Formation of transient and persistent multiple sclerosis lesions: serial follow-up with quantitative MR imaging and spectroscopy
Ivan Kirov1,2, Shu Liu1,2, Assaf Tal3, William E. Wu1,2, Matthew S. Davitz1,2, James S. Babb1,2, Henry Rusinek1,2, Joseph Herbert4, and Oded Gonen1,2

1Center for Advanced Imaging Innovation and Research (CAI2R), New York University School of Medicine, New York, NY, United States, 2Bernard and Irene Schwartz Center for Biomedical Imaging, New York University School of Medicine, New York, NY, United States, 3Chemical Physics, Weizmann Institute of Science, Rehovot, Israel, 4Neurology, New York University Langone Medical Center, New York, NY, United States

Synopsis

Using MR imaging and proton spectroscopy, we follow the evolution of transient and persistent multiple sclerosis lesions from pre-lesional state to long-term (over 2 years post-formation) status. The main finding was that the sharp drop in N-acetyl-aspartate associated with the formation of an acute lesion was reversible in resolving, but not in persisting black holes, substantiating the idea that transient new lesions revert to pre-lesional axonal state. The additional findings were a decrease in creatine after the appearance of a persisting lesion and the lack of metabolic differences between pre-lesional tissue giving rise to resolving versus persisting lesions.

Introduction

MRI assessment of white matter lesions is the primary diagnostic surrogate and clinical trial imaging outcome measure in multiple sclerosis (MS). Nevertheless, the processes leading to the formation of lesions and underlying their subsequent evolution on conventional imaging are poorly understood. Proton MR spectroscopy (1H-MRS) can inform about these processes; however, the technique’s inherent low spatial resolution poses challenges for monitoring all but the largest lesions. Here we implement 1H-MRS imaging (1H-MRSI) with stringent partial volume corrections and absolute quantification to enable the study of transient and persistent lesions over their full evolution: from pre-lesional state, through formation, to either resolved or chronic status.

Methods

Subjects: 10 relapsing-remitting MS patients within 6 years from diagnosis, scanned semi-annually for 3 years. Data acquisition: pre- and post-contrast T1-weighted MRI (MP-RAGE), T2-weighted MRI (FLAIR), B0 shimming, 10×8×4.5 cm (AP×LR×IS)=360 cm3 1H-MRS VOI (PRESS TE/TR=35/1800 ms), encoded to 480 voxels, each 1.0×1.0×0.75 cm3 (Fig. 1). Segmentation: Lesion masks were obtained from FLAIR1 and gray, white matter (GM, WM) and CSF masks were segmented from MP-RAGE2. Only lesions >0.3 cm3 (>40% of 1H-MRSI voxel) were retained. Co-registration: FLAIR was co-registered to the MP-RAGE and the transformation matrix was applied to the lesion mask co-registering it to the MP-RAGE space. All masks, now in MP-RAGE space, were co-registered with the 1H-MRSI, yielding their volume in every 1H-MRSI voxel. To delineate pre-lesional tissue, FLAIR from the timepoint at which the lesion first appeared were co-registered to the FLAIR of the preceding timepoint(s), and the transformation matrix was applied to the lesion mask, creating a “ghost” mask of the forthcoming lesion (Fig. 2). Lesion characterization: Based on their MP-RAGE contrast, lesions were quantitatively defined as isointense or hypointense. A T1-contrast ratio was calculated for each lesion as a continuous measure of T1-hypointensity3. The rubric followed for lesion definitions is presented in Fig. 3. Pre-lesional tissue was defined as a region in which a lesion satisfying the size inclusion criterion (>0.3 cm3) appeared at a subsequent time point. Metabolic quantification: Phantom replacement with MS tissue- and lesion-specific T1 and T2 relaxation times4,5. 1H-MRSI quality control and partial volume considerations: Voxel shifting6 was performed for each lesion and pre-lesional tissue mask assuring that only voxels with >40% mask, <30% CSF, <30% GM; metabolite Cramer Rao lower bounds<20% and 4<linewidths<13 Hz are retained. Metabolite concentrations were corrected for partial CSF volume. Statistics: ANCOVA, random coefficients regression and Pearson correlations with 2-sided p values. Analyses controlled for variable lesion/pre-lesion volume in the 1H-MRSI voxel.

Results

Six lesions were classified as acute; all were T1-hypointense, rendering them “acute black holes”7,8 (Fig. 3). They were distributed amongst four patients, as shown in Table 1, which also demonstrates contrast enhancement status and lesion evolution.

Metabolite levels in pre-lesional tissue giving rise to resolving black holes (n=5) were not different from those in pre-lesional tissue giving rise to chronic black holes (n=3) (all p>0.08).

After the appearance of a resolving acute black hole, there was significant increase in NAA (0.1 mM/month, p=0.01) and T1-contrast ratio (0.004/month, p=0.01) (Fig. 4).

