Here, we show in healthy subjects a significant negative correlation between BMI and baseline brain glucose metabolism in prefrontal regions and in the anterior cingulate gyrus. We also document a negative association between prefrontal metabolism and performance on tasks of executive function and verbal learning. In contrast, regional brain activation during cognitive stimulations was not associated with BMI nor with the neuuropsychological measures.
The negative association between BMI and prefrontal metabolism (BA 9, 10, 32) is consistent with the findings of reduced gray mater volumes in prefrontal cortex in obese subjects when compared to lean individuals (17
). They are also consistent with those from a large study done in Japanese healthy individuals (n
=1,428) that showed a negative correlation in males (not in females) between BMI and gray matter volumes in a small region within the prefrontal cortex (medial BA 9) (18
). However, the latter study also reported that males showed a positive correlation between BMI and gray volumes in ventral areas of the prefrontal cortices (medial areas BA 10 and BA 11 at z coordinates 0 and −10). This is different from our results because we found no brain areas that exhibited a positive correlation with BMI. This discrepancy could reflect the differences between volumetric and metabolic measures, but it could also reflect the relatively small sample of our study.
In this study, we also show an association between prefrontal and cingulate metabolism and cognitive function. In contrast, none of the correlations with motor tests were significant, which indicates that these associations were specific for cognitive tasks. For example, metabolic activity in prefrontal regions and in cingulate gyrus were significantly correlated with performance in tests of memory (California Verbal Learning Test) and of executive function (Symbol Digit Modalities Test, Stroop Interference, Trail A, and the WAIS subtests for digits backward). These findings are consistent with prior studies showing an association between metabolic activity in prefrontal regions and performance in cognitive tests of executive function (10
BMI was associated with performance on the WAIS (selected subtests) and the Wisconsin Card Sorting Test in this group of healthy subjects. This result corroborates prior findings of a negative association between BMI and cognitive performance in healthy adults (4
). Similar to the prior report, in our study the tests that correlated with BMI were tests of executive function indicating that this may be one of the most sensitive to the deleterious effects of excessive weight. Similarly, in obese subjects, cognitive impairment includes disruption in executive function and memory. Though in obese subjects comorbid medical complications (i.e., hypertension, diabetes) are likely to contribute to cognitive impairment, the fact that we show a similar association in healthy subjects suggests that high BMI may have a direct negative impact on certain aspects of cognition. The association between prefrontal metabolism and BMI suggests that decreased prefrontal activity may under-lie this effect. Though the mechanism underlying the relationship between BMI and prefrontal metabolism is unclear, we postulate that it reflects in part disrupted dopaminergic activity. Dopamine (DA) is one of the neurotransmitters that modulates prefrontal activity thus regulating executive function (19
). Indeed, studies in healthy subjects have shown a correlation between DA synthesis (assessed with PET and [18
F]-fluoro-L-DOPA) in striatum and cognitive performance in tasks linked to the prefrontal cortex (21
). Similarly studies of normal aging have reported that the age-related loss of DA markers (D2 receptors and DA transporters) is associated with decreases in prefrontal metabolism (22
) and with performance on tests of executive function (23
). The same associations have been documented by studies of patients with damage of the DA system (i.e., Parkinson’s Disease, methamphetamine abuse) in whom impairments in executive function have been shown to be associated with markers of DA damage (25
In obesity, both preclinical and clinical studies have documented impairments in brain DA activity (27
). Studies in obese subjects and in rodent models of obesity have reported an inverse relationship between BMI (humans) and weight (rodents) and D2 receptors (28
). In obese subjects, we have also observed a negative relationship between D2 receptor availability and prefrontal metabolism (32
). Thus, the impaired cognitive performance in obese subjects could reflect not only medical complications but also the detrimental effects of obesity on brain DA activity with a consequent disruption of prefrontal activity.
In interpreting these results one needs to consider the possibility that it is not BMI that is detrimental for prefrontal activity but that decreased prefrontal activity and reduced executive function may increase the risk to overeat. In fact, the prefrontal cortex is involved in regulating impulse control, self-monitoring, and goal-directed behaviors (33
), all of which could influence the ability of an individual to self-regulate his/her eating behavior. Indeed, it has been postulated that the decline in executive function that occurs with aging (34
) could contribute to the increased prevalence of overweight and obesity with age (4
The cognitive task increased brain metabolism and the largest effects were in prefrontal, parietal (regions involved in processing numerical calculations) (35
), and occipital regions. The regional increases were negatively associated with baseline metabolism; subjects with lower baseline metabolism had the largest increases with activation. Even though one would have, therefore, predicted that increases in prefrontal metabolism would have been larger in subjects with higher BMI who have lower baseline prefrontal metabolism; however, that was not the case. Indeed, the correlations between BMI and metabolic activation during cognitive performance were not significant. This suggests that BMI does not affect the amount of energy (glucose) required by the brain to perform the cognitive task. However, it is also possible that failure to see a correlation reflects the fact that the activation pattern is specific to the cognitive processes measured by the task. Thus, we cannot rule out the possibility that a different cognitive task may have yielded a significant association with BMI.
In our subjects, we did not find an association between brain metabolism and age. This differs from prior studies showing reductions in baseline prefrontal metabolism with age (22
). The reason for this discrepancy is likely to reflect the limited age range of subjects (22–44 years of age) because the steepest decline in prefrontal metabolism occurs in late middle age (36
). We also did not find an association between age and BMI. However, to the extent that BMI increases with age it would be relevant to assess the contribution of BMI to the age-related decreases in prefrontal metabolism.
A limitation for this study was that we did not measure physical activity; thus, we can not rule out its contribution, particularly because physical activity has been shown to have a beneficial effect on cognition (37
In summary, here we document a negative association between the BMI and the baseline prefrontal metabolic activity that is likely to contribute to the impairment in cognitive performance reported in healthy overweight/obese subjects. This further highlights the urgency to institute public health interventions to promote a healthy weight in individuals.