Exercise at Midlife Linked to Better Brain Health in Late Life

Higher levels of leisure-time physical activity in midlife are associated with a lower risk for cerebrovascular problems in later life, an analysis of data from a prospective cohort study suggests.

Persistently high levels of physical activity at midlife were associated with more intact white matter integrity and fewer lacunar strokes later in life, the authors report, although there was no such association with gray matter volumes. The results suggest that physical activity may affect cognition through effects on small-vessel disease, they add.

"Most prior studies have measured physical activity at one time point in older adulthood," Priya Palta, PhD, assistant professor of medicine and epidemiology at Columbia University Irving Medical Center, New York City, told Medscape Medical News. "Our study adds new knowledge, since it measured participant physical activity levels at multiple times in adulthood, which is important, given the changes in activity levels throughout one's life due to normal aging, work and retirement, and illness and injury."

The findings were published online January 6 in Neurology.

Research has indicated that moderate and high levels of physical activity during midlife are associated with lower levels of cognitive decline and a reduced risk for dementia. But randomized controlled trials that have investigated the benefits of exercise for brain health have produced mixed results, the authors note. Many of these trials had small sample sizes and were of short duration, and they did not examine physical activity throughout participants' lives.

To examine this question longitudinally, Palta and colleagues analyzed data from the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study of 15,792 community-dwelling adults who were between the ages of 45 years and 64 years in the period of 1987 to 1989.

MRI Analyses

The researchers focused on the 6538 participants who attended the fifth examination of ARIC between 2011 and 2013. These participants had more education and higher income, and the prevalence of diabetes, hypertension, smoking, and cardiovascular disease was lower at baseline than it was for those who died or were lost to follow-up.

Of this group, 1963 participants underwent MRI. The mean age at which MRI was conducted was 76.2 years. Participants who underwent MRI were older, more likely to be Black, had lower body mass index (BMI), and were less likely to have ever smoked. In addition, the prevalence of coronary heart disease was lower for these participants. The researchers excluded from analysis participants who attended visit 5 but did not undergo MRI.

Leisure time physical activity (LTPA) was measured at visits 1, 3, and 5 using the Modified Baecke Physical Activity Questionnaire, which solicits reports about physical activity during the previous year. Palta and colleagues assigned the activities metabolic equivalent of task (MET) values and calculated participants' MET-minutes per week. They also categorized participants as meeting or not meeting the 2008/2018 United States Physical Activity Guidelines of at least 150 minutes of moderate to vigorous physical activity (MVPA) per week.

The study outcomes were structural brain MRI measures. The investigators used the images to calculate regional cortical volumes and assess cerebrovascular lesions, white matter disease, white matter integrity (as measured by mean fractional anisotropy [FA] and mean diffusivity [MD]), and gray matter volumes.

The data were controlled for factors that included age, sex, education, race, APOE genotype, and smoking. Education was characterized as less than high school, high school or equivalent, and greater than high school. Smoking was categorized as ever or never. All covariates were assessed at the baseline ARIC visit.

White Matter Microstructure

The authors included 1604 participants in their analysis. The mean age of the participants was approximately 51 years, and about 63% of participants were women. Approximately 21% of participants were Black.

In midlife, 34% of participants reported no MVPA, 11% reported low MVPA, 16% reported middle MVPA, and 39% reported high MVPA. Participants who did not participate in physical activity were more likely to be Black and female and were more likely to have less education. In addition, their cardiometabolic risk profile was worse.

About 68% of participants "had persistent patterns in meeting physical activity guidelines" at visits 1 and 3. Of this group, 35.6% persistently met the guidelines, and 64.4% persistently failed to meet the guidelines.

Participants with high MVPA in midlife had a 32% lower risk for lacunar infarcts and a nominally lower risk for cortical infarcts or subcortical microhemorrhages in late life, compared with participants with no MVPA in midlife. In addition, among the former participants, white matter microstructural integrity was greater in late life (mean FA difference, 0.13 SD; mean MD difference, −0.11 SD). Among participants with middle MVPA, white matter microstructural integrity was also greater (mean FA difference, 0.23 SD; mean MD difference, −0.20 SD).

