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Contrasting frequency shifts and QSM in a longitudinal analysis of MS lesions to determine the nature of MR frequency and QSM signal changes
Vanessa Wiggermann1,2,3, Enedino Hernandez-Torres2,3, Irene M Vavasour3,4, Cornelia Laule1,5,6, David KB Li4,7, Anthony Traboulsee7, Alexander MacKay1,3,4, and Alexander Rauscher1,2,4

1Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada, 2Pediatrics, University of British Columbia, Vancouver, BC, Canada, 3UBC MRI Research Centre, University of British Columbia, Vancouver, BC, Canada, 4Radiology, University of British Columbia, Vancouver, BC, Canada, 5Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada, 6International Collaboration on Repair Discoveries (ICORD), Vancouver, BC, Canada, 7Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada

Synopsis

Magnetic susceptibility and MR frequency shifts in MS lesions are sensitive measures of tissue damage. However, the sensitivity of FS and QSM to magnetic susceptibility effects as well as changes in tissue microarchitecture complicate data interpretation in biological systems. By contrasting QSM and resonance frequency shift maps these two mechanisms may be differentiated. We observed that the signal shifts at enhancement are reflective of microstructural changes indicating formation of myelin debris, as similar FS and QSM changes were observed. Signal reductions in MS lesions 5yrs-post-enhancement however are only present on QSM, suggesting removal of myelin debris and axonal loss as the underlying mechanisms.

Introduction

MR frequency shift (FS) imaging and quantitative susceptibility mapping (QSM) have become frequently used tools for the assessment of myelin damage in multiple sclerosis (MS) lesions, particularly during blood-brain barrier breakdown and initial lesion formation. Strong positive signal shifts have been observed at time of lesion enhancement1,2, persisting for 1-3 years before returning again to non-lesional white matter (WM) values3,4. However, it is unknown when MS lesions start to show reduced QSM values post-enhancement and the underlying nature of this signal reduction are not well understood. We compared FS and QSM changes in MS lesions from enhancement to 3-5 years.

Methods

Subjects: 11 MS patients and four healthy controls were scanned each month for 6 months and once 3.2-5.8 years post-baseline (long-term follow-up, LTFU, median 5.2yrs). Experiments: Data were acquired on a 3T Philips Achieva using an 8-channel SENSE head coil, including a single-echo gradient-echo (GRE) (TE/TR=20/40ms, voxel size=0.5x0.7x2mm3, FOV=240x166x64mm3, FA=19˚), contrast-enhanced T1w images and FLAIR. Single-echo GRE data were acquired to match the baseline data acquired in 20071.

Data analysis: FS and QSM maps were computed using an in-house developed pipeline of Laplacian unwrapping5,6, V-SHARP for background field removal7,8 and dipole inversion using an l1-norm minimization with sparsity priors9. Homodyne filtered FS maps were also produced1. Enhancing lesions were identified and delineated on Gadolinium (Gd)-enhanced T1w-images within the first six months. To ensure that differences in lesion delineation did not influence the observed signal shifts, additional lesion masks were created for the same enhancing lesions based QSM or the GRE-magnitude. Reference regions of normal-appearing (NAWM) and normal WM in controls were defined. NiftyReg10 and FSL11,12 were used to create a half-way space between baseline and LTFU. Quantitative images and lesion masks from all individual time points were subsequently mapped to the half-way space.

