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MRI measures of neuroprotection and repair in multiple sclerosis

  • Matilde Inglese
    Correspondence
    Correspondence: Matilde Inglese, MD, PhD, Associate Professor of Neurology, Radiology and Neuroscience, Mount Sinai School of Medicine, Annenberg 14, Box 1137, One Gustave L. Levy Place, New York, NY 10029, USA. Tel.: +1 212 241 4379; fax: +1 212 348 1310
    Affiliations
    Department of Radiology and Neurology, New York University, New York, USA
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      Summary

      Magnetic resonance imaging (MRI) has had an enormous impact on multiple sclerosis, enabling early diagnosis and providing surrogate markers for monitoring treatment response in clinical trials. Despite these advantages, conventional MRI is limited by lack of pathological specificity and lack of sensitivity to grey matter lesions and to microscopic damage in normal appearing tissue. Quantitative MRI techniques such as measures of parenchymal volume loss, magnetisation transfer imaging, diffusion tensor imaging, and proton magnetic resonance spectroscopy have enhanced our understanding of the nature and mechanism of tissue injury and repair in multiple sclerosis, and provided more specific correlates of neurological deficits and disability accrual. Some of these techniques may be of potential use in clinical trials as surrogate outcome measures for measuring treatment effects on neurodegenerative injury, which is currently difficult to quantify in clinical trials. In this respect, measures of brain volume, T1 hypointensity and magnetisation transfer ratio, and optical coherence tomography appear to be the most promising in the short term.
      The evidence for a role of neurodegeneration in the pathogenesis of multiple sclerosis, and particularly in the accumulation of irreversible disability, has become increasingly strong over recent years. This has prompted the search for new treatments that can effectively slow down, halt or even reverse such neurodegenerative processes, and in this way restore nervous system function. For this reason, there has been much interest in the development and validation of surrogate markers of neurodegeneration and neuroprotection for use in clinical trials. Advances in magnetic resonance imaging (MRI) technology have allowed the development and implementation of a number of methods that may be promising in this respect.
      To assess the utility of these methods and to identify needs for further research, sixty experts in neuropathology, clinical measurement, imaging and statistics participated in a meeting held in Amsterdam in 2008 under the aegis of the National Multiple Sclerosis Society. In the proceedings of the meeting, published in 2009 [1], brain volume changes, T1 hypointensity, magnetisation transfer ratio and optical coherence tomography were deemed the most promising measures for screening the neuroprotective capacity of new agents. Other MRI techniques, such as DTI, 1H-MRS and functional MRI, although potentially useful, require more observational data to help determine the optimal trial design.
      This article will review some of the issues that were discussed at this meeting, and present some of the imaging techniques that were considered to be the most promising.

