Associations between arterial stiffening and brain structure, perfusion and cognition in the Whitehall II Imaging Sub-study: a retrospective cohort study

Background: Aortic stiffness is closely linked with cardiovascular diseases, 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 Findings: The Whitehall II Imaging cohort is a randomly selected subset of the on-going Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 Phases. Aortic pulse wave velocity was measured in 2007-09 (Phase 9) and at a 4-year follow-up in 2012-13 (Phase 11). Between 2012-2016 (Imaging Phase), participants received a multi-modal 3T brain magnetic resonance imaging (MRI) scans 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 volume, white matter microstructure (fractional anisotropy and diffusivity), white matter lesions and cerebral blood flow. 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 white matter microstructure, viz. lower fractional anisotropy, higher mean and radial diffusivity in 23.9%, 11.8% and 22.2% of white matter 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 fractional anisotropy 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 grey matter, 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 grey matter volume or white matter lesions 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