Overview

Overview

Magnetic resonance imaging (MRI) has revolutionized both the diagnosis and treatment of multiple sclerosis (MS). MRI is used every day as a prognostic marker and in treatment response outcome assessment in clinical practice, and as an outcome measure in clinical trials. Despite the demonstrated utility of MRI, it has limited specificity to the pathological disease process and provides limited insight in the progressive forms of the disease.  Additionally, conventional MR metrics (T2w/FLAIR lesions) are insufficient to specify changes occurring at the macromolecular level (i.e., demyelination, remyelination, gliosis, and axonal loss). Although advance MRI techniques such as myelin water fraction (MWF) imaging, magnetization transfer ratio (MTR), macromolecular tissue volume (MTV), and diffusion tensor imaging (DTI) are being used to improve our understanding of the underlying pathophysiological process in MS, they suffer from poor reproducibility across different sites and different scanners. Accurate, reproducible imaging biomarkers are needed to understand the underlying biophysical processes behind the progression of disability, which, in turn, can enable improved therapies to stop and reverse disease progression.

At the Mellen Center for MS Treatment and Research, we are investigating several advanced MRI technologies with the aim of providing new insights into disease biology, improving specificity of MRI to pathological processes, and developing biomarkers for neurodegeneration/neural repair. Our group is focusing on using advanced quantitative MRI (qMRI) techniques in a multi-modal approach to improve the accurate quantification of basic MRI properties as a direct surrogate of tissue integrity in the voxel. This advance has the advantage of reproducibility across scanners of different strengths and the ability to detect change on an individual basis, leading to the development of more effective therapies to stop progression and improved prognostic tools to help clinicians personalize disease management.

 Advanced MRI research is conducted on a 3 tesla Siemens Skyra, a 3 tesla Siemens Prisma, and a 7 tesla Siemens Magnetom, all of which are housed within the Mellen Center in Cleveland, Ohio and in Las Vegas, Nevada. Over a dozen neuroradiologists, MRI physicists, and MRI technologists leverage a state of the art image analysis laboratory dedicated to MS research. The Mellen Center Imaging group pioneered and implemented the following methods to better understand MS:

Techniques under investigation include:

  • Whole brain and segmented atrophy (i.e., thalamus, cortex)
  • Diffusion tensor imaging
  • Functional MRI (including resting state functional MRI)
  • Magnetic resonance fingerprinting
  • Multi-model myelin imaging
  • Central vein imaging
  • GABA spectroscopy
  • Myelin PET Imaging
  • USPIO contrast based Imaging

Contact person:

Daniel Ontaneda, MD MSc
ontaned@ccf.org
Cleveland

Le Hua, MD
hual@ccf.org
Las Vegas

Publications

Publications

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. Fox, R.J., Coffey, C.S., Conwit, R., Cudkowicz, M.E., Gleason, T., Goodman, A., Klawiter, E.C., Matsuda, K., McGovern, M., Naismith, R.T., Ashokkumar, A., Barnes, J., Ecklund, D., Klingner, E., Koepp, M., Long, J.D., Natarajan, S., Thornell, B., Yankey, J., Bermel, R.A., Debbins, J.P., Huang, X., Jagodnik, P., Lowe, M.J., Nakamura, K., Narayanan, S., Sakaie, K.E., Thoomukuntla, B., Zhou, X., Krieger, S., Alvarez, E., Apperson, M., Bashir, K., Cohen, B.A., Coyle, P.K., Delgado, S., Dewitt, L.D., Flores, A., Giesser, B.S., Goldman, M.D., Jubelt, B., Lava, N., Lynch, S.G., Moses, H., Ontaneda, D., Perumal, J.S., Racke, M., Repovic, P., Riley, C.S., Severson, C., Shinnar, S., Suski, V., Weinstock-Guttman, B., Yadav, V., Zabeti, A., NN102/SPRINT-MS Trial Investigators, 2018. N. Engl. J. Med. 379, 846–855. https://doi.org/10.1056/NEJMoa1803583

Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Trapp, B.D., Vignos, M., Dudman, J., Chang, A., Fisher, E., Staugaitis, S.M., Battapady, H., Mork, S., Ontaneda, D., Jones, S.E., Fox, R.J., Chen, J., Nakamura, K., Rudick, R.A., 2018. Lancet. Neurol. 17, 870–884. https://doi.org/10.1016/S1474-4422(18)30245-X

MOG-related disorders: A new cause of imaging-negative myelitis? Macaron, G., Ontaneda, D., 2019. Mult. Scler. 1352458519840746. https://doi.org/10.1177/1352458519840746

