Junghun Cho1, Thanh D. Nguyen2, Weiyuan Huang2, Shun Zhang2, Xianfu Luo2, Susan A. Gauthier3, Pascal Spincemaille2, Ajay Gupta2, and Yi Wang1,2
1Biomedical Engineering, Cornell University, New York, NY, United States, 2Radiology, Weill Cornell Medical College, New York, NY, United States, 3Neurology, Weill Cornell Medical College, New York, NY, United States
Synopsis
Impaired energy metabolism is
a major contributor to the ongoing inflammation and neurodegeneration in
multiple sclerosis (MS) brains, particularly MS lesions. Cerebral regional
oxygen extraction fraction mapping (rOEF) obtained from challenge-free multiecho
gradient echo data demonstrates that lesions identified on quantitative
susceptibility mapping (QSM) without rim (QSM rim-) have heterogenous OEF that
is higher than that in other type of lesions. rOEF may offer insight into MS
lesion remylination viability.
Introduction
Multiple
sclerosis (MS) is an inflammatory demyelinating neurologic disease and the
disease progression involves neurodegeneration. One contributing tissue injury
pathway is impaired energy metabolism with damaged mitochondrial ATP production
(1). MRI as
the method of choice MS diagnosis and follow-up (2) is being developed
to image iron accumulation in proinflammatorily activated microglia/macrophages
as a measure of neuroinflammation behind the sealed blood-brain-barrier using
quantitative susceptibility mapping (QSM)(3,4), and to
measure oxygen extraction fraction (OEF) using deoxyheme sensitive MRI (5,6). However, current
OEF measurements have been limited to global and cortical venous territories,
and a voxel-wise regional OEF mapping (rOEF) is critical to allow investigating
tissue damage in each MS lesion individually. In this study, a recently developed
QSM+qBOLD method for rOEF (7) is used to
study MS lesions.Materials and Methods
rOEF
Phase
and magnitude of 3D multiple echo gradient echo
(mGRE) signal were modeled using QSM and qBOLD, respectively (7,8). $$Y^{*},v^{*},R_{2}^{*},S_{0}^*,\chi_{nb}^{*}=\begin{array}{c}argmin\\Y,v,R_{2},S_0,\chi_{nb}\end{array}\left\{ \begin{array}{c}\begin{array}{c}w||F_{QSM}\left(Y,v,\chi_{nb}\right)-\chi||_{2}^{2}\\+||S(t)-S_{qBOLD}\left(S_{0,},Y,v,R_{2,}\chi_{nb},t\right)||_{2}^{2}+\lambda\left(\overline{OEF(Y)}-OEF_{wb}\right)^{2}\end{array}\end{array}\right\} $$ where $$$w$$$ is a weighting term. Here, the susceptibility
of a voxel is the sum of susceptibilities of the blood (determined by its
oxygenation) and the non-blood tissue: $$F_{QSM}(Y,v,\chi_{nb})=\left[\frac{\chi_{ba}}{\alpha}+\psi_{Hb}\cdot\Delta\chi_{Hb}\cdot\left(-Y+\frac{1-\left(1-\alpha\right)\cdot Y_{a}}{\alpha}\right)\right]\cdot v + \left(1-\frac{v}{\alpha}\right)\cdot \chi_{nb}$$ with $$$\chi_{ba}$$$ = -108.3 ppb the fully oxygenated blood susceptibility (9), $$$\alpha$$$ =0.77 the ratio between the venous and total blood
volume $$$v/CBV$$$ (10), $$$\psi_{Hb}$$$ the hemoglobin volume fraction calculated from
measured Hct (11-14), $$$\Delta \chi_{Hb}$$$ the susceptibility difference between deoxy-
and oxyhemoglobin (15,16), venous blood volume ($$$v$$$), and
non-blood tissue susceptibility ($$$\chi_{nb}$$$). The qBOLD term
models the effect of blood oxygenation on the magnitude: $$S_{qBOLD}\left(t\right)=S_0\cdot e^{-R_2\cdot t}\cdot F_{BOLD}\left(Y,v,\chi_{nb},t\right)\cdot G(t)$$ with $$$G(t)$$$ a
macroscopic field effect (8), $$$F_{BOLD}\left(Y,v,\chi_{nb},t\right)=exp\left(-v\cdot f_{s}\left(\delta\omega\cdot t\right)\right)$$$ (17) where $$$f_s$$$ is the signal decay by the blood vessel network (18), and $$$\delta \omega$$$ is the
characteristic frequency due to the susceptibility difference between
deoxygenated blood and the surrounding tissue (8): $$\delta \omega\left(Y,\chi_{nb}\right)=\frac{1}{3}\cdot \gamma \cdot B_{0}\cdot \left[Hct\cdot \Delta \chi_{0}\cdot \left(1-Y\right) + \chi_{ba}-\chi_{nb}\right]$$ with $$$\gamma$$$=267.513MHz/T the gyromagnetic ratio, $$$B_0$$$ the main
magnetic field, $$$\Delta \chi_{0}=4\pi \times 0.27 ppm$$$ the susceptibility difference between fully
oxygenated and fully deoxygenated red blood cells (19). The third term in the right side of Eq.1 is the
physiological constraint that the whole brain average,$$$\overline{OEF(Y)}$$$, should be
similar to $$$OEF_{wb}$$$, the OEF value estimated from the straight sinus (7). We used cluster analysis of time evolution to
improve the robustness against noise (7).