Among participants who reported middle MVPA in midlife, gray matter volume was greater than it was for participants who reported no MVPA. The investigators found no difference in gray matter volume, however, between participants with high MVPA and those with no MVPA.

High levels of physical activity in late life were associated with fewer cerebrovascular lesions, less white matter disease, and larger gray matter volumes in late life. However, after adjustment for comorbid vascular risk factors, such as BMI and hypertension, the effect estimates for physical activity in late life were no longer significant.

In addition, adjusting for vascular risk factors attenuated the association between midlife physical activity and lacunar infarcts.

"This evidence suggests that the association of physical activity with vascular risk factors may be partially responsible for any potential effect on cerebrovascular injury," Nicole L. Spartano, PhD, research assistant professor of medicine at Boston University School of Medicine, Boston, Massachusetts, and Leonardo Pantoni, MD, PhD, professor of biomedical and clinical sciences at the University of Milan, Milan, Italy, write in an accompanying editorial.

Adjusting the data for vascular risk factors did not affect the association between midlife physical activity and white matter microstructure.

"Therefore, evidence from this study supports a hypothesis that the mechanisms linking physical activity and the brain are likely multidimensional, including mechanisms other than simply improving cerebrovascular health," write Spartano and Pantoni.

Underestimated Association?

The rate of attrition between visits 1 and 5 of ARIC was approximately 60%. "We expect individuals who are not examined to be less healthy than those who remain in the study," said Palta. "The association we reported here likely is a conservative estimate of the association between physical activity and measured brain outcomes. If 100% of participants had been re-examined, the associations we calculated would likely be stronger."

The lack of effective pharmacologic treatments for dementia underscores the importance of physical activity, a modifiable behavior, which benefits brain health. "If [our] findings are confirmed by clinical trials, this would enable neurologists to prescribe physical activity to promote brain health beginning in midlife," said Palta.

"Further research needs to be conducted on other types of behaviors that individuals engage in during the day, including sedentary behavior, such as television watching or reading, and the role of light physical activity, such as housework, child care, or nonexercise walking," she added. "In addition, the recommended amount of physical activity and necessary intensity level of physical activity to promote brain health have not been identified and require further study."

Dr Michelle Mielke

"A major strength of the study is the assessment of physical activity in both mid- and late life," said Michelle M. Mielke, PhD, professor of epidemiology and neurology at the Mayo Clinic College of Medicine, Rochester, Minnesota, commenting for Medscape Medical News. "Many previous studies retrospectively collected data on midlife physical activity from those in later life, which is largely affected by recall bias and cognitive status."

Some potential confounders could not be assessed. For example, people who exercise regularly may have a healthier lifestyle in general, which would reduce their risk for cerebrovascular disorders.

"One aspect that was not examined in this study was sex differences," Mielke added. Women historically have had less access to sports and have been less likely to exercise than men. In midlife, more female ARIC participants reported not exercising than male participants.

"Previous studies have shown sex differences in white matter integrity and the prevalence of infarcts. Understanding which risk factors are most important for men and for women will provide the best individualized preventive approach for brain health," Mielke said.

Dr Fredrik Piehl

"The study by Palta and coworkers adds to a growing body of evidence supporting neuroprotective effects mediated by physical exercise," Fredrik Piehl, MD, PhD, professor of neurology at Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News. The study is interesting for its size, its long follow-up, and its reliance on a community-based sample, he added.

"Further studies will be needed to incorporate a molecular perspective, such as inflammatory or exercise-related markers. This [approach] could unravel in more detail the underlying mechanisms and perhaps also help in stratifying patients better than with self-reported physical activity, as done here."

ARIC is supported by contracts with the National Heart, Lung, and Blood Institute. Palta received a grant from the National Institute on Aging. Spartano has received research support from the National Institutes of Health, the Alzheimer’s Association, and the American Heart Association. Pantoni serves on the editorial board for the journals Stroke, Cerebrovascular Diseases, European Stroke Journal, Acta Neurologica Scandinavica, and Neurological Sciences. Mielke and Piehl have disclosed no relevant financial relationships.

Neurology. Published online January 6, 2021. Abstract, Editorial

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