Association between arterial stiffening and brain function — Whitehall II cohort study

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Targeting arterial stiffening earlier in a person’s lifespan could provide cognitive benefits in older age and may help to delay the onset of dementia. Researchers at the University of Oxford and University College London investigated 542 older adults who received two measurements of aortic stiffness, at 64 years old and 68 years old. Subsequent cognitive tests and brain magnetic resonance imaging (MRI) scans assessed the size, connections and blood supply of different brain regions.

The body’s largest artery, the aorta,  gets stiffer with age, and the study found that faster aortic stiffening in mid-life to older age was linked to markers of poorer brain health, for example: lower brain blood supply; reduced structural connectivity between different brain regions; and worse memory.

Medical interventions and changes of lifestyle made earlier in the lifespan could help to slow down arterial stiffening. In an ageing society where we expect a near tripling in the number of people living with dementia by 2050, identifying ways to prevent or delay its onset could have significant societal and economic impact.

Dr Sana Suri, Alzheimer’s Society research fellow at the department of psychiatry, University of Oxford, said: “Our study links heart health with brain health, and gives us insights into the potential of reducing aortic stiffening to help maintain brain health in older ages. Reduced connectivity between different brain regions is an early marker of neurodegenerative diseases such as Alzheimer's disease, and preventing these changes by reducing or slowing down the stiffening of our body's large blood vessels may be one way to maintain brain health and memory as we grow older.”

This study shows the importance of interdisciplinary work in this field and stresses the benefits of studying the brain in conjunction with other organ systems. Arteries stiffen faster if someone has pre-existing heart diseases, high blood pressure, diabetes and other vascular diseases. Arterial stiffening is also progressively faster with long-term exposure to poor health behaviours and lifestyle risk factors, such as smoking or poor diets. It is possible to reduce arterial stiffening by medical treatments or lifestyle interventions, such as modifying the diet and exercising.

Dr Scott Chiesa, research associate at the UCL Institute of Cardiovascular Science, said: “With no cure for dementia, there is an increased focus on understanding how to prevent or delay its onset. Importantly, our study helps us understand when in the lifespan it will be best to target and improve cardiovascular health to benefit the brain.”

Dr Richard Oakley, head of research at Alzheimer’s Society, which funded the study, said: “Dementia devastates lives, and with the number of people with dementia set to rise to 1m by 2025 and more families affected than ever before, reducing our risk has never been more important. This Alzheimer’s Society funded study didn’t look for a link between heart health and dementia directly, but it has shed important light on a connection between the health of our blood vessels and changes in the brain that indicate brain health.

“We know that what’s good for your heart is good for your head, and it’s exciting to see research that explores this link in more detail. But we need even more research to understand the impact of heart health on brain health as we age, and how that affects our own dementia risk. Alzheimer’s Society is committed to funding research into dementia prevention as well as research into a cure. But coronavirus has hit us hard, so it’s vital the government honours its commitment to double dementia research spending to continue research like this.”

Participants in this study were part of the Imaging subset of the Whitehall II Study, a cohort of British civil service members who have received clinical follow-ups for over 30 years. Participants were predominantly white males and were selected if they had no clinical diagnosis of dementia. Further research in diverse samples and people with more advanced cognitive deficits will be needed to confirm these findings in a wider population.

The Whitehall II Study and the Whitehall II Imaging Sub-study are funded by grants from the UK Medical Research Council, British Heart Foundation, and US National Institute on Aging.


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

Sana Suri, Scott T Chiesa, Enikő Zsoldos, Clare E Mackay, Nicola Filippini, Ludovica Griffanti, Abda Mahmood, Archana Singh-Manoux, Martin J Shipley, Eric J Brunner, Mika Kivimäki, John E Deanfield, Klaus P Ebmeier

Published in PLOS Medicine on 29 December 2020


Aortic 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 findings
The 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.

Our 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.


Oxford University material


PLOS Medicine study




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