MS patient
study
12
MS patients (39 ± 7 years) who underwent 3T MRI were selected. Imaging
sequences included T1-weighted (T1w), Gadolinium enhanced T1-weighted (T1W+Gd),
T2-weighted (T2w), and multi-echo-gradient-echo (mGRE) (FOV=24cm, acquisition matrix size=320-416×205-320, TE1/ΔTE/=
4.5-6.7/4.1-4.8, last TE=47.7 ms, TR= 49-58 ms, slice thickness=3 mm). QSM and rOEF
maps were obtained using MEDI+0 and QQ-CAT, respectively (7,20).
Lesions were identified on T2w, and classified into three types relative to
surrounding normal-appearing white matter (NAWM): QSM isointense (QSM-, n=46),
QSM hyperintense with rim (QSM rim+, n=32) and QSM hyperintense without rim
(QSM rim-, n=101). For statistical analysis (Kruskal-Wallis test) among the
three lesion types, the average OEF of each lesion was referenced to the
average of its corresponding NAWM. Additionally, global OEF was compared with
11 healthy controls (34 ± 12 years) using an unpaired t-test.Results
Global
and cortical gray matter OEF of MS patients was significantly lower than
healthy controls (33.3 ± 3.3 vs. 28.7 ± 2.9 %, p<0.01, and 32.7 ± 4.0 vs. 28.3
± 2.9 %, p<0.01 respectively) (Fig. 1). In a MS patient with all three
lesion types, QSM rim- shows heterogeneous OEF (Fig. 2). Significant OEF
differences were observed among the three lesion types (p<0.01, Kruskal-Wallis
test): relative to NAWM, QSM rim+, QSM rim-, QSM- showed -8 ± 7, -11 ± 6, -12 ±
6 % OEF (Fig. 3).Discussion
This
is the first report on MS lesion oxygen extraction fraction, to the best of our
knowledge. In the three MS white matter lesion types characterized by QSM in
this study, QSM- represents old chronic lesion with little metabolism, and QSM
rim+ represents lesions with substantial tissue damage (21). They
present lesser energy metabolism compared to QSM rim- type (Fig.3), which is
consistent with tissue damage measured on myelin water fraction mapping (22) and
neuroinflammation measured on translocator protein PET (23). The
heterogeneous OEF of QSM rim- lesions (Fig. 2) may reflects remyelination
possibilities in these lesions.
Lower
global OEF in MS brains compared to healthy controls as observed here agrees
well with the previously reported reduced OEF (5,6,24). The
cortical OEF value here (Fig.1) is quite similar to that in a previous 7T study
using vein susceptibility modeling (6), but the global OEF is slightly lower than that in a study using
vein T2 modeling (5). This
discrepancy may be explained by the complexity in estimating oxygenation from
T2 model, particularly T2 dependence on red blood cell shape (25). Conclusion
This study shows a voxel-wise regional OEF map in the
MS. In addition to widely used T1w, T2w, and QSM, the OEF map may provide
information regarding tissue viability in various MS lesions.Acknowledgements
No acknowledgement found.References
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