Results from our study indicate that SBP is associated with injury to white-matter microstructure and regional grey matter in healthy young adults. Injury worsened continuously as SBP increased and was significantly different between normotensive and prehypertensive individuals in some regions. Moreover, the anatomical locations of these differences at fairly young ages are similar to the distribution of WMH associated with SBP late in life36
and are associated with decreased cognitive performance, albeit in the normal range.13
Previous work from the Framingham Heart Study8,10,13,37
and other studies of elderly individuals have identified cross-sectional and longitudinal associations between midlife vascular risk factors, brain atrophy, WMH, and cognitive ability late in life (panel). Our study extends these findings by showing that raised SBP has a subtle negative effect on white-matter integrity and grey-matter volume at even young adult ages, with preferential susceptibility to specific anterior white-matter tracts and grey-matter regions even before evidence of increased WMH volumes.
Evidence of even subtle brain injury at young ages should affect how physicians think about hypertension diagnoses and treatment for two important reasons. First, our evidence strongly suggests that the effect of SBP on the brain is continuous with increasing pressure, suggesting that what might be the optimum SBP will have to be reconsidered.38
Second, these data strongly suggest that substantial brain injury could precede clinically manifest disease, indicating that prevention of stroke or cognitive impairment due to hypertensive vascular disease might require treatment at younger ages than presently thought.37
Although present medical treatment recommendations have had a clear effect on mean blood pressure in the population41
and mortality from hypertension-associated vascular disease,1
the incidence and prevalence of common hypertension-associated disorders such as myocardial infarction42
have not been greatly changed, indicating further need for early diagnosis and individual treatment.
Although our data clearly show that brain injury occurs at fairly young ages, the cause is unclear. The biological mechanisms triggered by increased SBP are complex43
and cannot be addressed with these data. With ageing, artery stiffening causes SBP to increase, which con tributes to loading of stiff components of the atrial wall and subsequently increases arterial stiffness.43
This process also affects small arteries and wave reflection. One hypothesis posits that vascular dysauto-regulation due to arterial remodelling causes transient reductions in blood flow to white-matter watershed areas of vascular supply,44
resulting in transient hyporaemia, hypoxaemia, and subtle myelin injury.45
This hypothetical process, however, explains neither the specific vulnerability of anterior white-matter tracts to increases in SBP nor the diffuse grey-matter atrophy reported in our study and others.4–6,18
Understanding of the regional specificity of this association is especially important in light of a growing body of scientific literature suggesting that reduced fractional anisotropy in these regions is associated with decreased cognitive performance in individuals aged 60 years or older46,47
and similar negative associations between cognition and brain atrophy in people with raised SBP.5,6
Because arterial stiffness has been associated with cognitive impairment in elderly individuals,48
studies investigating the effect of pulse wave velocity—the gold standard measure for clinical assessment of arterial stiffness in the cerebral microcirculation—are needed, as are interventional studies with cognitive deterioration as a predefined outcome to elucidate the chronology and factors linking arterial ageing, microvascular damage, and cognitive decline.
However, we recorded no effect of SBP on WMH. As previously suggested in elderly individuals, WMH could be the final stage of broadly distributed and progressive white-matter degeneration,49
which is a process that might not be sufficiently advanced in younger individuals and would therefore be a less sensitive measure than is diffusion tensor imaging of cerebrovascular disease in this otherwise healthy young cohort.50
This view is supported by the absence of a cross-sectional association between concurrent SBP and WMH in young individuals. Midlife SBP is strongly associated with WMH burden late in life when vascular brain injury processes have progressed to an advanced stage.5,51,52
Further substantiation of this hypothesis will necessitate longitudinal study of how diffusion tensor imaging measures and WMH coevolve spatially and temporally from midlife onward.
Notably, we focused on measures of only SBP as a marker of vascular health for two reasons. First, in this fairly young cohort, DBP and SBP measures were highly correlated. Second, increased SBP is the most common form of hypertension and is a more robust risk factor for cardiovascular disease than is DBP, particularly after 50 years of age.25
Additionally, we did not specifically investigate the effects of low blood pressure on brain integrity. Although evidence suggests that reduced SBP is associated with cerebral atrophy in elderly individuals,53
this finding has not been investigated in young adults and is worthy of further research. However, our results showed an inverse monotonic relation between SBP and brain atrophy.
Our study has some limitations. First, the Framingham Heart Study cohort is mostly of white descent and therefore does not fully represent the general population of the USA.35
Second, voluntary participation in MRI studies is often biased, with the healthiest individuals being more likely to participate, particularly in samples of older adults.54
This second concern is probably mitigated by the fairly good health and young age of our study cohort. Third, our study is cross-sectional. Further longitudinal studies are needed to investigate whether duration of increased SBP has cumulative effects on white-matter integrity in young adults.
Despite these limitations, the public health implications of our results are clear. Our findings support the need for early and optimum control of blood pressure, which is presently neither routinely achieved39
nor subject to testing in many randomised controlled clinical trials.40
Whether structural brain differences associated with chronic hypertension are preventable or if they can be reversed—as in a study reporting encouraging benefits of memory training on microstructure of white matter55
—is unclear. In view of evidence that both the degree and duration of hypertension are associated with continuous adverse effects on late-life brain injury and cognition,5,6
early and aggressive treatment could be necessary for success.