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Ultra-High-Field MR imaging in multiple sclerosis: Is there a role?

PART OF MS Alumni FEATURE
Ultra-High-Field MR imaging in multiple sclerosis: Is there a role?
  • Neurology

Maria A. Rocca [1,2] MD.

[1]Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, and [2]Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

In multiple sclerosis (MS), magnetic resonance imaging (MRI) is the most important paraclinical tool used to inform diagnosis and for monitoring disease evolution, either natural or modified by treatment. The increased availability of ultra-high-field magnets (7 Tesla or higher) gives rise to questions about the main benefits of and challenges for their use with MS patients. The main advantages of ultra-high-field MRI are the improved signal-to-noise ratio, greater chemical shift dispersion, and improved contrast due to magnetic susceptibility variations, which lead to increased sensitivity to the heterogeneous pathological substrates of the disease. At present, ultra-high-field MRI is mainly used to improve our understanding of MS pathogenesis.

 

Imaging WM lesions

Ultra-high-field MRI allows better definition of lesions located in the WM and GM, their morphology and their association with the vasculature[1-3] at a resolution which is similar to that of pathological assessment. Several studies have shown that 7T and 8T systems detect a higher number of lesions within the brain WM in patients with established MS in comparison to 1.5 and 3T scanners. This suggests that abnormalities detected using quantitative MR techniques in the normal-appearing WM (NAWM) are, at least in part, due to the presence of focal lesions which go undetected when using low-field magnets. Whether the assessment of lesion burden and distribution using ultra-high-field MRI scanners assists in making an earlier diagnosis of patients presenting with a clinically isolated syndrome suggestive of MS has not yet been evaluated. However, thanks to the morphological detail that can be seen with these scanners, several studies have contributed to the identification of some interesting lesion characteristics, which can aid the differential diagnosis between MS and other neurological conditions that can mimic the disease. Specifically, due to the better definition of the relationship between demyelinating lesions and the deep venous system, several studies [1, 3-6] have shown that MS plaques form around the microvasculature. This feature can help to distinguish WM lesions in MS patients from incidental WM lesions.[6] The presence of a central small vein and a rim of hypointensity on 7T T2*-weighted magnitude images can also assist in the differentiation of WM lesions found in MS patients from those of patients with neuromyelitis optica spectrum disorders[7] or Susac syndrome.[8]

The use of iron-sensitive MRI sequences has provided additional insights into MS lesion characteristics by showing, for example, the presence of a peripheral ring of iron deposition around many acute, but also some chronic, MS lesions.[1] A recent longitudinal study has shown that ring phase lesions remained unchanged over a 2.5 year period in five relapsing remitting MS patients, challenging the notion that such lesions reveal the presence of acute activated iron-rich macrophages.[9]

 

Imaging GM lesions

Cortical lesions have been imaged with improved spatial resolution both ex vivo5 and in vivo[4,10] using ultra-high-field MRI systems (≥7T). Several studies have tried to optimize 7T imaging in order to improve the detection and classification of cortical MS lesions and to develop a clinical acquisition protocol.[10-12] Sinneker et al.[10] showed that cortical lesions are hypointense on 3D magnetization-prepared rapid acquisition gradient-echo scans, while Kilsdonk et al.[11] found that 3D fast fluid attenuated inversion recovery (FLAIR) sequences detect a higher total number of GM lesions than 3D double inversion recovery (DIR) sequences.

The advantages of 7T and multichannel receive technology have enabled the identification of different cortical lesion types in a small MS population, based on visual inspection of focal cortical hyperintensities on T2*-weighted fast low-angle shot (FLASH) and T2-weighted turbo spin echo (TSE) images.[4] The frequency with which different lesion locations were observed in the cortical ribbon, including subpial lesions, conformed to previous descriptions of the neuropathology.[13] The number of subpial lesions correlated with clinical disease severity measures, suggesting that ultra-high-field MRI is potentially a sensitive and specific marker of cortical pathology in MS.

In vivo data in a heterogeneous cohort of MS patients showed that the use of an optimized FLASH T2*-weighted sequence at 7T MRI reveals about 5- to 7-times the number of in vivo cortical lesions than does DIR imaging at 3T,[14] which has so far been the best MR tool for identifying cortical lesions in patients with MS, although detection of subpial lesions is suboptimal with DIR. Advances in the study of diffuse subpial pathology in vivo can be achieved by combining T2*-weighted acquisition at 7T with a surface-based analysis of the cortex.[15] The use of this analysis, by selectively sampling 7T T2*-weighted signal at 50% depth from pial surface, demonstrated, in patients with established and late MS, distributed subpial T2*-weighted signal increases across the whole cortical mantle.[15]

 

Quantitative and metabolic techniques

One of the most promising research applications at ultra-high-field is MR spectroscopy (MRS) of brain metabolites with low concentrations (1-5 mM) that make their detection very challenging at lower field strengths.[16] Glutathione (GSH) is an indicator of oxidative status in the human brain. The application of this MRS technique to MS patients has shown that cortical GM and WM lesions are characterized by a significant reduction of GSH concentration in comparison to healthy controls, hinting at the potential of GSH to probe brain oxidative status.[17]

Increasing field strength also improves imaging and MR spectroscopy of nuclei other than hydrogen, such as sodium (23Na) and phosphorus (31P) that have lower MR sensitivity.[18] A preliminary study of MS patients has shown an increase of whole brain intracellular Na concentration in MS patients when compared to healthy controls.[19] Recent studies have suggested that intra-axonal Na accumulation contributes to axonal degeneration by reversing the action of the sodium/calcium exchanger and thus inducing a lethal rise in intra-axonal calcium concentration.[20]