Results

Seventy-one enhancing lesions were identified; 19 were located outside the GRE-data field-of-view, and 17 were excluded due to contamination by large vessels or proximity to the basal ganglia, ventricles or cortex. The majority of the 35 remaining enhancing lesions appeared either in regions of previous hyperintense signal on FLAIR or at baseline, with no pre-enhancement data available. Figure 1 displays examples of lesions appearing in a region free of prior hyperintense signal (left) and on top of prior FLAIR-hyperintensity (right). Lesions appeared at enhancement either FS/QSM-isointense or hyperintense compared to surrounding WM. The range of FS/QSM-values within lesions can be appreciated from Figure 2. Lesions showed no patient-specific FS/QSM-offset. QSM-defined lesions appeared to capture greater change between baseline and LTFU than Gd-T1 defined lesions. Average FS and QSM values (Figure 3) displayed the characteristic signal increase at time of enhancement, followed by a stabilization of the FS/QSM-signal, before the return to baseline values. The average FS/QSM-shifts between these segments, depending on lesion definition, are summarized in Table 1. The average non-filtered FS did not show a signal reduction at LTFU, but remained at post-enhancement values.

Discussion

Previous studies suggested that QSM may replace Gadolinium-contrast T1w-scans for the detection of blood-brain barrier breakdown. However, the signal shift at time of enhancement is dependent on whether the area showed prior FLAIR-hyperintensity. Thus, not all lesion activity will be captured by QSM. On average, all image processing techniques produced similar signal shifts at enhancement, indicating that the shifts are due to microstructural changes, not magnetic susceptibility shifts. The signal decrease occurring 5yrs post-enhancement was not reflected in the FS maps and thus may be due to magnetic susceptibility changes. The signal reduction observed at 5yrs in this study is earlier than other studies have indicated2. Homodyne FS detected the return to baseline values as the filtering flattened non-local field inhomogeneities. The signal reduction towards LTFU may in part relate to clearance of myelin debris13,14. Remyelination also reduces QSM; however remyelination is believed to occur earlier during lesion development (<1year). while oligodendrocytes are still present and axons intact15,16. 20-40% of acute lesion develop into black holes, i.e. lesions showing axonal loss and scaring17,18. Axonal degeneration in the transition from new lesions into black holes may further contribute to the signal reduction at LTFU. BH show small positive FS and QSM values, although large variation exist1.

Conclusion

FS and QSM are both sensitive to microstructural changes occurring at time of enhancement, but FS may not fully capture susceptibility-related signal changes 5yrs post-enhancement due to the changes' non-local nature. Furthermore, if prior FLAIR-hyperintensity was present in a region of recent lesion activity, e.g. lesion re-enhancement, it may not be detected by QSM.

Acknowledgements

No acknowledgement found.

References

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Figures

Figure 1: Example evolution of enhancing lesions appearing in regions without (left) and with (right) prior FLAIR-hyperintensity. FS and QSM curves follow the same trends and are in line with the visually observed contrast changes. Both lesions were only diffusely visible at LTFU, with the lesion on the right being absorbed within underlying FLAIR-hyperintensities. The FS and QSM curves demonstrate the difference between these two lesions types, despite the fact that both showed enhancement. FS and QSM values are given relative to the Larmor frequency at 3T.

Figure 2: FS and QSM evolution of all individual enhancing MS lesions. The time point of enhancement is denoted as “time point 0”. The range of FS and magnetic susceptibility changes over time is smaller than differences between different lesions. Lesions from different patients are coded in different colors. Note that there was no patient-specific offset. FS and QSM values are given relative to the Larmor frequency at 3T.

Figure 3: Average FS and QSM evolutions were largely independent of their method of lesion definition, despite an offset for QSM/Mag-defined lesions, which presented with overall higher FS and QSM values. FS and QSM values are given relative to the Larmor frequency at 3T. All techniques showed the expected signal increase at time of enhancement, but only homodyne filtered FS and QSM showed a significant signal reduction at LTFU. Non-filtered FS remained stable. For reference, the average FS and QSM values in NAWM and NWM are shown; both did not change over time.

Table 1: Signal differences between pre-enhancement (signal average month -6 to -4) to post-enhancement (signal average month 1 to 5), compared to LTFU. FS and QSM values are given relative to the Larmor frequency at 3T. In most cases, the shifts were of comparable magnitude independent of how the lesions were delineated.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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