Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study

Abstract

Background: Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life.

Methods: In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders.

Findings: 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann's area 48 on the medial surface of the temporal lobe and Brodmann's area 21 of the middle temporal gyrus.

Interpretation: Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure.

Funding: National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.

Figure 1. Regions of the cerebral white matter in which systolic blood pressure (A, B) and age (C, D) are associated with decreased fractional anisotropy and increased mean diffusivity

The voxel-based regression included diffusion tensor imaging measures (fractional anisotropy or mean diffusivity) as the dependent variable, and age and systolic blood pressure as independent variables. Number of cigarettes smoked per day, hypertension treatment (presence or absence), intracranial volume, and sex were covariates.

Figure 2. Regression analyses for brain areas in which associations between variables were significant and box plots showing comparisons between hypertension categories after adjustment for age

N=normotensive. P=prehypertensive. H=hypertensive.

Figure 3. Cerebral regions in which decreasing grey-matter volumes were significantly associated with increasing systolic blood pressure (A) and age (B)

The voxel-based regression included grey-matter probability as the dependent variable and age and systolic blood pressure as independent variables. Number of cigarettes smoked per day, hypertension treatment (treated or not), intracranial volume, and sex were covariates.

Figure 4. Regression curves relating brain integrity as expressed by the first principal component as a function of the hypertension category and age of the individual (A) and the difference in brain ageing increase between hypertension categories according to age (B)

Red dotted lines indicate brain integrity of a 40-year-old by hypertensive status; brain integrity of a 40-year-old prehypertensive individual corresponded to that of a normotensive individual 3·3 years older, but this difference was 7·2 years for hypertensive individuals. N=normotensive. P=prehypertensive. H=hypertensive.

Figure 5. Number of patients with white-matter hyperintensities at a voxel location