Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College

Dr. Ishii reports no financial relationships relevant to this field of study.

SYNOPSIS: In this prospective longitudinal study investigating the potential mechanistic link between adiposity and vascular cognitive impairment, anthropometric and metabolic hormone adiposity predictors were differentially associated with cerebrovascular and brain volumetry outcomes by sex in older individuals.

SOURCE: Arnoldussen IAC, Gustafson DR, Leijsen EMC, et al. Adiposity is related to cerebrovascular and brain volumetry outcomes in the RUN DMC study. Neurology 2019;93:e864-e878.

With a rapidly aging population and no effective interventions for late-onset dementia, there is a strong interest in identifying modifiable dementia risk factors. Obesity in midlife is associated with an increased risk of cerebrovascular events and late-onset dementia; however, the mechanisms linking obesity to vascular cognitive impairment have not been entirely elucidated. Therefore, the study investigators examined in a prospective longitudinal study (the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort, RUN DMC) whether anthropometric adiposity predictors and metabolic adiposity hormones were associated with cerebral small vessel disease (CSVD) markers and brain volumetry measures.

Adults without dementia were recruited from consecutive patients referred to the Department of Neurology at Radboud University (Netherlands) between October 2002 and November 2006 because of CSVD symptoms, including transient ischemic attack, lacunar syndromes, and subacute manifestations (e.g., cognitive and gait disturbances). Study participants were evaluated at baseline and nine-year follow-up. Anthropometric measures of adiposity including body mass index (BMI) and waist circumference (WC) were obtained at baseline and follow-up visits, while adiposity hormones leptin and adiponectin were measured in the serum only at the baseline visit. The investigators obtained 1.5T MRI scans at both visits and analyzed for CSVD markers and regional brain volumes. Dementia screening using DSM-IV criteria was performed at the follow-up visit. Multivariable regression analyses examined the cross-sectional and longitudinal associations between adiposity and brain MRI measures.

A total of 503 subjects were recruited at baseline (56.5% male; mean age 65.6 ± 8.8 years); 209 subjects were lost to follow-up. At the follow-up visit, 65 subjects were diagnosed with dementia. In cross-sectional analyses, there were significant sex differences in the association of adiposity measures with CSVD outcome measures. In men, leptin was protective for CSVD outcomes (lower white matter intensities [WMH] and lower odds of lacunes) at baseline, while obese WC decreased the odds of microbleeds and lacunes at the nine-year follow-up. In women, having high BMI or an obese WC was associated with the presence of lacunes at the follow-up visit.

For cross-sectional analyses of brain volumetry outcomes, higher adiposity measures were associated with lower brain volumes when men and women were pooled together for the analyses. However, there were significant sex differences, with men having stronger associations than women. At baseline, in men, higher BMI, WC, and leptin levels were associated with lower grey matter volumes [GMV] and total brain volumes [TBV], and increasing BMI and WC were associated with lower hippocampal volumes [HV]. At the follow-up visit, cross-sectional analyses found higher BMI was associated with lower GMV in men. These associations were not significant for women.

Longitudinal analyses of baseline adiposity predictors found no significant associations with CSVD or brain volumetry outcomes. However, a baseline obese WC was associated over nine years with decreasing HV in men but not women and increasing WMH when men and women were pooled together. Finally, there were no associations between adiposity measures and dementia.

COMMENTARY

The RUN DMC study investigators sought to address several important questions regarding the mechanistic link between adiposity and dementia focusing on brain imaging measures of CSVD and regional volumes. Despite conflicting results, there were several notable findings. First, significant sex differences were found, including some findings that were contradictory between men and women. For example, adiposity measures were protective for CSVD outcomes in men but detrimental in women. Furthermore, higher adiposity measures were significantly associated with lower brain volumes in men but not in women. The reasons for the sex differences are not clear and require verification in additional cohorts. Also, in men, adiposity predictors had a detrimental effect on regional brain volumes despite the protective effect on CSVD outcomes. This suggests that there is not a simple direct relationship between CSVD and brain volume. In addition, adiposity may be beneficial in some circumstances but detrimental in others. One intriguing possibility is that the association between adiposity predictors and brain outcomes may be dependent on age, as other studies have found that midlife obesity is associated with reduced GMV and increased dementia risk, whereas later-life overweight and obesity are associated with decreased dementia risk. Unfortunately, the current study does not allow for the evaluation of life-course trajectories necessary to test this hypothesis. Finally, none of the adiposity measures were associated with dementia, but this may be due to the relatively small number of individuals who developed dementia during the follow-up period.

The overall study design is strong with a relatively large number of well-characterized participants and outcome measures at baseline and after nine-year follow-up; however, there are several limitations. First, blood was not collected at follow-up to study the longitudinal effects of leptin or adiponectin. Second, sociodemographic and health status information were not updated at follow-up. Third, the findings from this study may not be generalizable, as all participants were diagnosed with CSVD and from Northern European ancestry. Fourth, no cognitive measures were investigated. Additionally, the investigators found differential loss to follow-up due to death, where those individuals who died during follow-up had at baseline higher adiposity predictors, more cardiovascular risk factors, lower brain volumes, and worse CSVD outcome measures, suggesting survival bias. While the results from the RUN DMC study are conflicting at times and more questions were generated than answered, the authors highlighted the critical need for additional well-designed investigations looking into the relationship between adiposity and dementia, with a particular emphasis on sex differences.