The major finding of this study was that greater BMI was significantly associated with the following characteristics: (1) lower NAA concentrations in frontal, parietal, and temporal WM; 2) lower NAA concentration in frontal GM; and 3) lower Cho concentration in frontal WM. No significant associations of BMI with lobar brain volumes or regional concentrations of Cr or m-Ino were detected.
Lower NAA is consistent with derangement of neurometabolism, lower dendritic/axonal density, and/or axonal loss. Lower Cho in frontal WM suggests membrane and/or myelin alterations and/or alterations in membrane turnover. Thus, these results point to axonal and myelin abnormalities in frontal, parietal, and temporal WM, as well as decreased neuronal viability in the frontal lobe that are associated with greater BMI. This pattern of associations is not consistent with regions demonstrating volumetric and spectroscopic changes in preclinical39
and symptomatic AD.40
Spectroscopic studies in AD consistently demonstrated lower NAA40,41
and greater m-Ino42
levels in GM of medial temporal lobe and parietal lobes, but reports about Cho were inconclusive.43
Nevertheless, given the epidemiological associations between midlife adiposity and increased chances of AD, our results suggest that some processes leading to AD may have their origin in WM.
The strongest associations of BMI with NAA and Cho concentrations in the brain were found in the frontal WM, a region that myelinates later than the other lobes and is thought to be more prone to damage during aging.44
Consistently, age-related decreases of fractional anisotropy (a diffusion marker of WM microstructural fiber integrity) are also more pronounced in anterior versus posterior WM.31
This suggests that our results may reflect accelerated aging of WM in individuals with high levels of adiposity. Alternatively, because overweight or obese adults are likely to be overweight or obese as children,45
our findings could also reflect the adverse effects of adipose tissue10
on brain development. Taken together, our data suggest that adiposity has an adverse impact on aging and/or developmental processes of the brain, and thus may increase the odds of aging-related diseases such as AD. In addition, virtually identical relationships between BMI and metabolite concentrations in male and female individuals (reflected through insignificant interactions between BMI and sex) suggest that independent risk factors/processes explain why obese women appear to be more vulnerable to the development of late-life dementia than do men.
Based on many epidemiological studies, our results of frontal metabolic abnormalities with greater BMI may reflect increased risk for development of dementia later in life, possibly linked to compromised neuronal energetics.20
Stokin and colleagues46
demonstrated axonal transport defects and axonal swelling in mice models of AD and occasionally in aged wild-type mice, which preceded amyloid deposition by at least 1 year (this corresponds to several decades in human life). They also identified similar axonal defects in postmortem brains from individuals who showed early symptoms of AD but no amyloid plaques.46
This axonal swelling might be consistent with our findings of larger frontal WM volume with greater BMI (insignificant after correction for multiple comparisons), and with reports of associations between greater BMI and enlarged WM volume in young overweight and obese individuals.15,16
NAA abnormalities may also reflect insulin dysregulation (insulin resistance or hyperinsulinemia) that is often found among obese individuals.47
This dysregulation leads to reduced insulin transport into the brain, which results in impaired glucose utilization47
that could be associated with lower NAA.48
However, given the relatively small number of obese participants in our study, we do not believe that this mechanism explains our findings.
The limitations of our study include lack of assessment of potentially important covariates, such as total cholesterol, systolic and diastolic blood pressure, glucose and insulin levels, family history of AD, and apolipoprotein E genotype. However, in epidemiological studies, apolipoprotein E ε4 did not correlate with BMI8
and did not explain the associations between greater BMI and smaller brain volumes.6
Other markers of body fat and its distribution, potentially more strongly associated with brain abnormalities, such as waist/hip ratio or waist circumference,4
were not available for our analyses. Finally, potential unrecorded group differences in nutrition, stress, exercise and general fitness, overall physical health, and genetic predispositions (other then via apolipoprotein E) may contribute to the results described in this study.
In summary, this study is the first to demonstrate that greater BMI in otherwise healthy middle-aged adults is associated with axonal and/or myelin abnormalities in WM, primarily in the frontal lobe, and with neuronal injury in frontal GM. Because WM in the frontal lobes is more prone to the effects of aging than in other lobes, our results may reflect accelerated aging in individuals with high levels of adiposity, which may be associated with greater probabilities of development of AD. Significant associations of BMI with regional brain metabolite concentrations and with lobar brain volumes (the latter insignificant after correction for multiple comparisons) suggest that neuronal/glial metabolic abnormalities precede volumetric changes that may become detectable later in life or in individuals with more adipose tissue. Our findings extend previous associations between brain structure and adiposity. However, the data did not allow us to discern whether these abnormalities were associated with body fat per se, comorbid conditions, nutrition, or sedentary lifestyle. If our observations are confirmed in prospective studies that control for other important factors associated with adiposity, they may help understand important neurobiological changes preceding late-life dementia.