Abstract
BackgroundAortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.Methods and findingsThe Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007–2009 (Phase 9) and at a 4-year follow-up in 2012–2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = −5.65, 95% CI −9.75, −1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = −1.12, 95% CI −1.95, −0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = −10.85, 95% CI −17.91, −3.79, p < 0.0125) and parietal lobes (B = −12.75, 95% CI −21.58, −3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = −0.47, 95% CI −0.76 to −0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = −0.36, 95% CI −0.60 to −0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort.ConclusionsOur findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age.Trial registrationClinicalTrials.gov NCT03335696
Highlights
50 million people currently live with dementia worldwide, and this figure is expected to triple by 2050 [1]
Our findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain white matter (WM) microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature
We note that the absolute differences in these measures were very small; body mass index (BMI) and sex have been included as covariates in all analyses of pulse wave velocity (PWV) with brain and cognitive outcomes
Summary
50 million people currently live with dementia worldwide, and this figure is expected to triple by 2050 [1]. Aortic stiffness refers to the loss of elasticity in the artery wall and occurs gradually with age [4]. Acceleration of this process can compromise the artery’s ability to dampen the pulsatile energy flowing from the heart to delicate target organs like the brain. Numerous studies have demonstrated a relationship between aortic stiffness and accelerated cognitive decline, suggesting that this may be an important risk factor for dementia ([5,6,7,8]; for review, see[9]). Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is a risk factor for cognitive decline and dementia. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study
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