with high compared with lower cardiorespiratory fitness (CRF) in contrast to transcranial Doppler studies. However, whether BOLD-CVR changes following chronic aerobic exercise in older, cognitively intact adults is unclear. This study evaluated relations between BOLD-CVR with CRF (V̇o 2peak ) using a cross-sectional and interventional study design. We hypothesized that 1 ) greater CRF would be associated with lower BOLD-CVR in older adults ( n = 114; 65 ± 6.5 yr) with a wide range of CRF and 2 ) BOLD-CVR would be attenuated after exercise training in a subset ( n = 33) randomized to 3-mo of moderate- or light-intensity cycling. CVR was quantified as the change in the BOLD signal in response to acute hypercapnia using a blocked breath-hold design from a region-of-interest analysis for cortical networks. In the cross-sectional analysis, there was a quadratic relation between V̇o 2peak ( P = 0.03), but not linear ( P = 0.87) and cortical BOLD-CVR. BOLD-CVR increased until a V̇o 2peak ∼28 mL/kg/min after which BOLD-CVR declined. The nonlinear trend was consistent across all networks ( P = 0.04-0.07). In the intervention, both the active and light-intensity exercise groups improved CRF similarly (6% vs. 10.8%, P = 0.28). The percent change in CRF was positively associated with change in BOLD-CVR in the default mode network only. These data suggest that BOLD-CVR is nonlinearly associated with CRF and that in lower-fit adults default mode network may be most sensitive to CRF-related increases in BOLD-CVR. NEW & NOTEWORTHY Earlier studies evaluating associations between cardiorespiratory fitness (CRF) and cerebrovascular reactivity (CVR) have demonstrated conflicting findings dependent on imaging modality or subject characteristics in individuals across a narrow range of CRF. This study demonstrates that CRF is nonlinearly associated with CVR measured by blood oxygen level dependent (BOLD) fMRI in a large sample of middle-aged and older adults across a wide range of CRF, suggesting that conflicting prior findings are related to the range of CRFs studied.

Aortic stiffness increases with advancing age, more than doubling during the human life span, and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle and older age the aorta continues to remodel to a larger diameter, thinning the pool of permanent elastin fibers, increasing intramural wall stress and resulting in the transfer of load bearing onto stiffer collagen fibers. Whereas aortic stiffening in early middle age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically "good" early in the life span, the negative clinical consequences of accelerated aortic stiffening beyond middle age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the "windkessel effect" with advancing age result in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high-flow, low-resistance organs such as brain, kidney, retina, and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased arterial tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness, and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the United States, aortic stiffening will likely contribute to substantial CVD burden over the next 2-3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.

