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, conventional MRI may have limited specificity to the pathological disease processes. 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). Advanced MRI techniques such as Central vein sign (CVS) imaging, paramagnetic rim lesion identification (PRL),  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. 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 susceptibility based T2*-EPI sequences to identify CVS and PRL. We also are 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 Terra, 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 and clinical trials in MS. All clinical MRI studies are also analyzed quantitatively proving a large dataset of images ideal for big data applications. 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.
  • Paramagnetic rim lesion imaging.
  • 7T imaging of the spinal cord.

Contact person:

Daniel Ontaneda, MD MSc
ontaned@ccf.org
Cleveland

Le Hua, MD
hual@ccf.org
Las Vegas

Publications

Publications

Koenig KA, Sakaie KE, Ontaneda D, Mahajan KR, Oh SH, Nakamura K, Jones SE, Rao SM, Lowe MJ. Mult Scler J Exp Transl Clin. 2024 May 6;10(2):20552173241240937. doi: 10.1177/20552173241240937. PMID: 38715892; PMCID: PMC11075608.

Fox RJ, Cree BAC, de Sèze J, Gold R, Hartung HP, Jeffery D, Kappos L, Montalban X, Weinstock-Guttman B, Singh CM, Altincatal A, Belviso N, Avila RL, Ho PR, Su R, Engle R, Sangurdekar D, de Moor C, Fisher E, Kieseier BC, Rudick Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis. Neurology. 2024 May 14;102(9):e209357. doi: 10.1212/WNL.0000000000209357. Epub 2024 Apr 22. PMID: 38648580.

Levit E, Ren Z, Gonzenbach V, Azevedo CJ, Calabresi PA, Cree BA, Freeman L, Longbrake EE, Oh J, Schindler MK, Sicotte NL, Reich DS, Ontaneda D, Sati P, Cao Q, Shinohara RT, Solomon AJ. Choroid plexus volume differentiates MS from its mimics. Mult Scler. 2024 Mar 13:13524585241238094. doi: 10.1177/13524585241238094. Epub ahead of print. PMID: 38481081.

Nakamura K, Thoomukuntla B, Bena J, Cohen JA, Fox RJ, Ontaneda D. Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis. Mult Scler. 2024 Mar;30(3):369-380. doi: 10.1177/13524585231224702. Epub 2024 Jan 29. PMID: 38286755.

Bagnato F, Sati P, Hemond CC, Elliott C, Gauthier SA, Harrison DM, Mainero C, Oh J, Pitt D, Shinohara RT, Smith SA, Trapp B, Azevedo CJ, Calabresi PA, Henry RG, Laule C, Ontaneda D, Rooney WD, Sicotte NL, Reich DS, Absinta M. Imaging chronic active lesions in multiple sclerosis: a consensus statement. Brain. 2024 Jan 16:awae013. doi: 10.1093/brain/awae013. Epub ahead of print. PMID: 38226694.

Amin M, Nakamura K, Ontaneda D. Differentiating multiple sclerosis from non-specific white matter changes using a convolutional neural network image classification model. Mult Scler Relat Disord. 2024 Feb;82:105420. doi: 10.1016/j.msard.2023.105420. Epub 2023 Dec 31. PMID: 38183693.

Daboul L, O'Donnell CM, Amin M, Rodrigues P, Derbyshire J, Azevedo C, Bar-Or A, Caverzasi E, Calabresi PA, Cree BA, Freeman L, Henry RG, Longbrake EE, Oh J, Papinutto N, Pelletier D, Prchkovska V, Raza P, Ramos M, Samudralwar RD, Schindler MK, Sotirchos ES, Sicotte NL, Solomon AJ, Shinohara RT, Reich DS, Sati P, Ontaneda D. A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis. Mult Scler. 2024 Jan;30(1):25-34. doi: 10.1177/13524585231214360. Epub 2023 Dec 13. PMID: 38088067; PMCID: PMC11037932.

Aboseif A, Li Y, Amin M, Lapin B, Milinovich A, Abbatemarco JR, Cohen JA, Punia V, Rae-Grant AD, Galioto R, Kunchok A. Clinical Determinants of Longitudinal Disability in LGI-1-IgG Autoimmune Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2023 Nov 10;11(1):e200178. doi: 10.1212/NXI.0000000000200178. PMID: 37949667; PMCID: PMC10691218.

Ontaneda D, Chitnis T, Rammohan K, Obeidat AZ. Identification and management of subclinical disease activity in early multiple sclerosis: a review. J Neurol. 2024 Apr;271(4):1497-1514. doi: 10.1007/s00415-023-12021-5. Epub 2023 Oct 21. PMID: 37864717; PMCID: PMC10972995.

Ontaneda D, Gulani V, Deshmane A, Shah A, Guruprakash DK, Jiang Y, Ma D, Fisher E, Rudick RA, Raza P, Kilbane M, Cohen JA, Sakaie K, Lowe MJ, Griswold MA, Nakamura K. Magnetic resonance fingerprinting in multiple sclerosis. Mult Scler Relat Disord. 2023 Nov;79:105024. doi: 10.1016/j.msard.2023.105024. Epub 2023 Sep 27. PMID: 37783196.

Wilcox O, Amin M, Hancock L, Nakamura K, Lace J, Ontaneda D, Galioto R Associations Between Cognitive Impairment and Neuroimaging in Patients with Multiple Sclerosis. Arch Clin Neuropsychol. 2024 Feb 19;39(2):196-203. doi: 10.1093/arclin/acad070. PMID: 37699528.