Developing therapeutic strategies to promote myelin repair in multiple sclerosis. Baldassari, L.E., Feng, J., Clayton, B.L.L., Oh, S.-H., Sakaie, K., Tesar, P.J., Wang, Y., Cohen, J.A., 2019.Expert Rev. Neurother. 19, 997–1013. https://doi.org/10.1080/14737175.2019.1632192

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation. Baldassari, L.E., Planchon, S.M., Bermel, R.A., Nakamura, K., Fisher, E., Feng, J., Sakaie, K.E., Ontaneda, D., Cohen, J.A., 2019.  Mult. Scler. J. - Exp. Transl. Clin. 5, 2055217319887198. https://doi.org/10.1177/2055217319887198

Exploratory MRI measures after intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Feng, J., Offerman, E., Lin, J., Fisher, E., Planchon, S.M., Sakaie, K., Lowe, M., Nakamura, K., Cohen, J.A., Ontaneda, D., 2019.  Mult. Scler. J. - Exp. Transl. Clin. 5, 2055217319856035. https://doi.org/10.1177/2055217319856035

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up. Vollmer, B., Ontaneda, D., Harris, H., Nair, K., Bermel, R.A., Corboy, J.R., Fox, R.J., Vollmer, T., Cohen, J.A., Alvarez, E., Hersh, C.M., 2019.J. Neurol. Sci. 407, 116498. https://doi.org/10.1016/j.jns.2019.116498

Comprehensive Autopsy Program for Individuals with Multiple Sclerosis. Dutta, R., Mahajan, K.R., Nakamura, K., Ontaneda, D., Chen, J., Volsko, C., Dudman, J., Christie, E., Dunham, J., Fox, R.J., Trapp, B.D., 2019.J. Vis. Exp. https://doi.org/10.3791/59511

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice. Baldassari, L.E., Nakamura, K., Moss, B.P., Macaron, G., Li, H., Weber, M., Jones, S.E., Rao, S.M., Miller, D., Conway, D.S., Bermel, R.A., Cohen, J.A., Ontaneda, D., McGinley, M.P., 2019.  Mult. Scler. Relat. Disord. 38, 101525. https://doi.org/10.1016/j.msard.2019.101525

Vitamin D and MRI measures in progressive multiple sclerosis. Abbatemarco, J.R., Fox, R.J., Li, H., Ontaneda, D., 2019.. Scler. Relat. Disord. 35, 276–282. https://doi.org/10.1016/j.msard.2019.08.014

Advanced MRI in multiple sclerosis: current status and future challenges. Fox RJ, Beall E, Bhattacharyya P, Chen JT, Sakaie K.Neurol Clin 2011;29(2):357-80. PMID: 21439446.

Measuring myelin repair and axonal loss with diffusion tensor imaging. Fox RJ, Cronin T, Lin J, Wang X, Sakaie K, Ontaneda D, Mahmoud SY, Lowe MJ, Phillips MD.  AJNR 2011;32(1):85-91. PMID: 20947644.

CLADA: cortical longitudinal atrophy detection algorithm. Nakamura K, Fox R, Fisher E. 2011;54(1):278-89. PMID: 20674750.

A validation study of multicenter diffusion tensor imaging: reliability of fractional anisotropy and diffusivity values. Fox RJ, Sakaie K, Lee JC, Debbins JP, Liu Y, Arnold DL, Melhem ER, Smith CH, Philips MD, Lowe M, Fisher E. 2012;33(4):695-700. PMID: 22173748.

Sex differences in resting-state functional connectivity in multiple sclerosis. Koenig KA, Lowe MJ, Lin J, Sakaie KE, Stone L, Bermel RA, Beall EB, Rao SM, Trapp BD, Phillips MD.  2013;34(12):2304-11. PMID: 23811974.

Clinically feasible MTR is sensitive to cortical demyelination in MS. Chen JT, Easley K, Schneider C, Nakamura K, Kidd GJ, Chang A, Staugaitis SM, Fox RJ, Fisher E, Arnold DL, Trapp BD. Neurology 2013;80(3):246-52. PMID: 23269598.

Identifying the start of multiple sclerosis injury: a serial DTI study. Ontaneda D, Sakaie K, Lin J, Wang X, Lowe MJ, Phillips MD, Fox RJ. J Neuroimaging 2014;24(6):569-576. PMID: 25370339.

