Article In Brief
Among young adults with moderate to high levels of blood pressure, a gradual increase in blood pressure to middle-age may increase the risk in diffuse small vessel disease and lower brain perfusion, even after adjusting for sociodemographic and cardiovascular risk factors. Our experts say the study further supports the need to prevent blood pressure increases as early as young adulthood.
Sustained elevated levels or gradual increases in blood pressure from early adulthood to midlife are associated with decreased brain health, a new study reveals.
“Among young adults with moderate to high levels of BP [blood pressure], a gradual increase in BP to middle-age may increase the risk in diffuse small vessel disease and lower brain perfusion,” the authors concluded in the study, published in the March 10 issue of JAMA Network Open: Neurology.
The researchers found that these BP trajectory patterns led to a higher risk of cerebral pathology as measured by brain atrophy, white matter lesion volume, and cerebral perfusion—even after adjusting for sociodemographic and cardiovascular risk factors.
As a result, they suggested that “preventing blood pressure increases as early as young adulthood may be warranted.”
“Identifying early risk factors and early changes in the brain will have a major impact on future clinical and public health priorities related to the looming epidemic of dementia,” said the study's corresponding author Lenore J. Launer, PhD, chief of the Laboratory of Epidemiology and Population Sciences in the intramural research program at the National Institute on Aging in Bethesda, MD.
Dr. Launer told Neurology Today that “several studies based on older populations suggest midlife is an important period to start prevention measures. To date, control of blood pressure levels has been the most robust and promising candidate to target for prevention of future cognitive impairment.”
Although several studies have explored BP levels and risk for cognitive impairment, it was unknown whether research into trajectories from young adulthood to midlife studies could provide additional information about risk.
To investigate possible biomarkers of future risk, the researchers opted to examine the correlation between the mean arterial pressure (MAP) trajectories and the indicators of pathology visualized on MRI that are associated with cognition. They highlighted the results of the MAP measure, which integrates systolic and diastolic blood pressure.
The researchers utilized data of US adults from Coronary Artery Risk Development in Young Adults (CARDIA), a prospective longitudinal study of Black and White men and women. Participants had a baseline age of 18 to 30 years and were examined as many as eight times over 30 years, from 1985 or 1986 to 2015 or 2016.
In this cohort, the researchers found that individuals starting with higher levels of MAP, as well as those who began at lower levels of MAP and experienced a rise in MAP over the 30-year period, had significant indicators of microstructural changes in the white matter, and lower blood flow in the gray matter of the brain.
“The cohort is well characterized with relatively few dropouts,” Dr. Launer said. However, she added, “one limitation is that, because there are few such cohorts, it will be difficult to replicate the findings.” Perhaps this issue can be investigated within a health care system that has multiple measures of blood pressure, she said.
Dr. Launer noted that neurologists have been aware that high BP levels can lead to pathologic changes in the brain, measurable even in midlife, and that a progressive increase to high levels is unhealthy.
“This study shows that individuals with moderate levels of blood pressure who experience a more rapid increase in BP may have additional risk for subclinical changes in the brain that, in late life, are associated with poor cognitive function,” Dr. Launer said.
A total of 885 participants completed brain MRIs during examinations occurring during the 25th or 30th year of the study. Analyses were performed November 2019 to December 2020.
Using group-based trajectory modeling, the researchers identified five 25-year blood pressure trajectories for three blood pressure traits in the total CARDIA cohort of participants with three or more blood pressure measures.
After excluding individuals for missing covariates—diabetes diagnosis, antihypertensive medication use, smoking status, and no intracranial volume measure on MRI—the researchers applied these measures to analyses of a subset of 853 participants in the brain MRI substudy.
The researchers evaluated MAP as an integrative measure of systolic and diastolic blood pressure. Using a linear regression model, they analyzed associations of the BP trajectories with brain structures with sequential adjustments for demographics, cardiovascular risk factors, and use of antihypertensive medications.
Brain MRI outcomes consisted of total brain, total gray matter, normal-looking and abnormal white matter volumes, gray matter cerebral blood flow, and white matter fractional anisotropy.
The mean age of the 853 participants was 50.3 years; just under half were men, 41.5 percent were Black, and 58.5 percent were White. The MAP trajectory distribution showed 21.1 percent had a low-stable BP trajectory, 43.5 percent had moderate-gradual increasing BP, 8 percent had moderate-increasing BP, while 23.1 percent had an elevated-stable BP, and 4.3 percent had elevated-increasing blood pressure.
In a comparison with the MAP low-stable trajectory group, participants in the moderate-increasing and elevated-increasing groups were more likely to have higher abnormal white matter volume.
