Review
Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: A systematic review and meta-analysis

https://doi.org/10.1016/j.neubiorev.2015.03.011Get rights and content

Highlights

  • Arterial stiffness may contribute to cerebral small vessel disease and cognitive impairment.

  • Consistent evidence for these associations is, however, lacking.

  • We performed a systematic review/meta-analysis of studies on these associations.

  • Consistent associations were found, in particular for cerebral small vessel disease.

  • Results support the hypothesis that stiffness contributes to microvascular brain disease.

Abstract

Arterial stiffness may be a cause of cerebral small vessel disease and cognitive impairment. We therefore performed a systematic review and meta-analysis of studies on the association between stiffness, cerebral small vessel disease and cognitive impairment. For the associations between stiffness (i.e. carotid-femoral pulse wave velocity (cfPWV), brachial-ankle PWV (baPWV), carotid stiffness and pulse pressure) on the one hand and cerebral small vessel disease and cognitive impairment on the other, we identified 23 (n = 15,666/20 cross-sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal) and 41 studies (n = 57,671/26 cross-sectional; 11 longitudinal; 4 combined cross-sectional/longitudinal), respectively. Pooled analyses of cross-sectional studies showed that greater stiffness was associated with markers of cerebral small vessel disease with odds ratios, per +1 SD, of 1.29–1.32 (P < .001). Studies on cognitive impairment could not be pooled due to large heterogeneity. Some (but not all) studies showed an association between greater stiffness and cognitive impairment, and the strength of this association was relatively weak. The present study supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease.

Introduction

Increased arterial stiffness leads to an increased pulsatile pressure and flow load, which can damage the microcirculation (Mitchell, 2008, O’Rourke and Safar, 2005, Tzourio et al., 2014). The brain is more vulnerable for this increased load, because its microcirculation is characterized by low impedance, allowing the pulsatile load to penetrate deeply into its microvascular bed (Mitchell, 2008, O’Rourke and Safar, 2005, Tzourio et al., 2014). In the brain, microvascular damage can manifest itself as white matter hyperintensities (WMH), cerebral microbleeds and lacunar infarcts (Wardlaw et al., 2013b), which may ultimately result in cognitive impairment, including dementia (Mitchell et al., 2011).

Currently, consistent evidence is lacking, however, to support an association between increased arterial stiffness on the one hand and cerebral small vessel disease and cognitive impairment on the other, despite the fact that in recent years a growing number of studies have been done on this issue. Existing studies were done in diverse study populations and evaluated different measures of cerebral small vessel disease, cognitive function and arterial stiffness. Measures of arterial stiffness included carotid-femoral pulse wave velocity (cfPWV), brachial-ankle PWV (baPWV) and local distensibility measurements of the carotid artery (i.e. local carotid stiffness). These indices reflect stiffening of different parts of the arterial tree, and may be differentially associated with cerebral small vessel disease and cognitive impairment (Safar and O’Rourke, 2006). In addition, some studies used pulse pressure (PP) (i.e. the difference between systolic and diastolic blood pressure) as a surrogate measure of arterial stiffness. PP is, however, determined by factors other than arterial stiffness, including stroke volume and wave reflections (Safar and O’Rourke, 2006). This may affect the association between arterial stiffness and cerebral small vessel disease and cognitive impairment.

Three previous reviews (Pase et al., 2012, Rabkin and Jarvie, 2011, Singer et al., 2014) have examined the association between arterial stiffness and microvascular brain disease. However, these studies evaluated only cognitive impairment (Pase et al., 2012, Rabkin and Jarvie, 2011), included a limited number of measures of arterial stiffness and cognitive impairment (Pase et al., 2012, Rabkin and Jarvie, 2011), included only studies done in healthy individuals (Singer et al., 2014), did not perform a study quality assessment (Pase et al., 2012, Rabkin and Jarvie, 2011, Singer et al., 2014) and(or) did not do a meta-analysis (Singer et al., 2014).

In view of the above, we performed a systematic review and meta-analysis of observational studies on the association between, on the one hand, arterial stiffness (i.e. cfPWV, baPWV, local carotid stiffness and PP) and, on the other, markers of cerebral small vessel disease and cognitive impairment.

Section snippets

Methods

This systematic review and meta-analysis is reported in accordance with the PRISMA guidelines (Moher et al., 2009) (the PRISMA checklist is provided as Supplementary material).

Selection process and study characteristics

Fig. 1 shows the selection process of included studies. Of the 23 studies included on cerebral small vessel disease (n = 15,666; 20 cross-sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal), eight evaluated cfPWV (n = 5017), 7 baPWV (n = 3176), 1 local carotid stiffness (n = 912) and 12 PP (n = 10,775; 8 office PP, 2 ambulatory PP, 3 central PP). Of the 41 studies on cognitive impairment (n = 57,671; 26 cross-sectional; 11 longitudinal; 4 combined cross-sectional/longitudinal), 13 evaluated

Main findings

The present systematic review and meta-analysis had two main findings. First, with regard to the systematic review, most studies showed an independent association between greater arterial stiffness, as measured by cfPWV, baPWV, local carotid stiffness and PP, and markers of cerebral small vessel disease. In addition, studies found an association between higher cfPWV, baPWV and local carotid stiffness on the one hand and cognitive impairment on the other, but the strength of this association was

Conclusion

The present systematic review and meta-analysis shows a consistent association across different cross-sectional studies between greater arterial stiffness and markers of cerebral small vessel disease. This supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease. The strength of the association between greater arterial stiffness and cognitive impairment was, however, relatively weak, and might have been overestimated due to publication bias.

Conflicts of interest

None of the authors report any conflicts of interest.

Acknowledgement

Dr. Protogerou has received funding from the European Union Seventh Framework Programme ([FP7/2009–2013]) under grand agreement No. 299086.

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