      Keywords

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      References

        • Barkhof F
        • Calabresi PA
        • Miller DH
        • Reingold SC
        Imaging outcomes for neuroprotection and repair in multiple sclerosis trials.
        Nat Rev Neurol. 2009; 5: 256-266
        • van Waesberghe JH
        • Kamphorst W
        • De Groot CJ
        • et al.
        Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability.
        Ann Neurol. 1999; 46: 747-754
        • van Waesberghe JH
        • van Walderveen MA
        • Castelijns JA
        • et al.
        Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR.
        AJNR Am J Neuroradiol. 1998; 19: 675-683
        • Zivadinov R
        • Leist TP
        Clinical–magnetic resonance imaging correlations in multiple sclerosis.
        J Neuroimaging. 2005; 15: 10S-21S
        • Barkhof F
        • Karas GB
        • van Walderveen MA
        T1 hypointensities and axonal loss.
        Neuroimaging Clin N Am. 2000; 10 (ix.): 739-752
        • Truyen L
        • van Waesberghe JH
        • van Walderveen MA
        • et al.
        Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.
        Neurology. 1996; 47: 1469-1476
        • Filippi M
        • Rovaris M
        • Rocca MA
        • Sormani MP
        • Wolinsky JS
        • Comi G
        Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”.
        Neurology. 2001; 57: 731-733
        • Dalton CM
        • Miszkiel KA
        • Barker GJ
        • et al.
        Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis.
        J Neurol. 2004; 251: 407-413
        • Simon JH
        • Lull J
        • Jacobs LD
        • et al.
        A longitudinal study of T1 hypointense lesions in relapsing MS: MSCRG trial of interferon beta-1a. Multiple Sclerosis Collaborative Research Group.
        Neurology. 2000; 55: 185-192
        • Gasperini C
        • Pozzilli C
        • Bastianello S
        • et al.
        Interferon-beta-1a in relapsing–remitting multiple sclerosis: effect on hypointense lesion volume on T1 weighted images.
        J Neurol Neurosurg Psychiatry. 1999; 67: 579-584
        • Gasperini C
        • Paolillo A
        • Giugni E
        • et al.
        MRI brain volume changes in relapsing–remitting multiple sclerosis patients treated with interferon beta-1a.
        Mult Scler. 2002; 8: 119-123
        • Bagnato F
        • Gupta S
        • Richert ND
        • et al.
        Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations.
        Arch Neurol. 2005; 62: 1684-1688
        • Mikol DD
        • Barkhof F
        • Chang P
        • et al.
        Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.
        Lancet Neurol. 2008;
        • Cadavid D
        • Cheriyan J
        • Skurnick J
        • Lincoln JA
        • Wolansky LJ
        • Cook SD
        New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.
        J Neurol Neurosurg Psychiatry. 2009; 80: 1337-1343
        • O'Connor P
        • Filippi M
        • Arnason B
        • et al.
        250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing–remitting multiple sclerosis: a prospective, randomised, multicentre study.
        Lancet Neurol. 2009; 8: 889-897
        • van den Elskamp IJ
        • Lembcke J
        • Dattola V
        • et al.
        Persistent T1 hypointensity as an MRI marker for treatment efficacy in multiple sclerosis.
        Mult Scler. 2008; 14: 764-769
        • Smith SM
        • De Stefano N
        • Jenkinson M
        • Matthews PM
        Normalized accurate measurement of longitudinal brain change.
        J Comput Assist Tomogr. 2001; 25: 466-475
        • Rudick RA
        • Fisher E
        • Lee JC
        • Simon J
        • Jacobs L
        Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing–remitting MS. Multiple Sclerosis Collaborative Research Group.
        Neurology. 1999; 53: 1698-1704
        • Amato MP
        • Portaccio E
        • Goretti B
        • et al.
        Association of neocortical volume changes with cognitive deterioration in relapsing–remitting multiple sclerosis.
        Arch Neurol. 2007; 64: 1157-1161
        • Fisher E
        • Lee JC
        • Nakamura K
        • Rudick RA
        Gray matter atrophy in multiple sclerosis: a longitudinal study.
        Ann Neurol. 2008; 64: 255-265
        • Dalton CM
        • Chard DT
        • Davies GR
        • et al.
        Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.
        Brain. 2004; 127: 1101-1107
      1. De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology;74:1868–76.