Context: Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk., Objective: We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation., Methods: This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined., Results: During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041)., Conclusion: Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Women with a history of preeclampsia (hxPE) exhibit sustained arterial stiffness and elevated blood pressure postpartum. Aortic stiffness and 24-hour blood pressure variability (BPV) are associated with age-related cognitive decline. Although hxPE is related to altered cognitive function, the association between aortic stiffness and BPV with cognitive performance in young women with hxPE has not been investigated. The objectives of this study were to (i) test whether cognitive performance is lower in young women with hxPE and (ii) determine whether aortic stiffness and BPV are associated with cognitive performance independent of 24-hour average blood pressure., Methods: Women with hxPE (N = 23) and healthy pregnancy controls (N = 38) were enrolled 1-3 years postpartum. Cognitive performance was assessed in domains of memory, processing speed, and executive function. Twenty-four-hour ambulatory blood pressure monitoring and carotid-femoral pulse wave velocity (cfPWV) were used to measure BPV and aortic stiffness, respectively., Results: Women with hxPE had slower processing speed (-0.56 ± 0.17 vs. 0.34 ± 0.11 Z-score, P < 0.001) and lower executive function (-0.43 ± 0.14 vs. 0.31 ± 0.10 Z-score, P = 0.004) compared with controls independent of education, whereas memory did not differ. BPV and cfPWV (adjusted for blood pressure) did not differ between women with hxPE and controls. Greater diastolic BPV was associated with lower executive function independent of 24-hour average blood pressure and education in women with hxPE (r = -0.48, P = 0.03) but not controls (r = 0.15, P = 0.38)., Conclusions: Select cognitive functions are reduced postpartum in young women with a recent hxPE and linked with elevated 24-hour diastolic BPV., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Acceptance and Commitment Therapy (ACT) is a behavioral intervention demonstrating sustained improvements in anxiety in individuals with chronic anxiety and psychological distress. Because anxiety disorders are associated with the development of cardiovascular disease (CVD), we hypothesized that a novel 1-day ACT workshop would both lower anxiety and improve vascular function in persons with moderate/high anxiety., Methods: In a randomized controlled study, 72 adults (age 33.9 ± 8.6 (SD) years) with baseline moderate/high anxiety completed a one-day ACT intervention (n = 44, age 33.9 ± 8.7 years) or control (n = 28, age 37.1 ± 10.1 years). Pre-specified secondary outcomes were measured over 12 weeks: aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]), forearm vascular endothelial function (post-ischemic peak forearm blood flow [FBF] via plethysmography), and brachial artery flow-mediated dilation (FMD). Carotid artery stiffness (β-stiffness index), and inflammatory markers (C-reactive protein and tumor necrosis factor-alpha) were also explored., Results: Although the intervention had a significant and sustained effect on the primary outcome of anxiety as measured by the Beck Anxiety Inventory, the 1-day ACT workshop was not associated with improvement in vascular or inflammatory endpoints. The intervention was unexpectedly associated with increases in β-stiffness index that were also associated with changing trait anxiety., Conclusion: Anxiety improvements did not translate into improvements in any of the vascular function outcomes. This may reflect a less-than-robust effect of the intervention on anxiety, failure in design to select those with vascular dysfunction, or not intervening on a relevant causal pathway. (Trial registration NCT02915874 at www.clinicaltrials.gov)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aging is associated with reductions in endothelial function, observations primarily reported using brachial artery ultrasound. There is growing interest in the use of peripheral artery tonometry (PAT) of microvessels in the fingertip to assess endothelial function because it is less technically demanding and has a high sensitivity and specificity for assessing coronary endothelial function. Moreover, similar to brachial artery flow-mediated dilation (FMD), PAT predicts cardiovascular disease outcomes. However, the relationship between PAT and FMD have yet to be examined in the context of aging. To address this question, reactive hyperemic index (RHI) using EndoPAT and FMD using brachial artery ultrasound were assessed after 5 min of forearm ischemia in 20 younger (18-40 yr old; 29 ± 4 yr) and 20 older (60-75 yr old; 65 ± 4 yr) healthy adult men. Higher values of both FMD and RHI indicate better endothelial function. Endothelial function assessed via brachial artery FMD was lower in older (4.8 ± 2.1%), compared with younger (7.5 ± 1.6%) men ( P < 0.001). In contrast, the RHI assessed via PAT was greater in older (2.2 ± 0.6), compared with younger (1.8 ± 0.5) men ( P = 0.014). FMD and RHI were not correlated ( r = -0.15; P = 0.35). We conclude that PAT may not be an appropriate measure to evaluate age-associated changes in endothelial function. NEW & NOTEWORTHY Microvessel endothelial function assessed via finger plethysmography may not reflect age-associated reductions in large artery endothelial function assessed via brachial artery flow-mediated dilation.

Women with preeclampsia, a hypertensive disorder of pregnancy, exhibit greater beat-to-beat blood pressure variability (BPV) in the third trimester after clinical onset of the disorder. However, it remains unknown whether elevated BPV precedes the development of preeclampsia. A prospective study cohort of 139 women (age 30.2±4.0 years) were enrolled in early pregnancy (<14 weeks gestation). BPV was quantified by time domain analyses of 10-minute continuous beat-to-beat blood pressure recordings via finger photoplethysmography in the first, second, and third trimesters. Aortic stiffness (carotid-femoral pulse wave velocity) and spontaneous cardiovagal baroreflex sensitivity were also measured each trimester. Eighteen women (13%) developed preeclampsia. Systolic BPV was higher in all trimesters among women who developed versus did not develop preeclampsia (first: 4.8±1.3 versus 3.7±1.2, P =0.001; second: 5.1±1.8 versus 3.8±1.1, P =0.02; third: 5.2±0.8 versus 4.0±1.1 mm Hg, P =0.002). Elevated first trimester systolic BPV was associated with preeclampsia (odds ratio, 1.94 [95% CI, 1.27-2.99]), even after adjusting for risk factors (age, body mass index, systolic blood pressure, history of preeclampsia, and diabetes mellitus) and was a significant predictor of preeclampsia (area under the receiver operator characteristic curve=0.75±0.07; P =0.002). Carotid-femoral pulse wave velocity was elevated in the first trimester among women who developed preeclampsia (5.9±0.8 versus 5.2±0.8 m/s; P =0.002) and was associated with BPV after adjustment for mean blood pressure ( r =0.26; P =0.005). First trimester baroreflex sensitivity did not differ between groups ( P =0.23) and was not related to BPV ( P =0.36). Elevated systolic BPV is independently associated with the development of preeclampsia as early as the first trimester, possibly mediated in part by higher aortic stiffness.

