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, 11 (19), 8573-8586

High Body Mass Index, Brain Metabolism and Connectivity: An Unfavorable Effect in Elderly Females


High Body Mass Index, Brain Metabolism and Connectivity: An Unfavorable Effect in Elderly Females

Arianna Sala et al. Aging (Albany NY).


There are reported gender differences in brain connectivity associated with obesity. In the elderlies, the neural endophenotypes of obesity are yet to be elucidated. We aim at exploring the brain metabolic and connectivity correlates to different BMI levels in elderly individuals, taking into account gender as variable of interest.We evaluated the association between BMI, brain metabolism and connectivity, in elderly females and males, by retrospectively collecting a large cohort of healthy elderly subjects (N=222; age=74.03±5.88 [61.2-85.9] years; M/F=115/107; BMI=27.00±4.02 [19.21-38.79] kg/m2). Subjects underwent positron emission tomography with [18F]FDG. We found that, in females, high BMI was associated with increased brain metabolism in the orbitofrontal cortex (R=0.44; p<0.001). A significant BMI-by-gender interaction was present (F=7.024, p=0.009). We also revealed an altered connectivity seeding from these orbitofrontal regions, namely expressing as a decreased connectivity in crucial control/decision making circuits, and as an abnormally elevated connectivity in reward circuits, only in females. Our findings support a link between high BMI and altered brain metabolism and neural connectivity, only in elderly females. These findings indicate a strong gender effect of high BMI and obesity that brings to considerations for medical practice and health policy.

Keywords: PET; body mass index; brain; connectivity; gender.

Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest.


Figure 1
Figure 1
Gender-specific voxel-wise correlation between BMI levels and brain metabolism. (A) A significant positive correlation was found in orbitofrontal regions (partial R=0.44) in females. Statistical threshold was set at p<0.001 (uncorrected for multiple comparisons), with minimum cluster extent Ke:100 voxels (yellow). For visualization purposes, figure also shows voxels where correlation is significant at a more liberal threshold (p<0.01 uncorrected for multiple comparison; red). For both p<0.001 and p<0.01 voxel-level thresholds, only clusters surviving p<0.05 FWE-correction are shown. BrainNet Viewer ( was used for rendering [52]. (B) Scatter plot shows the significant BMI by gender interaction on orbitofrontal metabolism, with females showing a significant positive correlation between BMI levels (x axis) and average SPM-T values of glucose metabolism (y axis) (R=0.31, p<0.001; partial R=0.44, p<0.001) and males showing no correlation at all (R=-0.07, p=0.492; partial R=-0.01, p=0.881). Positive SPM-T values indicate higher-than-average mean orbitofrontal glucose metabolism: in females, higher BMI levels are associated with increased orbitofrontal glucose metabolism, crucially approaching critical hypermetabolism levels in the case with highest BMI levels (BMI ≈ 40kg/m2). Shaded areas represent confidence intervals for the regression line slope in each group. (C) Scatter plot shows the lack of a significant BMI by age interaction on orbitofrontal metabolism, despite of a significant principal effect of age (partial R=0.32, p<0.001), in the female cohort. The slope of the regression lines in the different (normal, overweight and obese) BMI groups does not differ: there is no significant interaction effect between age and BMI, but both age and BMI have an independent effect on orbitofrontal metabolism. Age (years) is plotted on the x axis and metabolism on the y axis. Shaded areas represent confidence intervals for the regression line slope in each group.
Figure 2
Figure 2
Gender-specific ROI-based correlations between BMI levels and regional metabolism. Graph shows significant correlations between BMI levels (x axis) and average SPM-T values of glucose metabolism in a series of a priori selected ROIs (y axis), in the female cohort. Positive SPM-T values indicate higher-than-average brain glucose metabolism in each ROI, as obtained through comparison with a reference control sample [see text]. Higher BMI levels are associated with increased glucose metabolism. Only ROIs where correlation is significant after Bonferroni correction are shown. Gray shaded areas represent confidence intervals for the regression line slope.
Figure 3
Figure 3
Results of the data-driven metabolic connectivity analysis in females. Figure shows results of the data-driven metabolic connectivity analysis, seeding from the BMI-related orbitofrontal cluster identified through whole-brain correlation analysis (see Figure 1 and text). The pattern of connectivity of the orbitofrontal cluster in females with normal BMI (upper panel) remarkably differs from the one observed in females with high BMI (lower panel) (A). In females with high BMI, loss of connectivity is evident between orbitofrontal cortex and high-order cortical regions, notably the dorsolateral prefrontal cortex (red arrows). Interconnections with reward-related brain circuits are also present (lacking in females with normal BMI), specifically involving the medial orbitofrontal cortex and nucleus accumbens (red arrows). Threshold for statistical significance was set at p<0.001 (uncorrected for multiple comparisons), minimum cluster extent k:100 voxels. Only clusters surviving SPM cluster-level FWE-correction (p<0.05) are shown Significant differences in connectivity strength between females with high BMI and females with normal BMI are also shown (p<0.01, uncorrected for multiple comparisons; p<0.05 at cluster-level; Ke: 100 voxels) (B). A high-resolution MRI anatomical template in MRIcron was used for rendering.

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