        • Jordy SS
        • Tilbery CP
        • Fazzito MM
        Immunomodulator therapy migration in relapsing remitting multiple sclerosis: a study of 152 cases.
        Arq Neuropsiquiatr. 2008; 66: 11-14
        • De Stefano N
        • Matthews PM
        • Filippi M
        • et al.
        Evidence of early cortical atrophy in MS: relevance to white matter changes and disability.
        Neurology. 2003; 60: 1157-1162
        • Gauthier SA
        • Berger AM
        • Liptak Z
        • et al.
        Rate of brain atrophy in benign vs. early multiple sclerosis.
        Arch Neurol. 2009; 66: 234-237
        • Simon JH
        • Jacobs LD
        • Campion MK
        • et al.
        A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
        Neurology. 1999; 53: 139-148
        • Zivadinov R
        • Stosic M
        • Cox JL
        • Ramasamy DP
        • Dwyer MG
        The place of conventional MRI and newly emerging MRI techniques in monitoring different aspects of treatment outcome.
        J Neurol. 2008; 255: 61-74
        • van den Elskamp IJ
        • Boden B
        • Dattola V
        • et al.
        Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis.
        Neuroradiology. 2010; 52: 875-881
        • Fisniku LK
        • Chard DT
        • Jackson JS
        • et al.
        Gray matter atrophy is related to long-term disability in multiple sclerosis.
        Ann Neurol. 2008; 64: 247-254
        • Chard DT
        • Griffin CM
        • Rashid W
        • et al.
        Progressive grey matter atrophy in clinically early relapsing–remitting multiple sclerosis.
        Mult Scler. 2004; 10: 387-391
        • Tiberio M
        • Chard DT
        • Altmann DR
        • et al.
        Gray and white matter volume changes in early RRMS: a 2-year longitudinal study.
        Neurology. 2005; 64: 1001-1007
        • Pagani E
        • Rocca MA
        • Gallo A
        • et al.
        Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype.
        AJNR Am J Neuroradiol. 2005; 26: 341-346
        • Tekok-Kilic A
        • Benedict RH
        • Weinstock-Guttman B
        • et al.
        Independent contributions of cortical gray matter atrophy and ventricle enlargement for predicting neuropsychological impairment in multiple sclerosis.
        Neuroimage. 2007; 36: 1294-1300
        • Calabrese M
        • Agosta F
        • Rinaldi F
        • et al.
        Cortical lesions and atrophy associated with cognitive impairment in relapsing–remitting multiple sclerosis.
        Arch Neurol. 2009; 66: 1144-1150
        • Sepulcre J
        • Masdeu JC
        • Goni J
        • et al.
        Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways.
        Mult Scler. 2009; 15: 337-344
        • Zivadinov R
        • Locatelli L
        • Cookfair D
        • et al.
        Interferon beta-1a slows progression of brain atrophy in relapsing–remitting multiple sclerosis predominantly by reducing gray matter atrophy.
        Mult Scler. 2007; 13: 490-501
        • Bendfeldt K
        • Egger H
        • Nichols TE
        • et al.
        Effect of immunomodulatory medication on regional gray matter loss in relapsing–remitting multiple sclerosis – a longitudinal MRI study.
        Brain Res. 2010; 1325: 174-182
        • Pike GB
        Magnetization transfer imaging of multiple sclerosis.
        Ital J Neurol Sci. 1997; 18: 359-365
        • Traboulsee A
        • Dehmeshki J
        • Peters KR
        • et al.
        Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities.
        Mult Scler. 2003; 9: 566-573
        • Schmierer K
        • Scaravilli F
        • Altmann DR
        • Barker GJ
        • Miller DH
        Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain.
        Ann Neurol. 2004; 56: 407-415
        • Barkhof F
        • Bruck W
        • De Groot CJ
        • et al.
        Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance.
        Arch Neurol. 2003; 60: 1073-1081
        • Richert N
        • Bagnato F
        • Howard T
        • et al.
        Whole brain magnetization transfer analysis of relapsing-remitting multiple sclerosis patients treated with IFNB-1b or glatiramer acetate.
        Multiple Sclerosis. 2003; 9: S64
        • Khan O
        • Mackenzie M
        • Shen Y
        • Zak I
        • Latif Z
        • Caon C
        Combined brain MTR and H-MRS multi-modality approach to investigate mechanism of action of interferon beta and glatiramer acetate in RRMS.
        Neurology. 2007; 68: P02.058
        • Richert ND
        • Ostuni JL
        • Bash CN
        • Leist TP
        • McFarland HF
        • Frank JA
        Interferon beta-1b and intravenous methylprednisolone promote lesion recovery in multiple sclerosis.
        Mult Scler. 2001; 7: 49-58
        • Kita M
        • Goodkin DE
        • Bacchetti P
        • Waubant E
        • Nelson SJ
        • Majumdar S
        Magnetization transfer ratio in new MS lesions before and during therapy with IFNbeta-1a.
        Neurology. 2000; 54: 1741-1745
        • Richert ND
        • Ostuni JL
        • Bash CN
        • Duyn JH
        • McFarland HF
        • Frank JA
        Serial whole-brain magnetization transfer imaging in patients with relapsing–remitting multiple sclerosis at baseline and during treatment with interferon beta-1b.
        AJNR Am J Neuroradiol. 1998; 19: 1705-1713
        • Inglese M
        • van Waesberghe JH
        • Rovaris M
        • et al.
        The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS.
        Neurology. 2003; 60: 853-860
      2. van den Elskamp IJ, Knol DL, Vrenken H, et al. Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis. Mult Scler;16:660–9.