Aortic stiffness is associated with augmented pressure pulsatility in large conduit arteries and remodeling of the microcirculation. However, studies in humans examining the relation between aortic stiffness and end-organ microvascular flow pulsatility are limited. Therefore, we used the retinal microvasculature as an end-organ in vivo model to examine the hypothesis that aortic stiffness would be positively associated with microvascular flow pulsatility index (PI) (flow pulse amplitude/mean flow) in humans. In 40 young/middle-age healthy adults (25-60 yr old, 50% women), aortic stiffness (carotid-femoral pulse wave velocity, CFPWV) and retinal arteriole flow (laser speckle flowgraphy) were examined at rest and during metabolic vasodilation (light flicker). CFPWV and related increases in central pulse pressure (PP) were inversely correlated with arteriole lumen diameter independent of age (CFPWV: R  = -0.52, P = 0.001; Central PP: R  = -0.39, P = 0.014). Accordingly, microvascular resistance was positively related to CFPWV independent of age ( R  = 0.35, P = 0.031). Multiple linear regression showed that CFPWV was not a significant determinant of resting arteriole flow PI (β = -0.10, P = 0.64). However, during reduced retinal microvascular resistance using light flicker ( P < 0.001), CFPWV was a significant determinant of the percent change in arteriole flow PI (β = 0.58, P = 0.046), but not mean flow (β = -0.17, P = 0.54), where reductions in arteriole flow PI were associated with lower CFPWV. In summary, our findings suggest that higher aortic stiffness and the related increase in central PP in healthy young/middle-age adults are associated with retinal arteriole narrowing and smaller reductions in arteriole flow pulsatility in response to dynamic conditions such as local metabolic vasodilation. NEW & NOTEWORTHY By using the human retinal microvasculature as an end-organ in vivo model, we confirm that aortic stiffness and related increases in central pulse pressure are inversely correlated with retinal arteriole lumen diameter and increased microvascular resistance among heathy young/middle-age adults. Additionally, higher aortic stiffness is not associated with excessive flow pulsatility in the retinal microvasculature under tonic conditions but may be related to limited reductions in retinal arteriole flow pulsatility in response to local vasodilation.

Declining episodic memory is common among otherwise healthy older adults, in part due to negative effects of aging on hippocampal circuits. However, there is significant variability between individuals in severity of aging effects on the hippocampus and subsequent memory decline. Importantly, variability may be influenced by modifiable protective physiological factors such as cardiorespiratory fitness (CRF). More research is needed to better understand which aspects of cognition that decline with aging benefit most from CRF. The current study evaluated the relation of CRF with learning rate on the episodic associative learning (EAL) task, a task designed specifically to target hippocampal-dependent relational binding and to evaluate learning with repeated occurrences. Results show higher CRF was associated with faster learning rate. Larger hippocampal volume was also associated with faster learning rate, though hippocampal volume did not mediate the relationship between CRF and learning rate. Furthermore, to support the distinction between learning item relations and learning higher-order sequences, which declines with aging but is largely reliant on extra-hippocampal learning systems, we found learning rate on the EAL task was not related to motor sequence learning on the alternating serial reaction time task. Motor sequence learning was also not correlated with hippocampal volume. Thus, for the first time, we show that both higher CRF and larger hippocampal volume in healthy older adults are related to enhanced rate of relational memory acquisition., (© 2019 Wiley Periodicals, Inc.)

