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Regional oxygen extract fraction mapping (rOEF) of multiple sclerosis brains
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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Figures

Average OEF between healthy controls (HC, 34 ± 12 years, n=11) and MS patients (39 ± 7 years, n=12) in cortical gray matter and whole brain. * indicates p<0.01 (unpaired t-test)

T1w, T2w, QSM, and OEF maps for an MS patient (disease duration 122 months). Arrows indicate QSM rim+ (yellow), QSM rim- (pink), and QSM- (black), respectively. The QSM rim- lesion has heterogeneous OEF. The QSM rim+ lesion has uniformly low OEF. All lesions are hypointense in T1w and hyperintense in T2w.

Lesion OEF referenced to surrounding NAWM ($$$OEF_{Lesion}$$$) in QSM rim+, QSM rim-, and QSM-. QSM rim-, QSM rim+, and QSM – showed -8 ± 7, -11 ± 6, -12 ± 6 % OEF compared to NAWM. Red line, blue box, black whisker, and red cross indicates median value, interquartile range, the range extending to 1.5 of the interquartile range, and outlier beyond the whisker range.

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