Compounds with a high magnetic susceptibility, such as those containing iron, increase the local magnetic field. This provides a contrast mechanism which is more pronounced at ultra-high-fields. Using the phase of a gradient-recalled echo image and a newly developed post-processing technique, a recent MRI study enabled high-resolution quantitative imaging of local magnetic field shifts in patients with MS.[1] The phase images showed an increased local field in the caudate, putamen, and globus pallidus of patients relative to control subjects, with contrast in 74% of WM lesions, and distinct peripheral rings in the larger lesions. Increased magnetic susceptibility (reflecting increased iron concentration) has been recently found in the deep GM of patients at presentation with clinically isolated syndromes suggestive of MS.[21] An in vivo contrast mechanism sensitive and specific to the presence of iron may help in understanding the role of iron in neurodegenerative pathology and in developing biomarkers for disease progression.

 

Conclusions

Ultra-high-field MRI is improving our understanding of MS pathogenesis. The main advantages demonstrated, so far, by the use of these scanners are: a better visualization of WM lesions and of some of their particular morphological characteristics; a net gain in the capability to visualize GM lesions and their location; the quantification of “novel” metabolites which may have a role in axonal injury; and greater sensitivity to iron accumulation. However, at present, the application of these magnets in standard clinical practice is still some way off, while their role in the diagnostic work up of patients at presentation with a clinically isolated syndromes or in monitoring disease progression or treatment response in patients with definite MS needs to be established.

 

References

[1]  Hammond KE, Metcalf M, Carvajal L, et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 Tesla with sensitivity to iron. Ann Neurol 2008;64:707-713.

[2]  Tallantyre EC, Brookes MJ, Dixon JE, Morgan PS, Evangelou N, Morris PG. Demonstrating the perivascular distribution of MS lesions in vivo with 7-Tesla MRI. Neurology 2008;70:2076-2078.

[3]  Tallantyre EC, Morgan PS, Dixon JE, et al. A comparison of 3T and 7T in the detection of small parenchymal veins within MS lesions. Invest Radiol 2009;44:491-494.

[4]  Mainero C, Benner T, Radding A, et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology 2009;73:941-948.

[5]  Kangarlu A, Bourekas EC, Ray-Chaudhury A, Rammohan KW. Cerebral cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla. AJNR Am J Neuroradiol 2007;28:262-266.

[6]  Tallantyre EC, Dixon JE, Donaldson I, et al. Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions. Neurology 2011;76:534-539.

[7]  Sinnecker T, Dorr J, Pfueller CF, et al. Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis. Neurology 2012;79:708-714.

[8]  Wuerfel J, Sinnecker T, Ringelstein EB, et al. Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis. Mult Scler 2012;18:1592-1599.

[9]  Bian W, Harter K, Hammond-Rosenbluth KE, et al. A serial in vivo 7T magnetic resonance phase imaging study of white matter lesions in multiple sclerosis. Mult Scler 2012;19:69-75.

[10]  Sinnecker T, Mittelstaedt P, Dorr J, et al. Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 2012;69:739-745.

[11]  Kilsdonk ID, de Graaf WL, Lopez Soriano A, et al. Multicontrast MR Imaging at 7T in Multiple Sclerosis: Highest Lesion Detection in Cortical Gray Matter with 3D-FLAIR. AJNR Am J Neuroradiol 2012.

[12]  de Graaf WL, Zwanenburg JJ, Visser F, et al. Lesion detection at seven Tesla in multiple sclerosis using magnetisation prepared 3D-FLAIR and 3D-DIR. Eur Radiol 2012;22:221-231.

[13]  Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003;62:723-732.

[14]  Nielsen AS, Kinkel RP, Tinelli E, Benner T, Cohen-Adad J, Mainero C. Focal cortical lesion detection in multiple sclerosis: 3 Tesla DIR versus 7 Tesla FLASH-T2. J Magn Reson Imaging 2012;35:537-542.

[15]  Cohen-Adad J, Benner T, Greve D, et al. In vivo evidence of disseminated subpial T2* signal changes in multiple sclerosis at 7 T: a surface-based analysis. Neuroimage 2011;57:55-62.

[16]  Tkac I, Oz G, Adriany G, Ugurbil K, Gruetter R. In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med 2009;62:868-879.

[17]  Srinivasan R, Ratiney H, Hammond-Rosenbluth KE, Pelletier D, Nelson SJ. MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn Reson Imaging 2010;28:163-170.

[18]  Bogner W, Chmelik M, Andronesi OC, Sorensen AG, Trattnig S, Gruber S. In vivo 31P spectroscopy by fully adiabatic extended image selected in vivo spectroscopy: a comparison between 3 T and 7 T. Magn Reson Med 2011;66:923-930.

[19]  Fleysher L, Oesingmann N, Brown R, Sodickson DK, Wiggins GC, Inglese M. Noninvasive quantification of intracellular sodium in human brain using ultrahigh-field MRI. NMR Biomed 2013;26:9-19.

[20]  Inglese M, Madelin G, Oesingmann N, et al. Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla. Brain 2010;133:847-857.

[21]  Al-Radaideh AM, Wharton SJ, Lim SY, et al. Increased iron accumulation occurs in the earliest stages of demyelinating disease: an ultra-high field susceptibility mapping study in Clinically Isolated Syndrome. Mult Scler 2012.

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Preceptorship
Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
EACCME®
by Excemed
Neurology

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.