Central artery aging, including elevated aortic stiffness, central blood pressure (BP), and pulse pressure (PP), is a novel risk factor for the development of age-associated cognitive dysfunction. Individuals with higher educational attainment may develop greater brain pathology prior to the onset of cognitive decline. However, whether education moderates relations between central artery aging and cognitive performance is unknown. We hypothesized that years of formal education would moderate the relation between central artery aging and cognitive performance in middle-aged/older (MA/O) adults (n = 113, age 67.3 ± 0.7 years). Significant interactions between education*central systolic BP (β = .21, p = .02) and education*central PP (β = .22, p = .01) demonstrated weaker associations between central BP and PP with processing speed performance in those with higher education. Similarly, education moderated the relation between aortic stiffness (carotid-femoral pulse wave velocity, cfPWV) and executive function performance (β = .21, p = .02). To test if the relation between central arterial aging and cognitive performance was captured by a predetermined education threshold, MA/O adults were secondarily categorized as ≤high school (HS) (i.e., ≤12 years, n = 36) or >HS (≥13 years, n = 77). Higher central systolic BP was associated with slower processing speed (≤HS: r = -.59, p < .001 vs. >HS: r = -.25, p = .03) and weaker executive function (r = -.39, p = .03 vs. r = -.32, p = .006). Higher cfPWV was selectively correlated with weaker executive function performance (r = -.39, p = .03) in ≤HS only and this association significantly differed between education groups. Educational attainment appears to moderate the adverse effects of central artery aging on cognitive performance among MA/O adults., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Aging is characterized by increased wall thickness of the central elastic arteries (i.e., aorta and carotid arteries), although the mechanisms involved are unclear. Evidence suggests that age-related increases in muscle sympathetic nerve activity (MSNA) may be a contributing factor. However, studies in humans have been lacking. Therefore, we tested the hypothesis that age-related increases in MSNA would be independently associated with carotid artery intima-media thickness (IMT) but not in young women given the reduced influence of MSNA on the vasculature in this group. In 93 young and middle-age/older (MA/O) adults (19-73 yr, 41 women), we performed assessments of MSNA (microneurography) and common carotid IMT and lumen diameter (ultrasonography). Multiple regression that included MSNA and other cardiovascular disease risk factors indicated that MSNA ( P = 0.002) and 24-h systolic blood pressure (BP) ( P = 0.024) were independent determinants of carotid IMT-to-lumen ratio (model R 2  = 0.38, P < 0.001). However, when examining only young women (<45 yr), no correlation was observed between MSNA and carotid IMT-to-lumen ratio ( R  =  - 0.01, P = 0.963). MSNA was significantly correlated with IMT-to-lumen ratio while controlling for 24-h systolic BP among young men ( R  = 0.49, P < 0.001) and MA/O women ( R  = 0.59, P = 0.022). However, among MA/O men, controlling for 24-h systolic BP attenuated the association between MSNA and carotid IMT-to-lumen ratio ( R  = 0.50, P = 0.115). Significant age differences in IMT-to-lumen ratio between young and MA/O men ( P = 0.047) and young and MA/O women ( P = 0.023) were removed when adjusting for MSNA (men: P = 0.970; women: P = 0.152). These findings demonstrate an association between higher sympathetic outflow and carotid artery wall thickness with a particular exception to young women. NEW & NOTEWORTHY Increased wall thickness of the large elastic arteries serves as a graded marker for cardiovascular disease risk and progression of atherosclerosis. Findings from the present study establish an independent association between higher sympathetic outflow and carotid artery wall thickness in adults with an exception to young women and extend findings from animal models that demonstrate hypertrophy of vascular smooth muscle following chronic sympathetic-adrenergic stimulation.