After the appearance of a persisting acute black hole, there was significant decrease in Cr (-0.1 mM/month, p=0.01) and T1-contrast ratio (-0.002/month, p=0.01).

Discussion

The key finding was that NAA levels showed a statistically significant recovery in the months following the appearance of an acute lesion which concurrently resolved on T2-weighted imaging. This correlated with decreasing T1-hypointensity, indicating that in transient black holes, retaining isointensity is associated with a normalization of axonal function. Previous 1H-MRS studies support the notion of post-acute NAA recovery9,10,11, but in this study we test it statistically, and distinguish between transient and persistent black holes. The results here have important implications for trials utilizing lesion MRI outcomes, as they substantiate the notion that transient new lesions represent a return to pre-lesional axonal state, and are therefore the preferred outcome after new lesion formation also from a metabolic point of view.

The decreasing Cr levels in persisting black holes were driven by a spike at the acute stage, with a return to pre-lesional levels at the next follow-up. Without concurrent changes in the other glial markers or NAA, this is best interpreted as inflammation-related energy imbalance without a post-acute manifestation.

Conclusion

NAA declines during the formation of all acute lesions, but recovery to pre-lesional levels occurs in only in transient lesions. This implies that transient lesions do not cause permanent axonal damage and are therefore a positive outcome after lesion formation.

Acknowledgements

This work was supported by NIH grants NS050520, NS29029, EB01015 and the Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net), a NIBIB Biomedical Technology Resource Center (NIH P41 EB017183). Assaf Tal acknowledges the support of the Monroy-Marks Career Development Fund, the Carolito Stiftung Fund, the Leona M. and Harry B. Helmsley Charitable Trust and the historic generosity of the Harold Perlman Family.

References

1. Rusinek H, Glodzik L, Mikheev A, Zanotti A, Li Y, De Leon M. Fully automatic segmentation of white matter lesions: error analysis and validation of a new tool. Intern J Computer Assisted Radiology & Surgery 2013; 8: 289-291.

2. Ashburner J, Friston K. Multimodal image coregistration and partitioning--a unified framework. Neuroimage 1997; 6: 209-17 .

3. van Walderveen MA, Barkhof F, Pouwels PJ, van Schijndel RA, Polman CH, Castelijns JA. Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 1999; 46: 79-87

4. Brief EE, Vavasour IM, Laule C, Li DK, Mackay AL. Proton MRS of large multiple sclerosis lesions reveals subtle changes in metabolite T(1) and area. NMR Biomed 2010; 23: 1033-7.

5. Kirov II, Liu S, Fleysher R, Fleysher L, Babb JS, Herbert J, et al. Brain metabolite proton T2 mapping at 3.0 T in relapsing-remitting multiple sclerosis. Radiology 2010; 254: 858-66.

6. Bracewell RN. The Fourier transform and its applications. New York: McGraw-Hill, 1978.

7. Filippi M, Rocca MA, De Stefano N, Enzinger C, Fisher E, Horsfield MA, et al. Magnetic resonance techniques in multiple sclerosis: the present and the future. Arch Neurol 2011; 68: 1514-20.

8. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121: 3-24.

9. Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, et al. Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 1994; 117: 49-58.

10. Narayana PA, Doyle TJ, Lai D, Wolinsky JS. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998; 43: 56-71.

11. Zaaraoui W, Rico A, Audoin B, Reuter F, Malikova I, Soulier E, et al. Unfolding the long-term pathophysiological processes following an acute inflammatory demyelinating lesion of multiple sclerosis. Magn Reson Imaging 2010; 28: 477-86.

Figures

Figure 1: 1H-MRSI positioning and example spectra

Sagittal (A), coronal (B) T1-weighted, and axial (C) T2-weighted MRI superimposed with the 8×10×4.5 cm 1H-MRSI volume-of-interest (solid line) and 16×16 cm field-of-view (dashed line). HSI=Hadamard Spectroscopic Imaging; CSI=Chemical Shift Imaging.

D. The spectral matrix from (C), with voxel size shown.


Figure 2: Segmentation of pre-lesional tissue

Lesions are segmented and their FLAIR is co-registered to the FLAIR at the preceding timepoint. The transformation matrix is then used to co-register the lesion mask on the pre-lesional tissue.


Figure 3: Flow chart for determining lesion types with sample sizes at baseline in each category

Table 1

Left: Patients' baseline demographic and clinical data, sorted by disease duration (months)

GA=Glatiramer Acetate, IFN-β1b=Interferon-β1b, IFN-β1a=Interferon-β1a.

Right: Timeline of lesion status at each semiannual scan. Gd- = non-enhancing lesion, Gd+ =enhancing lesion


Figure 4: 1H-MRSI and MRI in tissue transitioning from pre-lesional state to resolved acute black hole

Changes in NAA concentration (A) and in T1-contrast ratio (B) color-coded to correspond to the spectra in C, bottom and D.

C, top: The T1- and T2-weighed imaging corresponding to the below spectra.




Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
4062