Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults

Jefferson, Angela L.; Cambronero, Francis E.; Liu, Dandan; Moore, Elizabeth E.; Neal, Jacquelyn E.; Terry, James G.; Nair, Sangeeta; Pechman, Kimberly R.; Rane, Swati; Davis, L. Taylor; Gifford, Katherine A.; Hohman, Timothy J.; Bell, Susan P.; Wang, Thomas J.; Beckman, Joshua A.; Carr, J. Jeffrey

doi:10.1161/circulationaha.118.032410

Cited by 130 publications

(126 citation statements)

References 49 publications

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“…Increased arterial stiffness affects the hemodynamic function of the cerebral vasculature. For example, a recent study found an association between aortic stiffening and reduced rCBF in cognitively normal older adults, without clinical presentation of stroke and dementia [67]. Interestingly, the study also demonstrated that APOE-ε4 carriers were found to have higher pulse wave velocity and lower rCBF in the whole brain and in the temporal lobe, compared to non APOE-ε4 carriers.…”

Section: Klohsmentioning

confidence: 78%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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Section: Klohsmentioning

confidence: 78%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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“…The same is true for functional connectivity measured in resting‐state data (Brier et al, ). Increased carotid PWV in aging has been associated with reduced blood flow in aging (Fisher et al, ; Jefferson et al, ; Kroner et al, ) as well as higher blood pressure (Sawabe et al, ). Arterial stiffening has also been associated with reduced CVR (Flück et al, ).…”

Section: Introductionmentioning

confidence: 99%

The association between resting‐state functional magnetic resonance imaging and aortic pulse‐wave velocity in healthy adults

Hussein

Matthews

Syme

et al. 2020

Human Brain Mapping

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Resting-state functional magnetic resonance imaging (rs-fMRI) is frequently used to study brain function; but, it is unclear whether BOLD-signal fluctuation amplitude and functional connectivity are associated with vascular factors, and how vascularhealth factors are reflected in rs-fMRI metrics in the healthy population. As arterial stiffening is a known age-related cardiovascular risk factor, we investigated the associations between aortic stiffening (as measured using pulse-wave velocity [PWV]) and rs-fMRI metrics. We used cardiac MRI to measure aortic PWV (an established indicator of whole-body vascular stiffness), as well as dual-echo pseudo-continuous arterial-spin labeling to measure BOLD and CBF dynamics simultaneously in a group of generally healthy adults. We found that: (1) higher aortic PWV is associated with lower variance in the resting-state BOLD signal; (2) higher PWV is also associated with lower BOLD-based resting-state functional connectivity; (3) regions showing lower connectivity do not fully overlap with those showing lower BOLD variance with higher PWV; (4) CBF signal variance is a significant mediator of the above findings, only when averaged across regions-of-interest. Furthermore, we found no significant association between BOLD signal variance and systolic blood pressure, which is also a known predictor of vascular stiffness. Age-related vascular stiffness, as measured by PWV, provides a unique scenario to demonstrate the extent of vascular bias in rs-fMRI signal fluctuations and functional connectivity. These findings suggest that a substantial portion of age-related rs-fMRI differences may be driven by vascular effects rather than directly by brain function. K E Y W O R D Saging, aortic stiffness, arterial stiffening, blood pressure, blood-oxygenation level dependent signal (BOLD), BOLD signal amplitude, functional connectivity, functional MRI (fMRI), phasecontrast imaging, pulse wave velocity, resting-state fMRI

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“…Correlational studies in human subjects find that large elastic artery stiffness is associated with resistance artery dysfunction (Mitchell et al, 2005), lower cerebral blood flow (Jefferson et al, 2018;Tarumi, Shah, Tanaka, & Haley, 2011), cognitive impairment (Hanon et al, 2005;Meyer et al, 2017;Mitchell et al, 2011;Pase et al, 2016) and…”

Section: Introductionmentioning

confidence: 99%

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness

Walker

Kronquist

Chinen

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater risk of Alzheimer's disease. However, it is unknown whether stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance?In a mouse model with greater large artery stiffness (Eln+/−), we find an exacerbated vasoconstrictor response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness. Abstract Greater stiffness of the large elastic arteries is associated with end‐organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown whether large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/−) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wild‐type (Eln+/+) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response to angiotensin II (Ang II) was ∼40% greater in Eln+/− compared with Eln+/+ mice (P = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries, Eln+/− and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to noradrenaline, endothelin‐1 and potassium chloride were not different between Eln+/− and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln+/− versus Eln+/+ mice (P = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.

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Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults

Cited by 130 publications

References 49 publications

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

The association between resting‐state functional magnetic resonance imaging and aortic pulse‐wave velocity in healthy adults

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness

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