Nikkita Khattar1, Richard G. Spencer1, and Mustapha Bouhrara1
1NIA, NIH, Baltimore, MD, United States
Synopsis
Iron is
known to play a central role in neuronal viability and pathophysiology. Although
susceptibility weighted imaging (SWI) is highly sensitive to iron, few studies
have investigated the effect of age and sex on iron deposition using SWI. Further,
the potential association between iron deposition and myelination is unclear. It
has been suggested that myelin breakdown releases iron, which further acts to
potentiate myelin loss through oxidative mechanisms. Here, we investigate the
association between local iron deposition and age, sex, and myelination,
measured using an advanced myelin content imaging method, on a cohort of
cognitively unimpaired participants.
PURPOSE
Myelin loss releases substantial
stores of iron that, with lack of appropriate clearance, may accumulate in the
brain (1, 2).
However, the association between myelin breakdown and iron accumulation remains
to be established. Susceptibility weighted imaging (SWI) is highly sensitive to
iron deposition (3, 4).
SWI exploits magnetic field inhomogeneities caused by iron deposition, with
greater negative mean phase exhibited in regions with greater iron concentration
(4-6).
In this study we sought to investigate the regional associations between iron
deposition and age, sex, and local myelination in the brain (7-11),
in a large sample of healthy adults over a wide age range, and to develop
further insights into the mechanisms related to iron deposition in the human brain.METHODS
Subjects and MRI
The study cohort consisted of 97
subjects (50.8±22.9 years) with 42 women (47.8±20.1 years) and 55 men (53.4±24.3
years) spanning the age range between 22 and 94 years. Age was not
statistically different between men and women. The imaging protocol was:
- BMC-mcDESPOT for MWF mapping:
ten 3D spoiled-gradient-recalled-echo (SPGR) images acquired with flip angles
(FAs) [2 4 6 8 10 12 14 16 18 20]°, echo time (TE) 1.37ms and repetition time
(TR) 5ms, and ten 3D balanced steady-state free-precession images 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 (12). Images were acquired with
voxel size 1.6mm×1.6mm×1.6mm. DAM was used to correct for B1
inhomogeneity (13), with fast spin-echo images
acquired with FAs 45° and 90°; TE 102ms; TR 3s; acquisition voxel size
2.6mm×2.6mm×4mm; Field-of-view (FoV) 240mm×208mm×150mm; reconstructed voxel
size 1mm×1mm×1mm.
- SWI for iron
content mapping: 3D gradient-echo image acquired with FoV 240mmx240mmx185mm; voxel
size 0.64mmx0.64mmx0.64mm; EPI-factor 15, TR 47ms; TE 27ms.
Image processing and statistical analysis
SWI phase maps were generated using
the phase and magnitude SW images (3, 5, 6).
The magnitude image was nonlinearly registered to the MNI space and the
computed transformation matrix was applied to the corresponding SWI (14). MWF maps were generated using BMC-mcDESPOT analysis (9-11).
The averaged SPGR image over FAs was nonlinearly registered to the MNI space
and the computed transformation matrix was applied to the corresponding MWF map
(14).
Ten white matter (WM) and deep
gray matter (DGM) regions of interest (ROIs) were defined from the MNI atlas: WM
regions encompassing the frontal (FL), parietal (PL), temporal (TL), and
occipital lobes (OL), and DGM regions encompassing the caudate (Cau), thalamus
(Tha), putamen (Put), red nucleus (RN), substantia nigra (SN), and globus
pallidus (GP). Mean SWI phase and MWF values were calculated for each ROI. The
effects of age, sex, and MWF on the mean SWI phase were established using linear
regression with mean SWI phase value within the ROI as the dependent variable
and the mean MWF within the ROI, sex, and age as independent variables.
RESULTS & DISCUSSION
Figure 1 shows average SWI phase
maps of the youngest (ages 22-30, n = 12) and oldest (ages 80-94, n
= 11) groups of subjects. Results are shown for two slices covering the brain
structures investigated. Increased SWI phase shift as characterized by lower
(darker) signal indicates increased iron deposition, as is seen in several
brain regions in the older subjects. Indeed, the linear regression analysis shows,
aside from RN and GP, significantly decreased mean phase, that is, increased
iron content, with age in all ROIs (Fig. 2 and Table 1). These regions include
the WM lobes which, to the best of our knowledge, have not been investigated
previously using SWI. These results agree with previous SWI-based studies (4-6).
The relationship between MWF and
iron content was significant (p < 0.05) or close to significance (p
< 0.1) in three brain regions (Table 1), where decreased myelin content
corresponds to increased iron content (Fig. 3), consistent with release of iron
from breakdown of myelin. Interestingly, this effect is most prominent in the
frontal and parietal lobes, where the achievement of full myelination is
delayed as compared to other regions, and which are also the most vulnerable to
age- and disease-related degeneration. However, we note that diffusion of iron
into the extracellular space may shorten the corresponding transverse
relaxation time leading to an artificial overestimation of MWF values (15).
The effect of sex was significant
(p < 0.05) or close to significance (p < 0.1) in three
brain regions, where males exhibited greater iron content than females (Table
1). While this agrees with previous investigations (4-6),
the literature regarding sexual dimorphism in iron content remains sparse, and
further investigations on larger cohorts are required. Of note, recent studies
indicate lower myelin content in males as compared to females (16, 17).
We again attribute this finding of lower myelin content with greater iron
content in males to myelin breakdown and subsequent release of iron.CONCLUSIONS
Using SWI and an advanced method
of myelin content imaging, we show that iron content increases with age,
consistent with previous results. Most importantly,
we find that there is an inverse relationship between iron deposition and
myelination in critical WM and GM brain 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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