        • Chen JT
        • Collins DL
        • Atkins HL
        • Freedman MS
        • Arnold DL
        Magnetization transfer ratio evolution with demyelination and remyelination in multiple sclerosis lesions.
        Ann Neurol. 2008; 63: 254-262
        • Simmons ML
        • Frondoza CG
        • Coyle JT
        Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies.
        Neuroscience. 1991; 45: 37-45
        • Moffett JR
        • Ross B
        • Arun P
        • Madhavarao CN
        • Namboodiri AM
        N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology.
        Prog Neurobiol. 2007; 81: 89-131
        • Bjartmar C
        • Kidd G
        • Mork S
        • Rudick R
        • Trapp BD
        Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients.
        Ann Neurol. 2000; 48: 893-901
        • Dutta R
        • McDonough J
        • Yin X
        • et al.
        Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients.
        Ann Neurol. 2006; 59: 478-489
        • Arnold DL
        • Matthews PM
        • Francis G
        • Antel J
        Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease.
        Magn Reson Med. 1990; 14: 154-159
        • De Stefano N
        • Matthews PM
        • Antel JP
        • Preul M
        • Francis G
        • Arnold DL
        Chemical pathology of acute demyelinating lesions and its correlation with disability.
        Ann Neurol. 1995; 38: 901-909
        • Davie CA
        • Barker GJ
        • Thompson AJ
        • Tofts PS
        • McDonald WI
        • Miller DH
        1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 1997; 63: 736-742
        • Sharma R
        • Narayana PA
        • Wolinsky JS
        Grey matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging.
        Mult Scler. 2001; 7: 221-226
        • Inglese M
        • Liu S
        • Babb JS
        • Mannon LJ
        • Grossman RI
        • Gonen O
        Three-dimensional proton spectroscopy of deep gray matter nuclei in relapsing–remitting MS.
        Neurology. 2004; 63: 170-172
        • Arnold DL
        Magnetic resonance spectroscopy: imaging axonal damage in MS.
        J Neuroimmunol. 1999; 98: 2-6
        • De Stefano N
        • Matthews PM
        • Fu L
        • et al.
        Axonal damage correlates with disability in patients with relapsing–remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study.
        Brain. 1998; 121: 1469-1477
        • Khan O
        • Shen Y
        • Bao F
        • et al.
        Long-term study of brain 1H-MRS study in multiple sclerosis: effect of glatiramer acetate therapy on axonal metabolic function and feasibility of long-term H-MRS monitoring in multiple sclerosis.
        J Neuroimaging. 2008; 18: 314-319
        • Narayanan S
        • Caramanos Z
        • Arnold D
        The effect of glatiramer acetate treatment on axonal integrity in multiple sclerosis.
        Mult Scler. 2004; 10: S256
        • Sarchielli P
        • Presciutti O
        • Tarducci R
        • et al.
        1H-MRS in patients with multiple sclerosis undergoing treatment with interferon beta-1a: results of a preliminary study.
        J Neurol Neurosurg Psychiatry. 1998; 64: 204-212
        • Narayanan S
        • De Stefano N
        • Francis GS
        • et al.
        Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b.
        J Neurol. 2001; 248: 979-986
        • Parry A
        • Corkill R
        • Blamire AM
        • et al.
        Beta-interferon treatment does not always slow the progression of axonal injury in multiple sclerosis.
        J Neurol. 2003; 250: 171-178
        • Cree B
        • Ratiney H
        • Owen M
        • Evangelista A
        • Oh J
        • Pelletier D
        Magnetic resonance spectroscopy effects of natalizumab: single center results from the SENTINEL study.
        Neurology. 2007;
        • De Stefano N
        • Filippi M
        • Miller D
        • et al.
        Guidelines for using proton MR spectroscopy in multicenter clinical MS studies.
        Neurology. 2007; 69: 1942-1952
        • Comi G
        • Martinelli V
        • Rodegher M
        • et al.
        Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2009; 374: 1503-1511
        • Arnold D
        • Narayanan S
        • Antel S
        Treatment with glatiramer acetate protects axons in patients with clinically isolated syndromes: evidence from the PreCISe trial.
        Multiple Sclerosis. 2008; 14: S10
        • Parisi V
        • Manni G
        • Spadaro M
        • et al.
        Correlation between morphological and functional retinal impairment in multiple sclerosis patients.
        Invest Ophthalmol Vis Sci. 1999; 40: 2520-2527
        • Fisher JB
        • Jacobs DA
        • Markowitz CE
        • et al.
        Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis.
        Ophthalmology. 2006; 113: 324-332
        • Trip SA
        • Schlottmann PG
        • Jones SJ
        • et al.
        Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis.
        Ann Neurol. 2005; 58: 383-391
        • Trip SA
        • Wheeler-Kingshott C
        • Jones SJ
        • et al.
        Optic nerve diffusion tensor imaging in optic neuritis.
        Neuroimage. 2006; 30: 498-505
        • Gordon-Lipkin E
        • Chodkowski B
        • Reich DS
        • et al.
        Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis.
        Neurology. 2007; 69: 1603-1609
        • Frohman EM
        • Dwyer MG
        • Frohman T
        • et al.
        Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: a pilot study.
        J Neurol Sci. 2009; 282: 96-105
      3. Henderson AP, Trip SA, Schlottmann PG, et al. A preliminary longitudinal study of the retinal nerve fiber layer in progressive multiple sclerosis. J Neurol;257:1083–91.

      4. Talman LS, Bisker ER, Sackel DJ, et al. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol;67:749–60.

      5. Calabrese M, Rocca MA, Atzori M, et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse–onset multiple sclerosis. Ann Neurol;67:376–83.

        • Kollia K
        • Maderwald S
        • Putzki N
        • et al.
        First clinical study on ultra-high-field MR imaging in patients with multiple sclerosis: comparison of 1.5T and 7T.
        AJNR Am J Neuroradiol. 2009; 30: 699-702
        • Srinivasan R
        • Sailasuta N
        • Hurd R
        • Nelson S
        • Pelletier D
        Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T.
        Brain. 2005; 128: 1016-1025
        • 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
        • 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
        • Vellinga MM
        • Vrenken H
        • Hulst HE
        • et al.
        Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI to demonstrate diffuse inflammation in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients: an exploratory study.
        J Magn Reson Imaging. 2009; 29: 774-779
        • Stankoff B
        • Wang Y
        • Bottlaender M
        • et al.
        Imaging of CNS myelin by positronemission tomography.
        Proc Natl Acad Sci U S A. 2006; 103: 9304-9309