Background: Mood disorders have been associated with a variety of cardiovascular disease risk factors, including inflammation and large artery stiffness, particularly while depressed although longitudinal studies have been limited., Methods: With measurements at baseline and 8 weeks, the researchers prospectively assessed mood, levels of inflammatory markers (hsCRP and TNF-α), serum lipids, and large artery stiffness in a cohort of 26 participants with a diagnosis of a mood disorder, enriched for current depression. Depressive symptoms were measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and 8 weeks. Associations between depressive symptoms and other measures were assessed using linear mixed models, unadjusted and adjusted for age and BMI., Results: The mean age of the participants (n=26) was 41.6 (standard deviation [SD] 12.8) years, and 81% were female. During the study, there was a mean (SD) MADRS score improvement of 9.5 (9.4) from baseline to eight weeks. Reductions in the primary outcome TNF-α with improvement in depression fell short of significance ( P =0.076). In secondary analyses, there was a statistically significant association between improved cholesterol ratio ( P =0.038) and triglycerides ( P =0.042) with depression improvement. There was no statistically significant change in large artery stiffness during the study., Conclusion: Improved depressive symptoms were associated with improved cholesterol ratios even after adjustment, suggesting possible mechanism by which acute mood states may influence cardiovascular disease risk. Future longitudinal studies with extended and intensive follow-up investigating cardiovascular disease risk related to acute changes and persistence of mood symptoms is warranted.

Early stages of chronic obstructive pulmonary disease (COPD) are characterized by the loss and narrowing of terminal bronchioles in the lung, resulting in "air-trapping," often occurring before overt emphysema manifests. Individuals with an airway-predominant phenotype of COPD display extensive lung air-trapping and are at greater cardiovascular disease (CVD) risk than COPD patients with an emphysema-predominant phenotype. We hypothesized that the degree of computed tomography (CT)-quantified lung air-trapping would be associated with greater aortic and carotid artery stiffness and lower endothelial function, known biomarkers of CVD risk. Lung air-trapping was associated with greater aortic stiffness (carotid femoral pulse wave velocity, CFPWV) ( r  = 0.60, P = 0.007) and carotid β-stiffness ( r  = 0.75, P = 0.0001) among adults with ( n = 10) and without ( n = 9) a clinical diagnosis of COPD and remained significant after adjusting for blood pressure (BP) and smoking history (pack-years) (carotid β-stiffness: r  = 0.68, P < 0.01; CFPWV r  = 0.53, P  = 0.03). The association between lung air-trapping and carotid β-stiffness remained significant after additionally adjusting for age and forced expiratory volume 1(FEV 1 ) ( r  = 0.64, P = 0.01). In the COPD group only ( n = 10), lung air-trapping remained associated with carotid β-stiffness ( r  = 0.82, P = 0.05) after adjustment for age, pack-years, and FEV 1 . In contrast, no association was observed between CFPWV and lung air-trapping after adjustment for BP, pack-years, age, and FEV 1 ( r  = 0.12, P = 0.83). Lung air-trapping was not associated with endothelial function (brachial artery flow-mediated dilation) in the entire cohort ( P = 0.80) or in patients with COPD only ( P = 0.71). These data suggest that carotid artery stiffness may be a mechanism explaining the link between airway-predominant phenotypes of COPD and high CVD risk. NEW & NOTEWORTHY Previous cross-sectional studies have demonstrated greater large elastic artery stiffness and lower endothelium-dependent dilation in chronic obstructive pulmonary disease (COPD) patients compared with controls. Furthermore, COPD patients with emphysema have greater aortic stiffness than non-COPD controls, and the degree of stiffness is associated with emphysema severity. The present study is the first to demonstrate that even before overt emphysema manifests, lung air-trapping is associated with carotid artery stiffness in COPD patients independent of blood pressure, age, or smoking history.

Greater aortic stiffness and pulse pressure are associated with cerebrovascular remodeling, reduced white matter microstructure, and cognitive performance with aging in humans. However, it is unclear whether aortic stiffness and pulse pressure are associated with reduced basal global cerebral blood flow (CBF) and cerebrovascular reserve among older adults. Global CBF was quantified in 205 adults (range, 19-87 years; mean±SE: 30.6±1.3 years) using quantitative [ 15 O]water brain positron emission tomography imaging. In a subset of older adults (n=24; 70.0±2.0 years), aortic stiffness (carotid femoral pulse wave velocity) and cerebrovascular reserve (change in global CBF after intravenous infusion of acetazolamide) were assessed. In the entire cohort, global CBF was lower in older compared with young adults (36.5±1.1 versus 50.5±0.7 mL/min per 100 mL; P <0.001). Global CBF was higher in young women compared with young men (51.0±0.30 versus 47.4±0.03 mL/min per 100 mL; P <0.001) but did not differ between older women and men ( P =0.63). In older adults, greater carotid femoral pulse wave velocity was associated with lower cerebrovascular reserve ( r =-0.68; P =0.001 adjusted for age, sex, and mean arterial pressure) but not global CBF ( r =0.13; P =0.60). Brachial pulse pressure was not associated with lower cerebrovascular reserve ( r =-0.37; P =0.159) when adjusted for age and sex. These data indicate that the age-related increases in aortic stiffness may contribute, in part, to the brain's impaired ability to augment blood flow in response to a stimulus with aging in humans., (© 2018 American Heart Association, Inc.)

