No Protective Effect of Cognitive Reserve in Vascular Brain Injury

Cognitive reserve, through which normal cognition is preserved despite pathologic brain changes, does not protect cognitive function for patients with vascular brain injury, new research shows.

In a cross-sectional study, vascular brain injury was associated with a 0.35-point reduction in the Montreal Cognitive Assessment Tool (MoCA) and a 2.19-point decrease in score on the Digit Symbol Substitution Test (DSST).

However, neither the association of vascular brain injury with MoCA score nor with DSST score was modified by a cognitive reserve composite score.

"Although we did not find strong evidence for effect modification, we did find that lifestyle and social factors were independently associated with higher cognition, regardless of the presence of MRI-defined vascular brain injury," investigators led by Eric E. Smith, MD, medical director of the Cognitive Neurosciences Clinic at the University of Calgary, in Calgary, Canada, write.

The findings were published online September 9 in Neurology.

Two Large Cohorts

Many studies have shown that among older patients who have markers of Alzheimer's disease pathology, including beta amyloid, cognitive reserve is protective. However, fewer studies have assessed patients at midlife or have assessed cognitive impairment resulting from cerebrovascular pathology, such as white matter hyperintensity (WMH).

For the study, investigators analyzed cognitive reserve, vascular brain injury, and cognition in patients who participated in two large, population-based studies.

The Canadian Alliance for Healthy Hearts and Healthy Minds (CAHHM) combined several prospective, longitudinal studies. Participants were aged 35 to 69 years and were recruited from 2013 to 2019 at 14 sites.

The Prospective Urban and Rural Epidemiology MIND (PURE-Mind) study examined factors that influence health. Participants were from 26 countries, were between the ages of 35 and 81 years, and were without a history of stroke, dementia, or other central nervous system disease.

The CAHHM study was designed to record the same data elements as the PURE-Mind study so that the two investigations could be analyzed together. At enrollment, investigators recorded demographic information, medical history, lifestyle, cognition, and MRI imaging for all participants.

Cognitive Reserve Markers

The current investigators reviewed the literature in order to define cognitive reserve. The markers they chose to evaluate were education, involvement in social groups, marital status, level of stress, height, and level of physical activity during leisure time.

Patients were categorized as having university education or less and as participating in an organized social group or not. Moderate to severe stress was distinguished from low stress and was measured by self-report.

Height, which is a potential proxy for early life development, was dichotomized as greater than or less than 176 cm for men and 163 cm for women. Leisure-time physical activity was assessed on the basis of self-report and was classified as moderate to high (>4 h/w) or low (≤ 4 h/w).

Participants underwent cognitive assessment with the MoCA and DSST. The investigators grouped MoCA questions into the domains of memory, executive function, visuospatial function, language, attention, and orientation.

Participants also underwent T1- and T2-weighted MRI at either 1.5 T or 3 T. A central laboratory reviewed the scans and identified covert brain infarcts (CBIs) and WMH, which was rated using the Fazekas scale. High WMH was defined as a Fazekas score of 4–6.

The investigators included 10,916 participants (mean age, 58.1 years) in their analysis. Of this group, 55.8% were women, and 68.5% had a college or university education.

The prevalence of CBI in the population was 5.6%, and the prevalence of high WMH was 6.3%. About 73% of participants had a MoCA score of ≥26, indicating normal cognition. The mean MoCA score was 26.7. The mean DSST score was 71.5.

In the researchers' adjusted analysis, high WMH was associated with a significant 0.34-point reduction in MoCA score (P < .001) and a 2.11-point reduction in DSST score (P < .0001).

Similarly, nonlacunar CBI was associated with a 0.49-point decrease in MoCA score (P < .001) and a 4.22-point decrease in DSST score (P < .0001).

Among the variables related to cognitive reserve, education had the strongest association with cognition in the adjusted analysis. College or university education was associated with an increase in MoCA score of >1 point (P < .0001) and an increase of approximately 5 points in DSST score (P < .0001).

Of the other variables, participating in social groups, being married, and being taller were associated with a higher MoCA score and a higher DSST score. Greater amount of leisure-time physical activity also was associated with a higher DSST score.

However, the links between vascular brain injury and MoCA score and DSST score were not modified by the cognitive reserve composite score. Sensitivity analyses did not change these findings.

"Our data suggest that enhancing cognitive reserve through better early-life education, physical activity, and social engagement may potentially help improve cognition ― but is not likely to mitigate the deleterious effects of covert cerebrovascular disease," the researchers write.

Generalizable Results?

Commenting on the findings for Medscape Medical News, Beth Shaaban, PhD, MPH, visiting assistant professor in the Department of Epidemiology at the University of Pittsburgh, Pittsburgh, Pennsylvania, said the research adds to the evidence that early-life factors such as education set the stage for late-life cognitive health.

Dr Beth Shaaban

"But the larger need is for policy-level interventions to ensure access to high-quality education for all children, regardless of the country they live in, their ethnicity, gender, etc," said Shaaban, who was not involved with the research.

The results are consonant with existing evidence that physical activity and social activities support good cognitive performance, even in the presence of brain pathology, she added.

Shaaban noted that an advantage of the study was its inclusion of participants of various ethnicities from urban and rural locations in multiple countries. This makes the results "generalizable to a broader world population than is typical of neuroimaging studies," she said.

Interestingly, the study population's age range was wider than in many previous studies of vascular brain injury and cognitive reserve, she pointed out.

"Inclusion of people in midlife is important because we know that brain pathology accumulates slowly beginning in midlife, and midlife cardiovascular risk factors are more strongly associated with late-life cognitive impairment than late-life cardiovascular risk factors," she said.

However, Shaaban noted that the investigators did not include certain measures of brain integrity, such as brain function measures and measures of amyloid-beta, tau, gray matter volume, and cortical thickness. In addition, multimodal studies are needed to explain how patients maintain cognitive performance despite brain pathology.

Shaaban added that although the use of visual ratings in measures of vascular brain injury was appropriate, given that data from MRIs of different magnet strengths were combined, "newer approaches use automated methods to obtain WMH volume."

These approaches have more variance, are more sensitive overall, and are more sensitive to change over time compared with the investigators' dichotomized visual rating scale, Shaaban noted. However, in these approaches, it is not advisable to combine data from 1.5-T and 3-T MRI scanners, she added.

Shaaban also noted that the association between greater cognitive reserve and better cognitive performance remained throughout all the current investigators' analyses.

"What is interesting is that, based on their regression models, just one additional point of cognitive reserve composite score nearly offsets the negative association of vascular brain injury with the MoCA. Two additional points of cognitive reserve composite score would more than offset the negative association of vascular brain injury with DSST score," she said.

Although many studies do not investigate additive interaction, the current results suggest that testing for independent associations, interaction on the additive scale, and multiplicative interaction could be useful, said Shaaban.

"Testing more of a sum score for covert cerebrovascular injury may also be useful," she added.

CAHHM was funded by the Canadian Partnership Against Cancer, the Heart and Stroke Foundation of Canada, and the Canadian Institutes of Health Research. The PURE study was funded by the Population Health Research Institute, the Hamilton Health Sciences Research Institute, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Ontario. Smith and Shaaban have reported no relevant financial relationships.

Neurology. Published online September 9, 2021. Abstract

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