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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 in the transition from mid to late life affects brain structure and cognition. Methods and Findings: Aortic pulse wave velocity was measured in 2007-09 (Phase 9) and at a 4-year follow-up in 2012-13 (Phase 11) in the Whitehall II Imaging Sub-study cohort. 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), cerebral blood flow, and white matter lesions. Cognitive outcomes were performance on verbal memory, semantic fluency, working memory and executive function tests. Of 544 participants, 445 (81.8%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 67.9 (5.3) years at Phase 11 and 69.8 (5.2) years at the Imaging Phase. Voxel-based analysis revealed that accelerated aortic stiffening in mid-to-late life was associated with poor white matter integrity, viz. lower fractional anisotropy in 4.2% of white matter and higher radial diffusivity in 6.7% of white matter, including the corpus callosum, corona radiata, superior longitudinal fasciculus and corticospinal tracts. Accelerated aortic stiffening was also related to lower cerebral perfusion in 1.1% of grey matter including the parietal, frontal, and occipital cortices. No associations with grey matter volume or white matter lesions were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B=-0.48, 95%CI -0.77 to -0.19, p<0.005) and verbal learning outcomes (B=-0.36, 95%CI - 0.60 to -0.13, p<0.005). Conclusions: Faster aortic stiffening in mid-to-late life is associated with poor brain white matter 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.

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