Reduced neurovascular coupling is associated with increased cardiovascular risk without established cerebrovascular disease: A cross-sectional analysis in UK Biobank

Abstract

Mid-life vascular risk factors predict late-life cerebrovascular diseases and poor global brain health. Although endothelial dysfunction is hypothesized to contribute to this process, evidence of impaired neurovascular function in early stages remains limited. In this cross-sectional study of 31,934 middle-aged individuals from UK Biobank without established cerebrovascular disease, the overall 10-year risk of cardiovascular events was associated with reduced neurovascular coupling (p < 2 × 10^-16) during a visual task with functional MRI, including in participants with no clinically apparent brain injury on MRI. Diabetes, smoking, waist-hip ratio, and hypertension were each strongly associated with decreased neurovascular coupling with the strongest relationships for diabetes and smoking, whilst in older adults there was an inverted U-shaped relationship with DBP, peaking at 70-80 mmHg DBP. These findings indicate that mid-life vascular risk factors are associated with impaired cerebral endothelial-dependent neurovascular function in the absence of overt brain injury. Neurovascular dysfunction, measured by neurovascular coupling, may play a role in the development of late-life cerebrovascular disease, underscoring the need for further longitudinal studies to explore its potential as a mediator of long-term cerebrovascular risk.

Keywords: Cerebral small vessel disease; endothelial function; hypertension; neurovascular coupling; vascular risk factors.

Figure 1.

Neurovascular coupling decreases with increasing current 10-year cardiovascular disease risk. Neurovascular coupling is presented as dots (mean, expressed as z-statistic) with error bars (95% confidence interval). The size of each dot is proportional to the logarithm of the subgroup size. The horizontal dashed line marks the overall mean neurovascular coupling. ASCVD: atherosclerotic cardiovascular disease.

Figure 2.

Neurovascular coupling is lower in male participants, and declines faster after middle-age. Neurovascular coupling is presented as dots (mean, expressed as z-statistic) with error bars (95% confidence interval). The size of each dot is proportional to the logarithm of the subgroup size. The horizontal dashed line marks the overall mean neurovascular coupling.

Figure 3.

Higher blood pressure is associated with lower neurovascular coupling, while DBP in older participants shows an inverted U-shaped pattern. Neurovascular coupling is presented as dots (mean, expressed as z-statistic) with error bars (95% confidence interval). The size of each dot is proportional to the logarithm of the subgroup size. The horizontal dashed line marks the overall mean neurovascular coupling. Neurovascular coupling is stratified by age and blood pressure (DBP: <70, 70–80, 80–90, ≥90 mmHg; SBP: <120, 120–130, 130–140, ≥140 mmHg).

Figure 4.

Decreased neurovascular coupling is associated with concurrent vascular risk factors. (a) Neurovascular coupling is presented as bars (mean, expressed as z-statistic) with error bars (95% confidence interval). The horizontal dashed line marks the overall mean neurovascular coupling. Overall obesity is defined at BMI ≥30, central obesity as waist-hip ratio ≤0.85 for female and ≤0.9 for male. Between-group comparisons by t-test (* unadjusted p < 0.05, ** unadjusted p < 0.01, *** unadjusted p < 0.001). (b–d) Neurovascular coupling is presented as dots (mean, expressed as z-statistic) with error bars (95% confidence interval). The size of each dot is proportional to the logarithm of the subgroup size. The horizontal dashed line marks the overall mean neurovascular coupling. Blood pressure is stratified to optimal (<120/80 mmHg), normal (120–129/80–84 mmHg, reference group), high normal (130–139/85–89 mmHg), and hypertension (≥140/90 mmHg). BMI is stratified to underweight (<18.5), normal (≥18.5 & <25, reference group), overweight (≥25 & <30), and obese (≥30). Between-group comparisons by ANOVA (unadjusted p < 0.05 for all variables) with post-hoc t-test (* unadjusted p < 0.05, ** unadjusted p < 0.01, *** unadjusted p < 0.001). Normal blood pressure, normal BMI, and ≤10 smoking packyears are the reference groups, respectively.