Richard Wonjoong Kim1, Nikkita Khattar1, Wenshu Qian1, Joseph Alisch1, Richard G. Spencer1, and Mustapha Bouhrara1
1NIA, NIH, Baltimore, MD, United States
Synopsis
Emerging evidence indicates
that myelination and axonal abnormalities could lead to alterations of brain
connectivity, contributing to a myriad of neurological disorders. Measurement of myelin to axonal volume, as
defined by the g-ratio, has been shown to represent a sensitive and specific
metric of neurodevelopment and neurodegeneration. However, only a single study to
date has sought to evaluate age-related differences in g-ratio in the adult
human brain. Here, we introduce and compare two novel approaches to g-ratio
mapping. Both methods revealed a quadratic relationship between g-ratio and age
in a large cohort of cognitively unimpaired participants.
PURPOSE
The g-ratio
is defined as the inner-to-outer diameter of a myelinated axon; its calculation
requires estimation of myelin volume fraction (MVF) and axonal volume fraction
(AVF). A recent report found that g-ratio
increases linearly with age (1), interpreted as reduction in myelin
throughout adulthood and decreased axonal density at older ages. However, this is inconsistent
with several reports of increased myelination throughout adulthood followed by
decrease at older ages (2, 3). This discrepancy
is likely due to use of magnetization transfer saturation for estimation of MVF
which, while sensitive to myelin content, is not specific. Here, we introduce
two novel approaches for g-ratio mapping, the first based on NODDI (4), a multi-shell diffusion
technique, for AVF estimation, and the second based on NODDI-DTI (5), a single-shell diffusion approximation
of NODDI. MVF was determined using BMC-mcDESPOT, a direct method for myelin mapping
(2, 6-9). These new g-ratio approaches were compared on a large
age-range cohort of cognitively unimpaired participants and used to establish
the g-ratio differences across the lifespan. METHODS
Subjects and
MRI
The
study cohort for the NODDI-DTI-based approach to g-ratio estimation consisted of 133 subjects (49.2±21.5years);
59 women (47.7±19.9years) and 74 men (50.5±22.5years), spanning an age-range between
21 and 94 years. The NODDI-based method was applied to a subset of 53
participants (41.5±18.6years); 25 women (43.7±19.4years) and 28 men (39.7±17.5years),
spanning an age-range between 21 and 83 years. Age was not statistically
different between men and women in either group. The imaging protocol was:
·
NODDI-DTI: diffusion-weighted images (DWI) were
acquired with single-shot EPI, repetition time (TR) 10000ms, echo time (TE) 70ms, b-values 0 and 700s/mm2 in 32 directions, and voxel
size 2mm×2mm×2mm.
·
NODDI: DWI were acquired using single-shot EPI with
TR of 10000ms, TE of 67ms, three b-values of 0, 700, and 2000s/mm2
(encoded in 32 directions), and voxel size 3mm×3mm×3mm.
·
BMC-mcDESPOT: ten 3D spoiled-gradient-recalled-echo
(SPGR) images were acquired with flip angles (FAs) [2 4 6 8 10 12 14 16 18
20]°, TE 1.37ms, TR 5ms, and ten 3D
balanced steady-state free-precession images were acquired with FAs [2 7 11 16
24 32 40 60]°, TE 2.8ms, TR 5.8ms, and radiofrequency excitation pulse phase
increments of 0o or 180o to account for off-resonance
effects (10). Images were acquired with
voxel size 1.6mm×1.6mm×1.6mm. We used the dual angle method (DAM) to correct
for B1 inhomogeneity (11), based on two fast spin-echo
images acquired with FAs 45° and 90°, TE 102ms, TR 3000ms, and acquisition
voxel size 2.6mm×2.6mm×4mm.
All
images were obtained with field-of-view 240mm×208mm×150mm and reconstructed to
a voxel size 2mm×2mm×2mm.
Image
processing and statistical analysis
Whole-brain
myelin water fraction maps were generated using BMC-mcDESPOT (7-9),
and converted to MVF using the geometrical analysis suggested by Jung (12).
AVF was calculated from the intracellular volume fraction derived from NODDI (4, 12)
or NODDI-DTI (5). MVF and AVF were then used to calculate corresponding g-ratio
maps (1, 12-14).
The averaged SPGR image over FAs was nonlinearly registered to the MNI space, with
the transformation matrix then applied to the corresponding g-ratio map using
FSL (15). Ten regions of interest (ROIs) were derived from the MNI
structural atlas encompassing the main white matter (WM) regions (Figure 1) (15). For each ROI, the effects of age and sex on g-ratio were
investigated using linear regression with mean g-ratio within the ROI as
the dependent variable and sex, age, and age2 as independent
variables. Additionally, the correlation between mean g-ratio values
derived from the two g-ratio approaches was calculated within each ROI.RESULTS & DISCUSSION
Figure
2 shows g-ratio maps derived from the two g-ratio methods for
representative participants of three different ages. The two approaches provide
very similar g-ratio maps. Visual inspection and quantitative ROI analyses
(Figs. 2-3) indicate decreasing g-ratio from early adulthood through middle
age, followed by increase with age in most ROIs (Table 1). While the derived g-ratio
values agree with previous literature, the quadratic, U-shaped, trends are not
consistent with the previous observation of a linear relationship between g-ratio
and age (1). As indicated above, this discrepancy is likely due to methodological
differences in MVF determination. The quadratic association observed here suggests
progressive myelination through middle age, followed by reduction through late
adulthood (2, 3).
The
effect of sex on g-ratio was significant in several brain regions (Table
1), with females exhibiting overall lower values; this agrees with recent
studies indicating greater myelination in females (2, 3).
These results disagree with Cercignani (1), who reported no sexual dimorphism (1). However, our findings are consistent with previous
demonstrations that proliferation of oligodendrocytes and myelin proteins are modulated
by sex steroids and hence regulated
differently in males and females (16-19).
Finally,
in agreement with Fig. 1, correlation analysis of g-ratio values derived
from the two approaches showed strong correlations in most ROIs (Fig 4). Small discrepancies are likely due to the fact
that NODDI is more sensitive to intracellular water diffusion due to the use of
high diffusion b-values.CONCLUSIONS
We propose two new approaches for g-ratio mapping. Both showed
a U-shaped association between g-ratio and age across multiple white
matter regions.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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