Cerebral hemodynamics comparison using transcranial doppler ultrasound and 4D flow MRI.

Introduction: 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). Methods: 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% CO2, and 6% CO2) using TCD and 4D flow MRI. Cerebral hemodynamic measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity to hypercapnia. MCA flow was only assessed using 4D flow MRI. Results: MCA velocity between the TCD and 4D flow MRI methods was positively correlated across the normocapnia and hypercapnia conditions (r = 0.262; p = 0.004). Additionally, cerebral PI was significantly correlated between TCD and 4D flow MRI across the conditions (r = 0.236; p = 0.010). However, there was no significant 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 using conductance 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/mmHg vs. 0.68 ± 0.94 cm/s/mmHg/mmHg; p = 0.513). Conclusion: Our results demonstrated good agreement between the methods at measuring MCA velocity during normocapnia and in response to hypercapnia, but MCA velocity and MCA flow were not related. In addition, measurements using 4D flow MRI revealed effects of aging on cerebral hemodynamics that were not apparent using TCD.

Association between serum prostacyclin and cerebrovascular reactivity in healthy young and older adults.

NEW FINDINGS: What is the central question of this study? What is the relationship between prostacyclin and cerebrovascular reactivity to hypercapnia before and after administration of a cyclooxygenase inhibitor, indomethacin, in healthy young and older adults? What is the main finding and importance? Serum prostacyclin was not related to cerebrovascular reactivity to hypercapnia before or after administration of indomethacin. However, in older adults, serum prostacyclin was related to the magnitude of change in cerebrovascular reactivity from before to after indomethacin administration. This suggests that older adults with higher serum prostacyclin may rely more on cyclooxygenase products to mediate cerebrovascular reactivity. 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 at natural menopause impacts cerebrovascular reactivity and brain structure.

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.

Sympathoexcitatory Responses to Isometric Handgrip Exercise Are Associated With White Matter Hyperintensities in Middle-Aged and Older Adults.

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

The Impact of Aging on the Association Between Aortic Stiffness and Cerebral Pulsatility Index.

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

Impact of age and cyclooxygenase inhibition on the hemodynamic response to acute cognitive challenges.

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

Exercise, Arterial Stiffness, and Cerebral Vascular Function: Potential Impact on Brain Health.

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.

Influence of habitual aerobic and resistance exercise on cerebrovascular reactivity in healthy young adults.

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.

Vertebral artery hypoplasia influences age-related differences in blood flow of the large intracranial arteries.

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 ±â€¯3 years) and older adults (n = 19; age = 61 ±â€¯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 ±â€¯75 mL/min vs. 432 ±â€¯92 mL/min, respectively; p < 0.05). There was no difference in BA flow between VAH+ and No VAH (110 ±â€¯20 mL/min vs. 126 ±â€¯40 mL/min, respectively; p = 0.24). When comparing age-related differences in blood flow in the No VAH group, older adults demonstrated lower BA flow compared with young adults (111 ±â€¯38 mL/min vs. 140 ±â€¯38 mL/min, respectively; p < 0.05) but not ICA flow (428 ±â€¯89 mL/min vs. 436 ±â€¯98 mL/min, respectively; p = 0.82). In contrast, in the VAH+ group, older adults had lower ICA flow compared with young adults (312 ±â€¯65 mL/min vs. 421 ±â€¯35 mL/min, respectively; p < 0.01), but not BA flow (104 ±â€¯16 mL/min vs. 117 ±â€¯23 mL/min, respectively; p = 0.32). Our results suggest that the presence of VAH is associated with lower ICA blood flow. Furthermore, VAH may contribute to the variability in the age-related differences in cerebral blood flow in healthy adults.

Exercise Improves Vascular Function, but does this Translate to the Brain?

The number of adults with Alzheimer's disease (AD) or related dementia is expected to increase exponentially. Interventions aimed to reduce the risk and progression of AD and dementia are critical to the prevention and treatment of this devastating disease. Aging and cardiovascular disease risk factors are associated with reduced vascular function, which can have important clinical implications, including brain health. The age-associated increase in blood pressure and impairment in vascular function may be attenuated or even reversed through lifestyle behaviors. Greater volumes of habitual exercise and higher cardiorespiratory fitness are associated with beneficial effects on vascular health and cognition. Exercise and cardiorespiratory fitness may be most important during midlife, as physical activity and cardiorespiratory fitness during the middle-aged years are associated with future cognitive function. The extent to which exercise, and more specifically aerobic exercise, influences the cerebral circulation is not well established. In this review, we present our working hypothesis showing how cerebrovascular function may be a mediating factor underlying the association between exercise and cognition, as well as discuss recent studies evaluating the effect of exercise interventions on the cerebral circulation.