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.
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