Anatomic connectivity assessed using pathway radial diffusivity is related to functional connectivity in monosynaptic pathways. Lowe MJ, Koenig KA, Beall EB, Sakaie KA, Stone L, Bermel R, Phillips MD.Brain Connect 2014;4(7):558-65. PMID: 25117651.

Hippocampal volume is related to cognitive decline and fornicial diffusion measures in multiple sclerosis. Koenig KA, Sakaie KE, Lowe MJ, Lin J, Stone L, Bermel RA, Beall EB, Rao SM, Trapp BD, Phillips MD. Magn Reson Imaging 2014;32(4):354-8. PMID: 24512796.

Injury to a specific neural pathway detected by ultra-high-field MRI. Neurology 2014;82(2):182-3. Sakaie K, Takahashi M, Sagiyama K, Dimitrov I, Frohman T, Remington G, Frohman E, Fox RJ.: 24285615

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Fox RJ, Coffey CS, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Conwit R, Naismith R, Ashokkumar A, Bermel R, Ecklund D, Koepp M, Long J, Natarajan S, Ramachandran S, Skaramagas T, Thornell B, Yankey J, Agius M, Bashir K, Cohen B, Coyle P, Delgado S, Dewitt D, Flores A, Giesser B, Goldman M, Jubelt B, Lava N, Lynch S, Miravalle A, Moses H, Ontaneda D, Perumal J, Racke M, Repovic P, Riley C, Severson C, Shinnar S, Suski V, Weinstock-Gutman B, Yadav V, Zabeti A.  ClinTrials 2016;50:166-77. PMID: 27521810.CAL

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis. Fisher E, Nakamura K, Lee JC, You X, Sperling B, Rudick RA.  Scler J 2016;22(5):668-76. PMID: 26238463.

T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. Nakamura K, Chen JT, Ontaneda D, Fox RJ, Trapp BD. Ann Neurol 2017;82(4):635-639. PMID: 28833377.

The role of advanced magnetic resonance imaging techniques in multiple sclerosis clinical trials. Mahajan KR, Ontaneda D.  2017;14(4):905-923. PMID: 28770481.

Imaging as an outcome measure in multiple sclerosis. Ontaneda D, Fox RJ.  2017;14(1):24-34. PMID: 27699722.

Measuring brain tissue integrity during 4 years using diffusion tensor imaging. Ontaneda D, Sakaie K, Lin J, Wang XF, Lowe MJ, Phillips MD, Fox RJ.  2017;38(1):31-38. PMID: 27659189.

A new algebraic method for quantitative proton density mapping using multi-channel coil data. Cordes D, Yang Z, Zhuang X, Sreenivasan K, Mishra V, Hua LH. Med Image Anal. 2017 Aug;40:154-171.  Published online 2017 Jun 23. doi:10.1016/j.media.2017.06.007doi: 10.1016/j.media.2017.06.007. PMID: 28668358.

Quantifying the local tissue volume and composition in individual brains with magnetic resonance imaging. Mezer A.A, Yeatman J., Stikov N., Kay K., Cho N.M., Dougherty R.F., Perry M.L., Parvizi J., Hua L.H., Butts-Pauly K., Wandell B. Nature Medicine. 2013;19(12):1667-1672.doi:10.1038/nm.3390 PMID: 24185694.

Members & Collaborations

Members & Collaborations

 Cleveland Clinic Affiliations 

Las Vegas

  • Dietmar Cordes, PhD 
  • Virendra Mishra, PhD
  • Karthik Sreenivasan, MS

Funding:

NIH U01NS082329, A randomized, double-blind, placebo-controlled study of ibudilast in subjects with progressive multiple Sclerosis, Fox (PI) 07/2013 – 06/2018.

PCORI MS-1610-37047, Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis (DELIVER-MS), Ontaneda (PI), 20/2018 – 01/2023.

NIH R01NS091683, Pathogenesis of tissue destruction in multiple sclerosis, Trapp (PI) 07/2016 – 06/2020.

DOD W81XWH-16-1-0446, Longitudinal Evaluation of the Relation of Imaging Measures to Cognitive Decline in Multiple Sclerosis, Koenig (PI), 09/2016 – 09/2019.

Race to Erase MS Foundation Pilot Study, Central vein sign in the early diagnosis of multiple sclerosis (CAVS-MS), Ontaneda (PI) 06/2017 – 06/2020.

NIH R01EB025197 characterization and quantification of myelin in the central nervous System Fox (PI) 08/15/19-06/30/2022

Eric and Sheila Samson Foundation.
Keep Memory Alive Foundation