A research team led by the Borzage Laboratory at Children’s Hospital Los Angeles tested a new functional magnetic resonance imaging (fMRI) analysis method to measure cerebrovascular health in aging adults. What they found was unexpected and validated the usefulness of this method for measuring neurovascular aging in childhood diseases.

The researchers measured the cerebrovascular reactivity of the brains of 53 men and women between the ages of 51 to 83. Cerebrovascular reactivity is the ability of the blood vessels in the brain to dilate in response to a stimulus. The fMRI method they used—known as blood oxygen level dependent-cerebrovascular reactivity (BOLD-CVR)—measures the ability of the brain’s vessels to flexibly regulate blood flow in response to changes in carbon dioxide levels.

“How well the vessels react reveals a lot about your brain health,” says lead author Bethany Sussman, Ph.D., Research Scientist, Neonatology, at CHLA. “If a certain part of the brain can’t perform that function very well, that area is likely more susceptible to stroke.

“Our study had a surprising finding, previously unreported in neuro-MRI literature. There was an improvement in brain health in postmenopausal female participants, most prominently in the areas associated with movement, memory, and connections throughout the brain (subcortical gray matter, bilateral hippocampi, and white matter),” says Dr. Sussman.

“We expected that the CVR in female participants would either decrease with age or not show a difference, compared to male participants. We certainly did not expect an increase in cerebrovascular reactivity in female participants with age.”

Dr. Sussman presented the results at the International Society for Magnetic Resonance in Medicine conference in May. The study, “Sex Differences in the Neurovascular Health of Aging Adults,” was published in Stroke.

Vascular health as a proxy for brain health

“I’m interested in a type of research called individual differences—how human variability contributes to brain health,” says Dr. Sussman.

“In some ways, aging adults are very similar to children if you consider the entire lifespan. We wanted to verify that we could study these mechanisms in adults first to work out any challenges before starting a study in children.”

The researchers were part of the Mechanisms of Aortic arch Stiffness and Brain Insult (MASBI) study, which collected new data about an ongoing longitudinal dataset from the Health and Aging Brain Study-Health Disparities (HABS-HD) project that studies brain and overall health in aging among different communities.

The study enrolled adults, excluding people who had an earlier heart attack or stroke. This (MASBI) cross-sectional research took a snapshot of a group of people so the study couldn’t give insights into individual outcomes yet.

“Looking at the variables of age and sex in combination, did the female participants in this study age differently?” asked Dr. Sussman. “Realistically, people generally don’t have only high blood pressure or heart disease as a single condition.”

Earlier studies by other groups had linked changes in the hippocampi and cortical tissue of aging adults with higher cardiovascular risk and found poorer CVR—or less reactivity—in the brains of people with mild cognitive impairment compared to those of healthy adults.

Potential explanations

So what was going on? “The data set provided different variables about the volunteers’ health, medications, socioeconomic status, and demographics, like whether they were single, married, or retired,” says Dr. Sussman. “I thoroughly investigated other variables in the data to see if there was another explanation for why this was occurring. No other variables explained the results.”

One possibility was hormonal changes in menopause. Another is the cessation of cyclical anemia. Menstruation is the most common cause of anemia in menstruating individuals. “But after menopause, any cyclical anemia associated with menstruation that might damage blood vessels stops,” Dr. Sussman adds. Future work will investigate blood hemoglobin levels between women and men.

“We didn’t see an iron deficiency in either men or women, but we also don’t know their iron levels before this study,” she says.

CHLA-led studies explore understudied areas

CHLA is gaining international recognition for pediatric vascular research, notes Matthew Borzage, Ph.D., Faculty Researcher and Investigator in the Fetal and Neonatal Institute at CHLA, and the paper’s co-author. Aside from his lab’s work in imaging infants and adults, CHLA researchers collaborate across disciplines to investigate the placenta (Vidya Rajagopalan, Ph.D.) and cardiac imaging (John Wood, MD, Ph.D., and David Warburton, OBE).

The Borzage Lab is conducting ongoing pediatric studies that use advanced MRI techniques to identify circulation in the brain from birth to 18 years, and is planning an R01 grant with Shana Adise, Ph.D., at CHLA to investigate brain circulation before and after menstruation starts.

“This was an extremely large sample of patients for a study of this nature,” says Dr. Borzage. “This is a potentially huge finding. Dr. Sussman has deployed the best analysis and preprocessing that we’ve seen. We validated this method of looking at stroke risk across the lifespan.

“Now that we’ve used it to evaluate a population of adults, we’re going to start using this tool for kids, because diseases like diabetes, brain tumors, chemotherapy, and moyamoya all cause rapid vascular aging in children.”