Physical Activity and Gray Matter Volume Mediated by Changes in Insulin, BMI

When controlling for insulin and body mass index, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with gray matter volume was lost.

Data from the Age-Well study (NCT02977819) of cognitive unimpaired older adults showed that physical activity was directly associated with cerebral glucose metabolism, while the association with global gray matter (GM) volume was mediated by cardiovascular risk factors, and more specifically insulin and body mass index (BMI).

Although the results suggest associations between physical activity and global GM are mediated by changes in insulin and BMI, the study investigators concluded that "older adults practicing physical activity have cardiovascular benefits, through the maintenance of lower insulin and BMI, which in turn promote greater structural brain integrity. In contrast, the association with global and precuneus cerebral glucose metabolism seems to be independent from cardiovascular risk factors."

A total of 134 cognitive unimpaired older adults, at least 65 years of age, were recruited from the general population from November 2016 until March 2018. Each participant underwent structural MRI, along with a physical activity questionnaire, blood sampling, and a clinical exam including information on cardiovascular risk factors, within a 3-month period. Cardiovascular risk factors measures included insulin, cholesterol (total and high-density lipoprotein [HDL]), systolic blood pressure (SBP), BMI, and smoking habits.

Senior author Geraldine Poisnel, PhD, research engineer, Normandie University, and colleagues used multiple regressions to assess the association between physical activity, cardiovascular risk factors, and neuroimaging. At the conclusion of their analysis, they found that higher physical activity was associated with higher GM volume (ß = 0.174; P = .030) and cerebral glucose metabolism (ß = 0.247; P = .019), but not with amyloid deposition or white matter (WM) hyperintensities or WM microstructural integrity.

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Higher physical activity was also associated with lower insulin and BMI, but not with total and HDL-cholesterol, SBP, or current smoker status. When insulin and BMI were entered in the same model, they were no longer associated with physical activity, suggesting that the link of physical activity with insulin and BMI is not independent one from another. Throughout the study, investigators found consistent correlations between insulin and BMI.

"This study has strong implications as understanding how physical activity affects brain health may help developing strategies to prevent, or delay, age-related brain decline," Poisnel et al wrote.

When evaluating the association between cardiovascular risk factors and global neuroimaging measures, lower insulin and BMI were both correlated to each other. When BMI and insulin were included in the same model, the correlation of GM volume with insulin was lost, while the association with BMI remained unchanged, suggesting that the association between insulin and GM volume was driven by BMI.

Lower insulin and BMI were found to be correlated with higher GM volume, but neither was associated with cerebral glucose metabolism. The correlation of GM volume with insulin was lost when BMI and insulin were included in the same model; however, the association with BMI remained unchanged, suggesting that the association between insulin and GM volume was driven by BMI.

A secondary analysis investigated whether the effect of physical activity, cardiovascular risk factors and the mediations were present in regions specifically involved in Alzheimer disease (AD). Analyses replicated in AD-sensitive regions of interest showed that higher physical activity was correlated to higher hippocampal volume and glucose metabolism in the precuneus, but not to glucose metabolism.

There were limitations to the study, including the fact that physical activity was assessed using a subjective, self-reported questionnaire; however, this approach has been used extensively in the literature, according to study investigators. In addition, as participants were cognitive unimpaired, it seems unlikely that major recollection issue affected the questionnaire. Third, the cross-sectional nature of the design prevented the investigators from inferring causal relationship regarding the association of physical activity with GM volume and cerebral glucose metabolism.

1.Felisatti F, Gonneaud J, Palix C, et a. Role of cardiovascular risk factors on the association between physical activity and brain integrity markers in older adults. Neurology. Published online April 13, 2022. doi:10.1212/WNL.00000000000200270