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Visceral fat is associated with lower brain volume in healthy middle-aged adults
 
 
  Annals of Neurology May 2010
 
"In a large sample of middle-aged community participants, we observed a significant inverse association of anthropometric markers and CT-based measurements of abdominal fat with total brain volume, the most prominent association being observed with visceral fat. Anthropometric and CT-based adiposity measurements were not associated with MRI-markers of cerebrovascular disease. Although these findings are preliminary, they could improve our understanding of the mechanisms underlying the relationship of obesity with dementia, with potentially important implications for prevention strategies"
 
"Global body mass and obesity, particularly in midlife, are associated with an increased risk of dementia and Alzheimer disease (AD)......Higher levels of BMI, WC (waist), WHR (waist-hip ratio), SAT, and VAT (belly fat) were associated with smaller TCBV (brain volume).....When adjusting for CRP levels, the inverse associations of all adiposity measurements with TCBV were weakened and no longer significant.....inflammation could be an important mediator. Indeed obesity is highly associated with inflammatory markers. Cytokines such as interleukin 6 and tumor necrosis factor alpha are produced in adipose tissue and induce hepatic production of CRP......Adipose tissue also contains inflammatory cells.....Diabetes and insulin resistance, both strongly related to obesity, are other potential mediators of the inverse association between adiposity and brain volume.....visceral fat is more likely to mediate insulin resistance.....adipose tissue-derived hormones, such as adiponectin, leptin, resistin, or ghrelin, could also play a role in the relation between adipose tissue and brain atrophy"

 
Stephanie Debette, MD, PhD 1 2, Alexa Beiser, PhD 1 2 3, Udo Hoffmann, MD 4 5, Charles DeCarli, MD 6, Christopher J. O'Donnell, MD, MPH 2 7, Joseph M. Massaro, PhD 2 3, Rhoda Au, PhD 1 2, Jayandra J. Himali, MS 1 2 3, Philip A. Wolf, MD 1 2, Caroline S. Fox, MD, MPH 2 4, Sudha Seshadri, MD, DM 1 2 * 1Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA 2National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 3Department of Biostatistics, Boston University School of Public Health, Boston, MA 4Division of Endocrinology, Metabolism, and Diabetes, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 5Department of Radiology, Masachusetts General Hospital and Harvard Medical School, Boston, MA 6Department of Neurology, University of California at Davis, Sacramento, CA 7Department of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA email: Sudha Seshadri (suseshad@bu.edu) *Correspondence to Sudha Seshadri, Department of Neurology, Boston University School of Medicine; B602, 72 East Concord Street, Boston, MA 02118 Funded by: Framingham Heart Study's National Heart, Lung, and Blood Institute; Grant Number: N01-HC-25195 National Institute of Neurological Disorders and Stroke; Grant Number: R01 NS17950 National Institute on Aging; Grant Number: R01 AG16495, AG08122, AG033193, AG031287, AG033040, P30AG013846 Bettencourt-Schueller Foundation
 
Abstract
 
Objective

 
Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and computed tomography (CT)-based measurements of subcutaneous (SAT) and visceral (VAT) adipose tissue with various magnetic resonance imaging (MRI) markers of brain aging in middle-aged community adults.
 
Methods
 
Participants from the Framingham Offspring cohort were eligible if in addition to having measurements of BMI, WC, WHR, SAT, and VAT, they had undergone a volumetric brain MRI scan with measurements of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV), and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex, and time interval between abdominal CT and brain MRI.
 
Results
 
In a sample of 733 community participants (mean age, 60 years; 53% women), we observed an inverse association of BMI (estimate by standard deviation unit ± standard error = -0.27 ± 0.12; p = 0.02), WC (-0.30 ± 0.12; p = 0.01), WHR (-0.37 ± 0.12; p = 0.02), SAT (-0.23 ± 0.11; p = 0.04), and VAT (-0.36 ± 0.12; p = 0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (-0.35 ± 0.15; p = 0.02) and insulin resistance (-0.32 ± 0.13; p = 0.01). When adjusting for C-reactive protein levels, the associations were attenuated (-0.17 ± 0.13; p = 0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measurements and THV, WMHV, or BI.
 
Interpretation
 
In middle-aged community participants, we observed a significant inverse association of anthropometric and CT-based measurements of abdominal, especially visceral, fat with total brain volume.
 
