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,

Background

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov NCT03335696

Author summary

Why was this study done?

• Stiffening of large arteries such as the aorta has been closely linked to the onset of heart diseases, but recent studies show that this may also increase risk for dementia.
• Understanding the brain changes which underlie this risk could help identify strategies to prevent or delay dementia in old age.

What did the researchers do and find?

• We investigated 542 community-dwelling older adults who received 2 measurements of aortic stiffness, first at approximately 64 years old and again at approximately 68 years old.
• Shortly after that, at mean age 69 years, they underwent cognitive tests and brain magnetic resonance imaging (MRI) scans to assess the size, connections, and blood supply of different brain regions.
• We observed that a faster rate of aortic stiffening during the 4 years in mid-to-late life was linked to lower blood flow and poorer markers of brain connectivity across several brain regions.
• We also found that lower memory performance in older age was most closely linked to the first measures of aortic stiffness, taken at baseline, rather than the later measures of stiffness.

What do these findings mean?

• Faster stiffening of the aorta in mid-to-older ages may influence brain health, specifically, the brain’s delicate blood vessels and the connectivity between different brain regions.
• However, in order to benefit memory in older age, strategies to prevent or slow down arterial stiffening may be required even earlier in the life span.
• Although this was a large study, it was conducted in a relatively well-educated and largely male sample, so future research on more representative samples are needed to allow us to generalise the findings to the wider population.
  • Sana Suri  ,
  • Scott T. Chiesa ,
  • Enikő Zsoldos,
  • Clare E. Mackay,

  Background

  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.

  Conclusions

  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.

  Trial registration

  ClinicalTrials.gov NCT03335696

  Author summary

  Why was this study done?

  • Stiffening of large arteries such as the aorta has been closely linked to the onset of heart diseases, but recent studies show that this may also increase risk for dementia.
  • Understanding the brain changes which underlie this risk could help identify strategies to prevent or delay dementia in old age.

  What did the researchers do and find?

  • We investigated 542 community-dwelling older adults who received 2 measurements of aortic stiffness, first at approximately 64 years old and again at approximately 68 years old.
  • Shortly after that, at mean age 69 years, they underwent cognitive tests and brain magnetic resonance imaging (MRI) scans to assess the size, connections, and blood supply of different brain regions.
  • We observed that a faster rate of aortic stiffening during the 4 years in mid-to-late life was linked to lower blood flow and poorer markers of brain connectivity across several brain regions.
  • We also found that lower memory performance in older age was most closely linked to the first measures of aortic stiffness, taken at baseline, rather than the later measures of stiffness.

  What do these findings mean?

  • Faster stiffening of the aorta in mid-to-older ages may influence brain health, specifically, the brain’s delicate blood vessels and the connectivity between different brain regions.
  • However, in order to benefit memory in older age, strategies to prevent or slow down arterial stiffening may be required even earlier in the life span.
  • Although this was a large study, it was conducted in a relatively well-educated and largely male sample, so future research on more representative samples are needed to allow us to generalise the findings to the wider population.