Aging is associated with increased carotid artery stiffness, a predictor of incident stroke, and reduced cognitive performance and brain white matter integrity (WMI) in humans. Therefore, we hypothesized that higher carotid stiffness/lower compliance would be independently associated with slower processing speed, higher working memory cost, and lower WMI in healthy middle-aged/older (MA/O) adults. Carotid β-stiffness ( P < 0.001) was greater and compliance ( P < 0.001) was lower in MA/O ( n = 32; 64.4 ± 4.3 yr) vs. young ( n = 19; 23.8 ± 2.9 yr) adults. MA/O adults demonstrated slower processing speed (27.4 ± 4.6 vs. 35.4 ± 5.0 U/60 s, P < 0.001) and higher working memory cost (-15.4 ± 0.14 vs. -2.2 ± 0.05%, P < 0.001) vs. young adults. Global WMI was lower in MA/O adults ( P < 0.001) and regionally in the frontal lobe ( P = 0.020) and genu ( P = 0.009). In the entire cohort, multiple regression analysis that included education, sex, and body mass index, carotid β-stiffness index (B = -0.53 ± 0.15 U, P = 0.001) and age group (B = -4.61 ± 1.7, P = 0.012, adjusted R 2 = 0.4) predicted processing speed but not working memory cost or WMI. Among MA/O adults, higher β-stiffness (B = -0.60 ± 0.18, P = 0.002) and lower compliance (B = 0.93 ± 0.26, P = 0.002) were associated with slower processing speed but not working memory cost or WMI. These data suggest that greater carotid artery stiffness is independently and selectively associated with slower processing speed but not working memory among MA/O adults. Carotid artery stiffening may modulate reductions in processing speed earlier than working memory with healthy aging in humans. NEW & NOTEWORTHY Previously, studies investigating the relation between large elastic artery stiffness, cognition, and brain structure have focused mainly on aortic stiffness in aged individuals with cardiovascular disease risk factors and other comorbidities. This study adds to the field by demonstrating that the age-related increases in carotid artery stiffness, but not aortic stiffness, is independently and selectively associated with slower processing speed but not working memory among middle-aged/older adults with low cardiovascular disease risk factor burden., (Copyright © 2017 the American Physiological Society.)

A diet high in trans-fatty acids (TFAs) is associated with a higher risk of cardiovascular disease (CVD) than a diet high in saturated fatty acids (SFAs), but the mechanisms remain unclear. We hypothesized that a beverage high in TFAs would cause a larger reduction in postprandial endothelial function and an increase in arterial stiffness, in part from greater reductions in insulin sensitivity, compared with a beverage high in SFAs. Eleven healthy adults (aged 47±5 years) ingested a warm test beverage (520 kcal, 56 g total fat, 5 g carbohydrate, 1 g protein) high in either TFAs or SFAs in a randomized cross-over study. Ingestion of the beverage high in TFAs (p<0.01) but not high in SFAs (p=0.49) decreased endothelial function (brachial artery flow-mediated dilation, mmΔ) at 3-4 hours (p<0.01 for time; p=0.034 for interaction), but did not alter aortic stiffness or carotid β-stiffness. The homeostasis model of insulin resistance (interaction p=0.062) tended to decrease after SFAs but not TFAs. A beverage high in TFAs but not SFAs results in a postprandial reduction in endothelial function and a trend for decreased insulin sensitivity, potentially explaining the higher risk of CVD with a diet high in TFAs., (© The Author(s) 2016.)