Introduction

Iron accumulation frequently occurs at the edge of chronic active multiple sclerosis (MS) lesions, where chronically activated microglia are present and continued demyelination is occurring^{1, 2}. The ability to study these lesions in-vivo requires an imaging modality to identify iron within the MS lesion. Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources including iron by solving the field-to-source inversion problem³. In general, an increase in susceptibility on QSM in the MS lesion may be related to iron deposition and myelin loss, and combining QSM with a measurement of myelin by the well-validated myelin water fraction (MWF)^4-6 would allow for a more accurate assessment of iron deposition⁷. In particular, hyperintense rim on QSM must contain iron, as myelin loss biophysically is less at the lesion rim than at the lesion center. The objective of this study was to combine the information from QSM and MWF to 1) identify a subset of MS lesions with higher iron deposition occurring at the rim (QSM hyperintense rim+ lesions) and 2) to investigate the consequence of increased iron deposition on lesion myelin tissue damage.

Methods

QSM was reconstructed from a multi-echo gradient echo (GRE) imaging by using the morphology-enabled dipole inversion method. A multi-voxel nonlinear least-squares data-fitting algorithm with spatial smoothness constraints was used to reconstruct MWF maps from T2w images obtained with Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) sequence^{8, 9}. Eighty-one QSM hyperintense rim positive (rim+) lesions and 185 rim negative (rim-) lesions were identified on QSM from 47 MS patients (15 men and 32 women, mean age 43.2 years ± 10.7) who underwent brain MRI at 3T. Classification of QSM rim+ vs. rim- lesions was a consensus of two neuroradiologists. Lesion MWF and QSM measurements were obtained using ITK-SNAP software. ROIs for whole lesion as well as core and rim areas of rim+ lesions were placed on standard T2WI and then were overlaid on QSM and MWF with manual adjustment as required. ROIs were also drawn in normal appearing white matter (NAWM) on contralateral mirror site of the lesions with similar shape and size to serve as a QSM reference. Two mixed-effects-models were implemented to assess the variables of interest: 1) QSM and 2) MWF between rim+ and rim- groups at lesion level. The modeling strategy accounts for patient variability and the following covariates: subtype of lesion (rim+ or rim-), QSM lesion volume, gender, and age. The final model is reported after using a back fitting procedure.

Results

Figure 1 shows an example of T2WI and QSM and MWF maps from one patient, illustrating the appearance of rim+ and rim- lesions on QSM. QSM and MWF values for both rim and core ROI’s from QSM rim+ lesions were evaluated. For rim+ lesions, their QSM volume tend to be larger than T2w volume (Fig.2), the QSM value decreased from the rim (45.29 ± 13.6) to the core (31.52 ± 12.01) (p<0.01) (Fig 3a), and similarly, the MWF value decreased from the rim (0.045 ± 0.017) to the core (0.033 ± 0.018) (p<0.01) (Fig.3b). This pattern is consistent with iron deposition at the edge of rim+ lesions. QSM rim+ had higher whole-lesion susceptibility (38.07 ± 11.72) as compared to rim- lesions (26.4 ± 14.15), p<0.01 (Fig 4a). After accounting for patient variability as random effect (mixed-effects-model), the QSM values of rim + lesions remained significantly higher (7.91 ± 1.850), p<0.0001, and no significant association was found with any potential covariates. The whole-lesion MWF in QSM rim+ lesions was lower (0.041± 0.017) as compared to rim- (0.061 ± 0.019), (p<0.01) (Fig 4b). In the mixed-effects-model, the MWF values of rim+ lesions remained significantly lower (-0.013 ± 0.003), p<0.0001, with QSM lesion size remaining the only other significant covariate in the final model (p<0.0001).

Discussion

We found that both QSM and MWF decrease centripetally from rim to core within MS lesions demonstrating a QSM hyperintense rim. Centripetal MWF decrease has corresponding susceptibility centripetal increase. The observed centripetal QSM decrease accompanying MWF centripetal decrease can be biophysically explained by the presence of highly paramagnetic iron that is also centripetally decreasing. Therefore, for identifying chronic active MS lesions, we can use dual QSM and MWF centripetal decrease to assess iron existence in lesion, in addition to the use of hyperintense QSM rim to assess iron existence. QSM hyperintense rim+ lesions demonstrated more demyelination suggesting iron involvement in myelin damage in the MS lesion.

Conclusions

Hyperintense rim on QSM may provide a biomarker to study the role of iron on lesion myelin injury.

Acknowledgements

We are acknowledged support from grants: R01NS072370, R01NS090464, R01NS095562,Genzyme, Biogen, Novartis, Mallincrodt.

References

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