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Increased oxygen extraction fraction following acute multiple sclerosis (MS) lesion formation is associated with increased myelin repair.
Junghun Cho1, Thanh D Nguyen1, Lily Zexter1, Elizabeth M Sweeney2, Pascal Spincemaille1, Ajay Gupta1, Susan A Gauthier1, and Yi Wang1,3
1Radiology, Weill Cornell Medicine, New York, NY, United States, 2Population Health Sciences, Weill Cornell Medicine, New York, NY, United States, 3Biomedical Engineering, Cornell University, Ithaca, NY, United States

Synopsis

Understanding the cause and progress of remyelination in MS is critical for developing potential therapeutic targets of remyelination to restore neural connectivity and brain functions. In this study, we utilized a novel MRI-based oxygen extraction fraction (OEF) mapping method, namely “QQ”, and found that early lesion oxygen metabolism increase, as measured by QQ-based OEF, is positively associated with lesion myelin recovery, as measured by myelin water fraction. This study suggests that QQ-based OEF mapping may be a useful tool readily and widely available for studying MS lesion oxygen metabolism and its association with MS lesion remyelination.

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating neurologic disease, and the disease progression involves neurodegeneration. In response to injury, remyelination can occur in the central nervous system, which may be in different levels1, 2 and sometimes unsuccessful without clear reasons3. As remyelination is expected to restore neuronal connectivity and further brain functions4, understanding the cause and progress of remyelination will provide insight into potential therapeutic targets. As a recent study showed myelin recovery may be energy intensive5, we hypothesize that the early lesion oxygen metabolism increase contributes to the lesion myelin recovery.
In this longitudinal study, to check our hypothesis, a novel integrative model of quantitative susceptibility mapping and quantitative blood level dependent magnitude (QSM+qBOLD or QQ) was used for oxygen metabolism estimation. QQ enabled voxel-wise oxygen extraction fraction (OEF) to study MS lesions6, using a routinely available MRI sequence without burdensome vascular challenges7-12. QQ has been validated against calibrated fMRI12 and 15O-PET9, and its clinical feasibility has been shown in the studies of ischemic stroke13, 14 and brain tumor15. For myelin recovery measurement, myelin water fraction (MWF) was used, a well-established quantitative MR biomarker for myelin16-19.

Methods

Data acquisition: 14 MS patients (40 ± 11 years old, 9 females, 7.6 ± 3.7 years disease duration) were recruited. For each patient, the baseline scan was defined as the appearance of a new Gd-enhancing lesion and longitudinal scans were acquired at 3 months (±30 days) and 12 months (+90 days). In each scan, gadolinium-enhanced T1-weighted (T1w+Gd), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), 3D multi-echo gradient recalled echo (mGRE), and Fast Acquisition Spiral Trajectory and T2prep (FAST-T2) were acquired using a 3T Siemens Skyra scanner.
Data processing: QSM was estimated from mGRE using the MEDI algorithm20, 21. OEF was then estimated from QSM and mGRE magnitude using the QQ algorithm7, 8, 10. QQ combines two biophysics models of mGRE data: 1) QSM processing of phase data to estimate the susceptibility contribution of venous blood (i.e., OEF effect) and diffusive neural tissue22-24 and 2) qBOLD modeling of magnitude signal decay by the intravoxel field variation due to the susceptibility difference between cylindrical venous blood and the surrounding tissue25-27. For robust OEF reconstruction against noise, temporal and spatial sparsity in the mGRE signal was used7. MWF was estimated from FAST-T2 using a three-pool non-linear least squares data fitting16.
Statistical analysis: All images were co-registered to the baseline QSM resolution using FSL FLIRT, and a lesion mask was manually drawn on the co-registered T2-FLAIR (L.Z. and S.G.). A linear mixed-effect model was used 1) to assess the OEF and MWF between time points (e.g., baseline = 1, 3 months = 2) and 2) to study the relationship between the OEF change and the MWF change with a random effect for patient, adjusting for lesion volume, subjects’ age, sex, disease duration.

Results

57 new Gd-enhancing lesions were identified. Of these, lesion volume was 572.7 ± 850.7 mm3. Both OEF and MWF were significantly increased from baseline to 3 months: OEF = 14.0 ± 6.0% vs. 23.5 ± 5.6% (p<0.001) and MWF = 6.8 ± 2.2 % vs. 8.3 ± 2.6 % (p<0.001) and (Figures 1 and 2). The MWF change showed a significantly positive association with OEF change from baseline to 3 months (p=0.001) (Figure 3).
However, OEF and MWF did not show significant change from 3 months to 12 months: OEF = 23.5 ± 5.6% vs. 22.4 ± 4.7% (p=0.188) and MWF = 8.3 ± 2.6 % vs. 8.7 ± 2.6 % (p=0.383), and no significant association of MWF change with OEF change was found from 3 months to 12 months (p=0.323).

Discussion

This longitudinal study of newly formed MS lesions demonstrated that QQ-based high-resolution OEF mapping can be used for investigating MS lesion-specific oxygen utilization. We showed for the first time that greater OEF increase is associated with greater myelin recovery early after lesion development. This result suggests that increased lesion OEF at the acute phase may contribute to remyelination and is consistent with extensive energy metabolism required for events associated with remyelination, such as migration of oligodendrocyte progenitor cells to demyelinated lesions, proliferation, and myelin synthesis5.
QSM has become a reliable tool for measuring susceptibility change in the brain28, 29. QQ for further extracting blood deoxyheme iron (OEF effect) from QSM provides a direct and challenge-free tool of wide and easy availability for studying tissue oxygen metabolism. QQ is shown here to be useful for assessing oxygen metabolism in acute MS lesions.

Conclusion

This study suggests that QQ-based OEF mapping may serve as a useful tool to study oxygen metabolism in tissue. The temporal evolution of MS lesion oxygen metabolism is related to remyelination in acute lesions. QQ-based OEF may be used to inform the development of novel MS therapeutic targets for remyelination.

Acknowledgements

No acknowledgement found.

References

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Figures

Figure 1. Example of T1w+Gd, T2-FLAIR, OEF, and MWF image from an MS lesion showing OEF increase accompanied by myelin recovery. Both OEF and MWF substantially increases from baseline to 3 months.

Figure 2. Comparison of OEF and MWF among baseline, 3 months, and 12 months (n=57). Both OEF and MWF showed a significant increase from baseline to 3 months, but not a significant change from 3 months to 12 months. 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. Asterisk (*) indicates the significance difference (p<0.05, linear mixed-effect model).

Figure 3. Scatter plots of OEF change and MWF change from baseline to 3 months and from 3 months to 12 months. ΔMWF shows a significant positive association with ΔOEF from baseline to 3 months. Each dot indicates each lesion, and different colors indicate different subjects. Asterisk (*) indicates the significance difference (p<0.05, linear mixed-effect model).

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
0136
DOI: https://doi.org/10.58530/2022/0136