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Association of decreased cerebral myelination with obesity
Mustapha Bouhrara1, Nikkita Khattar1, Luis E. Cortina1, Abinand C. Rejimon1, Elango Palchamy1, Susan M. Resnick1, and Richard G. Spencer1
1NIA, NIH, Baltimore, MD, United States

Synopsis

Diffusion tensor imaging (DTI), relaxation time, and magnetization ratio (MTR)-based studies have shown that obesity negatively impacts microstructural white matter (WM) integrity. However, the specific impact of obesity on myelin content has not previously been evaluated. Here, we examined the relationship between obesity status, measured using body mass index (BMI), and myelin content, measured using myelin water fraction (MWF) mapping, a surrogate of myelin content, in a large age cohort of cognitively unimpaired lean, overweight, and obese subjects. Our results indicate that BMI is negatively associated with MWF in several brain WM regions.

PURPOSE

Growing epidemiological evidence establishes a link between obesity and central nervous system (CNS) degeneration. These observations have been corroborated by conventional quantitative MR parameter mapping, highlighting microstructural changes in white and gray matter that occur with obesity (1-4). However, to the best of our knowledge, the specific effect of obesity on myelination has not been investigated. In this study, we examined the potential association between myelin loss and obesity in a wide age-range cohort of cognitively unimpaired subjects. Our main goals were to characterize the regional association between myelination status, measured using an advanced method of myelin water fraction (MWF) mapping (5, 6), and obesity, measured using the body mass index (BMI), and to develop further insights into the specific effect of obesity on regional myelin integrity.

METHODS

Subjects and MRI
The study cohort consisted of 115 cognitively unimpaired participants (55.5 ± 20.8years) of 55 women and 60 men spanning the age range between 22 and 94 years. The cohort consisted of 52 lean (BMI < 25) and 63 overweight (N = 48, 25 ≤ BMI < 30) and obese (N = 16, BMI ≥ 30) participants. Mean age did not differ between lean and overweight/obese participants. For each participant, ten 3D spoiled-gradient-recalled-echo (SPGR) images were acquired with flip angles (FAs) of [2 4 6 8 10 12 14 16 18 20]°, echo time of (TE) 1.37ms and repetition time (TR) of 5 ms, and ten 3D balanced steady-state free-precession images were acquired with FAs of [2 7 11 16 24 32 40 60]°, TE of 2.8ms, TR of 5.8ms, and radiofrequency excitation pulse phase increments of 0o or 180o to account for off-resonance effects (7). All images were acquired with a voxel size of 1.6mm×1.6mm×1.6mm. Further, we used the dual-angle method (DAM) to correct for B1 inhomogeneity (8). The DAM protocol consists of two fast spin-echo images acquired with FAs of 45° and 90°, TE of 102ms, TR of 3s, and acquisition voxel size of 2.6mm×2.6mm×4mm. All images were obtained with a field-of-view of 240mm×208mm×150mm and reconstructed on the scanner to a voxel size of 1mm×1mm×1mm.

Image processing and statistical analysis
For each participant, a whole-brain MWF map was generated using the BMC-mcDESPOT analysis from the SPGR, bSSFP, and DAM images (5, 6, 9). Further, the SPGR image over FAs was nonlinearly registered to the MNI space, with the computed transformation matrix then applied to the corresponding MWF map; this analysis was performed using FSL software (10). Nineteen white matter (WM) regions of interest (ROIs) were defined from the MNI structural atlas (Fig. 1) (10). Finally, for each ROI, the effect of BMI on MWF was investigated using linear regression with mean MWF within the ROI as the dependent variable and BMI, sex, age, and age2 as independent variables. The inclusion of age2 as an independent variable is based on our and others’ recent observations that MWF follows a quadratic relationship with age (11, 12).

RESULTS & DISCUSSION

Figure 2 shows regression analysis of MWF and BMI, indicating a statistically significant (pBMI < 0.05) or close to significant (pBMI < 0.1) negative correlation in most WM brain regions evaluated after adjusting for age and sex. The plots indicate that increase in BMI correspond to a decrease in MWF. These results agree with, and are complementary to, previous DTI-, relaxation time-, and magnetization transfer ratio (MTR)-based investigations showing that obesity is associated with regional WM microstructural alterations in cognitively normal subjects (1-4). However, DTI-outcomes, including fractional anisotropy and mean diffusivity, while sensitive to WM microstructural changes, are not specific. Indeed, various factors such as axonal degeneration and demyelination can affect DTI-derived eigenvalues. Similarly, although most conventional quantitative MRI measures, including DTI, relaxation times, and MTR, are sensitive to myelin content changes, they cannot serve as specific markers of myelin; this is mainly due to their sensitivity to multiple other tissue properties such as hydration, macromolecular content, temperature, flow, and architecture, including fiber crossing and fanning. Therefore, in terms of these conventional measures, it remains unclear whether the consistently observed decline in MW integrity with obesity is a consequence of myelin loss, axonal damage, or other pathohistological changes. Thus, our work adds new insights highlighting the specific implications of obesity for demyelination.

While the mechanism of myelin loss with obesity is not clear at present, it has been recently shown that chronic exposure to a high fat diet triggers myelin disruption (13). Furthermore, it has been shown that this dietary exposure is likely associated with CNS inflammation (14-16), potentiating loss of oligodendrocytes, the myelin-producing cells of the CNS (17). However, many of these studies were conducted on animal models. Further study of the effects of obesity on the CNS is imperative, given the increasing prevalence of obesity, including at advanced ages (18, 19).

CONCLUSIONS

As far as we know, this is the first study examining the association between regional brain myelin content and obesity. We found that myelin content declines with obesity in many brain regions in a population of cognitively normal participants. This decreased myelin could promote accelerated cognitive aging in obese individuals (20).

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.

References

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Figures

Figure1. 1) Frontal lobes, 2) Parietal lobes, 3) Occipital lobes, 4) Cerebellum, 5) Splenium of corpus callosum (CC), 6) Body of CC, 7) Genu of CC, 8) Internal capsule (IC), 9) Temporal lobes, 10) Forceps major (FM), 11) Inferior longitudinal fasciculus (ILF), 12) Anterior corona radiata (ACR), 13) Forceps minor (Fm), 14) Anterior thalamic radiation (ATR),15) Posterior corona radiata (PCR),16) Superior longitudinal fasciculus (SLF), 17) Posterior thalamic radiation (PTR), 18) Inferior fronto-occipital fasciculus (IFOF), and 19) Superior fronto-occipital fasciculus (SFOF).

Figure 2. Regressions of MWF with BMI. Results are shown for the 19 WM brain structures/ROIs displayed in Fig. 1. For each ROI, the coefficient of determination, R2, of the multiple linear regression model, as well as the slope, βBMI, and the significance, pBMI, of BMI as an independent parameter are reported. Most ROIs exhibited significant (pBMI < 0.05) or close to significant (pBMI < 0.1) negative correlations between MWF and BMI.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)
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