Article Text
 
Global body mass and obesity, particularly in midlife, are associated with an increased risk of dementia and Alzheimer disease (AD).[1-6] Published data on the association of obesity and body mass index (BMI) with brain volumes are limited, suggesting overall an inverse association of BMI and obesity with temporal lobe volume,[7] total brain volume,[8][9] and hippocampal volume,[10][11] in cohorts of <300 individuals of various ages and risk profiles. Data on the relation between body mass and magnetic resonance imaging (MRI) markers of vascular brain injury are equally limited, suggesting a positive association of increasing BMI with incident MRI-defined brain infarcts in patients with white matter disease,[12] and an association of BMI and waist-to-hip ratio (WHR) with increasing white matter hyperintensity volume.[13][14]
 
Different fat compartments carry differential metabolic risks,[15] and there is growing evidence that abdominal obesity and visceral fat are more correlated with vascular risk than global body mass.[16][17] However, limited data exist demonstrating this concept in association with cognition and dementia. In the Framingham Offspring and the Kaiser Permanente studies, individuals with higher WHR or sagittal-abdominal-diameter (2 anthropometric markers of abdominal obesity) performed worse on cognitive tests,[18] and had an increased risk of dementia.[19] In the Health-ABC study, computed tomography (CT) measurements of subcutaneous fat and total fat mass, but not visceral fat, were associated with worsening global cognitive function.[20] A negative association between WHR and hippocampal volume was observed in 122 older individuals.[14] No study has evaluated the association of radiography-based measurements of abdominal fat compartments with MRI markers of brain aging. Interestingly, recent data suggest that higher leptin levels may have a protective effect on brain atrophy and dementia,[21][22] and, given that leptin expression is higher in subcutaneous than in visceral adipose tissue,[23][24] we hypothesized that subcutaneous adipose tissue may be less deleterious than visceral adipose tissue for neurodegenerative processes leading to dementia.
 
The purpose of the present study is to examine the cross-sectional association of BMI, waist circumference (WC), WHR, and radiography-based measurements of subcutaneous and visceral abdominal fat with MRI measurements of total cerebral brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV), and MRI-defined brain infarcts (BI) in middle-aged community participants.
 
Discussion
 
Principal Findings

 
In middle-aged Framingham Offspring participants, we observed an inverse association of BMI, WC, SAT, and VAT with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust of all, and was also independent of BMI and insulin resistance. When adjusting for CRP levels, the associations were attenuated. No consistently significant association was observed between the anthropometric or radiographically based measurements of adipose tissue and THV or MRI markers of vascular brain injury. WHR only was associated with increasing THV. An inverse association of borderline significance was observed between BMI, VAT, and EXT-WMHV and between WC, VAT, and MRI-defined BI, only in the model adjusted for vascular risk factors.
 
In the Context of the Current Literature
 
Several studies on samples of <300 individuals have recently suggested an association of BMI and obesity with lower total or regional brain volumes, in both older persons and younger or middle-aged adults.[7-9][37] Our study confirms the inverse association of increasing body mass with lower total brain volume and extends it to a large cohort of >700 middle-aged community participants. More importantly, our data suggest that the association is stronger for central obesity versus global adiposity, and is particularly prominent and robust for the visceral fat component of abdominal obesity.
 
A few studies of <150 participants have suggested an inverse association of BMI[10][11] and WHR[14] with hippocampal volume. WHR was associated with increasing THV, a surrogate marker of decreasing hippocampal volume. However, none of the other anthropometric or radiographically based measurements of adipose tissue was associated with THV. As we did not use a direct measurement of hippocampal volume, we cannot, however, formally exclude the possibility that such associations exist.
 
An association of BMI and WHR with increasing WMH volume has been reported in small series of individuals at high vascular risk.[13][14] In a recent study including patients with prevalent cerebral white matter disease, increasing BMI was associated with a higher incidence of brain infarcts.[12] In our large sample of middle-aged community participants, anthropometric markers and CT-based measurements of abdominal fat did not predict more extensive white matter hyperintensities or a higher prevalence of MRI-defined brain infarcts cross-sectionally.
 
Potential Mechanisms
 
The potential mechanisms underlying the inverse association of obesity and particularly visceral abdominal fat with total brain volume are speculative.
 