Individuals in the MAP elevated-increasing group exhibited lower gray matter cerebral blood flow after the researchers adjusted for socio-demographics and cardiovascular risk factors. After they adjusted for antihypertensive medication use, the difference was consistent for abnormal white matter volume. However, the results were no longer significant for gray matter cerebral blood flow.
Neurologists interviewed by Neurology Today expressed mixed opinions about the novelty and practical implications of the study.
Ashutosh P. Jadhav, MD, PhD, a vascular and interventional neurologist in the department of neurosurgery at the Barrow Neurological Institute in Phoenix, thought the study was important. “It highlights the role of blood pressure control and surveillance at a young age as it pertains to long-term cerebral pathology, brain health, and eventual implications for developing vascular-related cognitive impairment.”
While elevated BP has been well-established as a risk factor for vascular diseases, including heart attack and stroke, most studies have focused on static data points, often in patients presenting with a vascular event, Dr. Jadhav said.
Yet, in this case, the authors use a prospective longitudinal study examining blood pressures over a 30-year time period in previously healthy volunteers. “This approach allows for a trajectory-based pattern analysis of mean arterial blood pressure over time and the risk of developing cerebral pathology,” he said.
The utilization of a unique prospective longitudinal data set is a major strength of this study, underlining the importance of understanding trends over time rather than evaluating outcomes based on a single measurement, Dr. Jadhav noted. However, he added that “capturing longitudinal data over several decades is challenging and can lead to incomplete data and limited sample size. The authors, for example, have limited data to analyze the impact of sex or race on trajectories and brain health.”
A novel feature of this study is the use of a radiographic endpoint—imaging features of cerebral pathology—rather than cognitive testing. “Imaging surrogates for clinical outcomes can be powerful as they can allow a more objective measurement of disease progression within the same individual and between individuals over large data sets,” Dr. Jadhav said.
The overall study of 853 participants is “reasonably sized” particularly since the longitudinal follow-up spans two to three decades, said David S Liebeskind, MD, FAAN, FAHA, FANA, FSVIN, FWSO, professor of neurology, director of the neurovascular imaging research core, and director of the UCLA Stroke Center at the University of California, Los Angeles.
But the findings are “of incremental novelty,” said Dr. Liebeskind. “We've known that elevated blood pressure over time is a predisposing risk factor for small vessel disease and brain health,” he said.
That means physicians in general, including neurologists, should be paying attention to their patients' blood pressure readings. “Even subtle changes over time have important impacts on brain health,” he said.
In critiquing the study, Dr. Liebeskind noted that some BP trajectory groups who were stratified were much larger than others. For instance, 43.5 percent of participants were in the moderate-gradual group, whereas only 4.3 percent constituted the elevated-increasing group.
Then the researchers focused on comparing “the extremes”—how the moderate-increasing and elevated-increasing groups fared in relation to the low-stable trajectory group. It is not surprising that participants in the moderate-increasing and elevated-increasing groups were more likely to have higher abnormal white matter volume, Dr. Liebeskind said.
A new finding revealed that blood flow was lower in the elevated-increasing group, he said, but “you have to take that with a grain of salt because, once again, it's only 4 percent of the overall study population. This specific finding was no longer significant once confounding variables were considered.”
In addition, Dr. Liebeskind pointed out that the researchers used a special type of arterial spin labeled perfusion MRI, but one of the limitations of this technique is that it principally measures the superficial cortical regions, which are not located in the same area as the abnormal white matter volume being quantified.
Some associations observed in the study no longer existed after the researchers adjusted for vascular risk factors or use of blood pressure medications, but concerns remain that blood pressure trajectories may have played a role, said Hugo J. Aparicio, MD, MPH, assistant professor of neurology at Boston University School of Medicine and a vascular neurologist in the Stroke and Cerebrovascular Center at Boston Medical Center.
Dr. Aparicio praised the CARDIA study investigators for following a cohort of relatively younger participants over a long period of time. It also recorded detailed blood pressure measurements at interval examinations over a 30-year period, which is valuable in understanding how participants could be grouped according to blood pressure trajectories early in life.
However, Dr. Aparicio pointed out some limitations of the study. For instance, only a subset of the participants was able to undergo brain MRI in the later interval examinations, and these individuals tended to be healthier than the overall group. There also were fewer Black participants in the brain MRI substudy, which may have affected the final results and rendered them less representative of how BP trajectories can have an impact on brain imaging measures of vascular injury and aging in the general population, Dr. Aparicio said.
“As we continue to see further supportive evidence that early exposure to vascular risk factors, such as blood pressure, contribute to poor brain health overall, even as early as midlife, it seems clear that patients, physicians, families, public health officials, and communities need to come together to figure out how to improve the main drivers of vascular health,” he said. Such initiatives “may include a healthy diet, physical activity, access to health care, social networks that reinforce healthy lifestyle behaviors, or public health education efforts focused on early adults to improve brain health.”