Brain arterial dilatation modifies the association between extracranial pulsatile hemodynamics and brain perivascular spaces: the Northern Manhattan Study

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Abstract

Pulsatile hemodynamics are associated with brain small perivascular spaces (SPVS). It is unknown whether the stiffness of intermediary arteries connecting the aorta and brain modifies this association. Participants from the Northern Manhattan Study were assessed for SPVS (defined as ≤3mm T1 voids) and white matter hyperintensity volume (WMH) using MRI. Middle (MCA) and anterior cerebral arterial (ACA) diameters (measured on time-of-flight MRA) and CCA strain (assessed by ultrasound) were used as surrogates of stiffness. Brachial and aortic pulse pressure (PP) and aortic augmentation index (Aix, assessed by applanation tonometry) were used as markers of pulsatility. We tested whether stiffness in intermediary arteries modifies the association between extracranial pulsatility with SPVS and WMH. We found that among 941 participants (mean age 71±9 years, 60% women, 66% Hispanic), the right MCA/ACA diameter was associated with right anterior SPVS (B=0.177, P=0.002). Brachial PP was associated with right anterior SPVS (B=0.003, P=0.02), and the effect size was bigger with right MCA/ACA diameter in the upper tertile (P=0.001 for the interaction). The association between right CCA strain and ipsilateral SPVS was modified by MCA/ACA diameter, with the largest effect size in those with ipsilateral MCA/ACA diameter in the upper tertile (P=0.001 for the interaction). Similar dose-effects and statistical interactions were replicated using aortic AIx or aortic PP. We found no evidence of effect modification between pulsatile measures and WMH by stiffness measures. In summary, pulsatile hemodynamics relate to brain SPVS, and the association is the strongest among individuals with dilated brain arteries.

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Mechanical factors in arterial aging: a clinical perspective.

Michael F O'Rourke, Junichiro Hashimoto (2007)

The human arterial system in youth is beautifully designed for its role of receiving spurts of blood from the left ventricle and distributing this as steady flow through peripheral capillaries. Central to such design is "tuning" of the heart to arterial tree; this minimizes aortic pressure fluctuations and confines flow pulsations to the larger arteries. With aging, repetitive pulsations (some 30 million/year) cause fatigue and fracture of elastin lamellae of central arteries, causing them to stiffen (and dilate), so that reflections return earlier to the heart; in consequence, aortic systolic pressure rises, diastolic pressure falls, and pulsations of flow extend further into smaller vessels of vasodilated organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased stresses on small arterial vessels, particularly of brain and kidney. Clinical manifestations are a result of diastolic LV dysfunction with dyspnea, predisposition to angina, and heart failure, and small vessel degeneration in brain and kidney with intellectual deterioration and renal failure. While aortic stiffening is the principal cause of cardiovascular disease with age in persons who escape atherosclerotic complications, it is not a specific target for therapy. The principal target is the smooth muscle in distributing arteries, whose relaxation has little effect on peripheral resistance but causes substantial reduction in the magnitude of wave reflection. Such relaxation is achieved through regular exercise and with the vasodilating drugs that are used in modern treatment of hypertension and cardiac failure.

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Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility--Reykjavik study.

Gary F Mitchell, Mark van Buchem, Sigurdur Sigurdsson … (2011)

Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility--Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = -0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P<0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (-0.127 ± 0.037 SD/SD, P<0.001), grey matter (-0.079 ± 0.038 SD/SD, P = 0.038) and white matter (-0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid-femoral pulse wave velocity (-0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (-0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (-0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (-0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (-0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.

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Neuropathologic correlates of white matter hyperintensities.

Jillian Kril, Glenda Halliday, C. J. S. Young (2008)

White matter hyperintensities (WMH) are commonly seen on neuroimaging scans, but their underlying histopathologic substrate is unclear. The aim of this work was to establish the pathologic correlates of WMH in unselected elderly cases using two study designs. To avoid potential bias from comparisons of different anatomic regions, study 1 compared, region-by-region, the severity of WMH determined in vivo with measures of each of the major white matter (WM) components. Study 2 compared the histopathology of WMH with normal WM. Study 1: The periventricular and deep WM regions of three lobes in 23 brains with in vivo MRI scans were investigated using histologic and immunohistochemical stains. The severity of each pathologic measure was correlated with WMH severity determined using the Scheltens scale. Study 2: Lesioned and nonlesioned areas identified by postmortem MRI in the frontal WM of 20 brains were examined histologically and immunohistochemically. No single pathologic variable correlated with the severity of WMH; however, a multiple stepwise regression analysis revealed that vascular integrity predicted total Scheltens score (beta = -0.53, p = 0.01). Comparison of lesioned and nonlesioned areas demonstrated that vascular integrity was reduced in WMH [t(18) = 3.79, p = 0.001]. Blood-brain barrier integrity was also found to be reduced in WMH [t(5) = -5.31, p = 0.003]. White matter hyperintensities (WMH) involve a loss of vascular integrity, confirming the vascular origin of these lesions. This damage to the vasculature may in turn impair blood-brain barrier integrity and be one mechanism by which WMH evolve.