Inflammation could be an important mediator. Indeed obesity is highly associated with inflammatory markers.[26] Cytokines such as interleukin 6 and tumor necrosis factor alpha are produced in adipose tissue and induce hepatic production of CRP.[26] Adipose tissue also contains inflammatory cells such as monocytes and macrophages, which accumulate in obese states.[26] Inflammation was shown to predict a higher risk of dementia,[38] and several inflammatory markers were recently shown to be inversely associated with TCBV in the Framingham Offspring Study.[39] A recent study also found that persons on anti-inflammatory drugs show significantly smaller age-related volume changes in regions of both gray and white matter compared to controls. In the present dataset, the inverse association of all adiposity measurements with TCBV was attenuated after adjusting for CRP, suggesting that this mechanism could indeed be important.
 
Diabetes and insulin resistance, both strongly related to obesity,[40] are other potential mediators of the inverse association between adiposity and brain volume. In the Framingham Offspring cohort, we have recently shown an inverse association of diabetes, fasting glucose, and HOMA-IR with TCBV.[41] Our observation that the inverse association of VAT with TCBV was maintained, although weakened, after adjusting for diabetes and HOMA-IR, indicates that these are probably not the sole mediators of our finding.
 
Finally, adipose tissue-derived hormones, such as adiponectin, leptin, resistin, or ghrelin, could also play a role in the relation between adipose tissue and brain atrophy. In transgenic animal models, leptin receptor-deficient rodents were shown to have impaired memory performances[42] and long-term potentiation of neurons in the hippocampus.[43] Leptin has also been shown to reduce the extracellular amyloid beta load and the level of tau phosphorylation in neuronal cells.[44] A positive correlation between plasma leptin levels and gray matter volume in the right hippocampus was identified,[21] and in the Framingham Original cohort we have recently shown that higher circulating leptin levels were significantly associated with a reduced risk of incident dementia and AD, higher TCBV, and lower THV.[22]
 
Whereas the putative mediating effect of inflammation in the inverse association of anthropometrically and radiographically based measurements of adipose tissue with brain volume does not appear to be restricted to a specific fat compartment,[26] visceral fat is more likely to mediate insulin resistance[45][46] and has a specific pattern of adipose tissue-derived hormone secretion,[23][24][47] which could partly explain the stronger inverse association of visceral adipose tissue with total brain volume. Visceral fat is characterized by an enhanced rate of lipolysis and an increased plasma free fatty acid flux to the hepatic portal circulation, thus exacerbating insulin resistance.[47] The expression profile of adipose tissue-derived hormones has also been shown to differ substantially between visceral and subcutaneous adipose tissue, with a more proatherogenic pattern of gene expression in visceral fat.[48-50] This differential expression could also underlie the differential neurodegenerative effects of adipose tissue-derived hormones. Leptin expression, for instance, has been shown to be lower in visceral compared to subcutaneous adipose tissue.[23][24] Unfortunately, plasma levels of most adipokines with suspected neurodegenerative effects are not available at the present time in this dataset to formally explore this hypothesis.
 
Strengths and Limitations
 
The strengths of this study are the population-based setting, the large sample size, the young age of the participants compared to most previous studies with careful surveillance and exclusion of prevalent stroke and dementia, and the availability of quantitative measurements of both MRI markers of brain aging and CT-based abdominal adipose tissue compartments. It is usually assumed that anthropometric measurements of central obesity, such as WC, WHR, or sagittal-abdominal diameter, reflect visceral rather than total fat mass, the former being more strongly related to metabolic disorders and vascular disease. However, the validity of these measurements is questionable with increasing age,[51] and CT-based measurements of abdominal fat compartments allow a more accurate distinction between visceral and subcutaneous fat. The main limitations are the lack of a direct measurement of hippocampal volume and the cross-sectional design. The absence of longitudinal measurement of change in TCBV did not enable us to formally distinguish between an association of adipose tissue with a dynamic process of accelerated brain atrophy and an adverse effect of adiposity on brain development, as overweight middle-aged adults may have been overweight in childhood.[52] However, we used the ratio of total brain volume to intracranial volume and not the raw measurement of total brain volume, making it more likely that our results reflect brain atrophy occurring after the brain has reached its maximum size, reflected in the total intracranial volume.[22] Although the acceptance rate was high, persons included in this study are not perfectly representative of the general population, as they have fewer risk factors than persons excluded. This limitation is common to all population-based studies involving time-consuming examinations and follow-up. Finally, we did not perform any correction for multiple testing, as we considered our study to be exploratory.
 
Implications
 
First, although lower total brain volume or hippocampal volume and extensive white matter hyperintensities or covert brain infarcts were all shown to be powerful predictors of incident dementia,[53-57] our results suggest that accelerated global brain atrophy, rather than more extensive vascular brain injury, could be the predominant mechanism underlying the association of increased body mass and visceral fat with cognitive decline and dementia. However, only further follow-up of our cohort and additional independent studies will be able to confirm or refute this hypothesis. Indirectly our findings are corroborated by a recent MRI and proton magnetic resonance spectroscopic imaging study performed in 50 healthy middle-aged subjects, showing an inverse association of BMI with concentrations of N-acetylaspartate and choline-containing metabolites, especially in the frontal lobes, pointing to axonal and myelin abnormalities as well as decreased neuronal viability.[58]
 
Second, whereas abdominal obesity and visceral fat are already recognized as being more important in determining vascular risk than global body mass,[16][17] our data suggest that they may also be important determinants of the association between overweight and lower total brain volume.
 
Conclusions
 
In a large sample of middle-aged community participants, we observed a significant inverse association of anthropometric markers and CT-based measurements of abdominal fat with total brain volume, the most prominent association being observed with visceral fat. Anthropometric and CT-based adiposity measurements were not associated with MRI-markers of cerebrovascular disease. Although these findings are preliminary, they could improve our understanding of the mechanisms underlying the relationship of obesity with dementia, with potentially important implications for prevention strategies.
 
Results
 
Sample characteristics are presented in Table 1. Older age, diabetes mellitus, and increasing values of systolic blood pressure were associated with increasing tertiles of BMI, WC, WHR, SAT, and VAT (data not shown).
 
The Pearson correlation coefficient between SAT and VAT was r = 0.58 (p < 0.001). Both abdominal CT adipose tissue measurements were significantly correlated with BMI (r = 0.79, p < 0.001 for SAT; r = 0.67, p < 0.001 for VAT), WC (r = 0.80, p < 0.001 for SAT; r = 0.71, p < 0.001 for VAT), and WHR (r = 0.19, p < 0.001 for SAT; r = 0.67, p < 0.001 for VAT). WC, WHR, and BMI were all significantly correlated with each other (r = 0.72 for WC and WHR, r = 0.85 for WC and BMI, r = 0.38 for WHR and BMI, p < 0.001).
 
Association of Anthropometrically and Radiographically Based Measurements of Adipose Tissue with Brain Volumes
 
Higher levels of BMI, WC, WHR, SAT, and VAT were associated with smaller TCBV (Table 2). The inverse associations of BMI and WC with TCBV were maintained when running the analysis in the larger dataset of participants with a brain MRI scan and anthropometric measurements regardless of the availability of radiographically based measurements of adipose tissue (Supplementary Table 2). When adjusting for vascular risk factors, the associations with TCBV were weakened but remained significant. The association of VAT with TCBV remained significant when adjusting for BMI (see Table 2). When adjusting for HOMA-IR, the inverse associations of VAT with TCBV remained significant: -0.28 ± 0.13 (p = 0.035). When adjusting for CRP levels, the inverse associations of all adiposity measurements with TCBV were weakened and no longer significant (-0.17 ± 0.13, p = 0.17 for VAT). The inverse association of VAT with TCBV was substantially unchanged within strata defined by gender, presence of obesity or central obesity, and absence of diabetes (Supplementary Table 3).
 
WHR, but not BMI, WC, SAT, and VAT, was associated with increasing THV, independently of vascular risk factors (see Table 2).
 
Association of Anthropometrically and Radiographically Based Measurements of Adipose Tissue with MRI Markers of Vascular Brain Injury
 
BMI, WC, WHR, SAT, and VAT were not significantly associated with WMHV and EXT-WMHV or with MRI-defined BI in our primary model adjusted for age, sex, and time interval between abdominal CT and brain MRI (Table 3). In the model adjusted additionally for vascular risk factors and physical activity index, there was a weak association of increasing BMI and VAT with a lower frequency of EXT-WMHV (but not with WMHV) and of WC and VAT with a lower frequency of BI (see Table 3).
 
 
 
 
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