Corboy JR, Fox RJ, Kister I, Cutter GR, Morgan CJ, Seale R, Engebretson E, Gustafson T, Miller AE; DISCOMS investigators. Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non- inferiority trial. Lancet Neurol. 2023 Jul;22(7):568-577. doi: 10.1016/S1474-4422(23)00154-0. PMID: 37353277.

Alshehri E, Cohen JA, Ontaneda D, Nakamura K, Husak S, Love TE, Fox RJ, Briggs FB, Conway DS. The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis. Mult Scler. 2023 Jun;29(7):846-855. doi: 10.1177/13524585231172490. Epub 2023 May 19. PMID: 37204214.

Ontaneda D, Cohen JA, Sati P. Incorporating the Central Vein Sign Into the Diagnostic Criteria for Multiple Sclerosis. JAMA Neurol. 2023 Jul 1;80(7):657-658. doi: 10.1001/jamaneurol.2023.0717. PMID: 37067820.

Toljan K, Mahadeen A, Amin M, Rensel M, Jones SE, Ontaneda D, Kunchok AC. Pearls & Oy-sters: Hemorrhagic Myelitis Following SARS-CoV-2 Infection. Neurology. 2023 Aug 8;101(6):e672-e676. doi: 10.1212/WNL.0000000000207213. Epub 2023 Mar 29. PMID: 36990723; PMCID: PMC10424833.

Grezmak T, Lace JW, Nakamura K, Ontaneda D, Galioto R. "It's on the tip of my tongue!" exploring confrontation naming difficulties in patients with multiple sclerosis. Mult Scler Relat Disord. 2023 Mar;71:104579. doi: 10.1016/j.msard.2023.104579. Epub 2023 Feb 14. PMID: 36805174.

Kunchok AC, Ontaneda D, Lee J, Rae-Grant A, Foldvary-Schaefer N, Cohen JA, Jones SE. MRI Features of Anti-Ma1/Ma2 Paraneoplastic Neurologic Syndrome. Neurology. 2022 Nov 15;99(20):900-902. doi: 10.1212/WNL.0000000000201318. Epub 2022 Sep 7. PMID: 36376085.

Nakamura K, McGinley MP, Jones SE, Lowe MJ, Cohen JA, Ruggieri PM, Ontaneda Gadolinium-based contrast agent exposures and physical and cognitive disability in multiple sclerosis. J Neuroimaging. 2023 Jan;33(1):85-93. doi: 10.1111/jon.13057. Epub 2022 Oct 1. PMID: 36181666; PMCID: PMC9847209.

Daboul L, O'Donnell CM, Cao Q, Amin M, Rodrigues P, Derbyshire J, Azevedo C, Bar-Or A, Caverzasi E, Calabresi P, Cree BAC, Freeman L, Henry RG, Longbrake EE, Nakamura K, Oh J, Papinutto N, Pelletier D, Samudralwar RD, Suthiphosuwan S, Schindler MK, Sotirchos ES, Sicotte NL, Solomon AJ, Shinohara RT, Reich DS, Ontaneda D, Sati P. Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis. AJR Am J Roentgenol. 2023 Jan;220(1):115-125. doi: 10.2214/AJR.22.27731. Epub 2022 Aug 17. PMID: 35975888; PMCID: PMC10016223.

Nakamura K, Zheng Y, Ontaneda D. T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis-yes. Mult Scler. 2022 Mar;28(3):352-354. doi: 10.1177/13524585211066313. Epub 2022 Jan 22. PMID: 35067111.

Ontaneda D, Ross LA, Hohlfeld R. MRI, Big Data, and Artificial Intelligence: Rewards vs Risks. Neurology. 2021 Nov 23;97(21):975-976. doi: 10.1212/WNL.0000000000012883. Epub 2021 Oct 4. PMID: 34607921.

Gaj S, Ontaneda D, Nakamura K. Automatic segmentation of gadolinium- enhancing lesions in multiple sclerosis using deep learning from clinical MRI. PLoS One. 2021 Sep 1;16(9):e0255939. doi: 10.1371/journal.pone.0255939. PMID: 34469432; PMCID: PMC8409666.

Koenig KA, Beall EB, Sakaie KE, Ontaneda D, Stone L, Rao SM, Nakamura K, Jones SE, Lowe MJ. Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis. PLoS One. 2021 Jun 8;16(6):e0251338. doi: 10.1371/journal.pone.0251338. PMID: 34101741; PMCID: PMC8186801.

Sakaie K, Fedler JK, Yankey JW, Nakamura K, Debbins J, Lowe MJ, Raska P, Fox Influence of equipment changes on MRI measures of brain atrophy and brain microstructure in a placebo-controlled trial of ibudilast in progressive multiple sclerosis. Mult Scler J Exp Transl Clin. 2021 May 18;7(2):20552173211010843. doi: 10.1177/20552173211010843. PMID: 34046185; PMCID: PMC8138298.

Zheng Y, Dudman J, Chen JT, Mahajan KR, Herman D, Fox RJ, Ontaneda D, Trapp BD, Nakamura K. Sensitivity of T1/T2-weighted ratio in detection of cortical demyelination is similar to magnetization transfer ratio using post-mortem MRI. Mult Scler. 2022 Feb;28(2):198-205. doi: 10.1177/13524585211014760. Epub 2021 May 20. PMID: 34014144; PMCID: PMC8605037.

Ontaneda D, Raza PC, Mahajan KR, Arnold DL, Dwyer MG, Gauthier SA, Greve DN, Harrison DM, Henry RG, Li DKB, Mainero C, Moore W, Narayanan S, Oh J, Patel R, Pelletier D, Rauscher A, Rooney WD, Sicotte NL, Tam R, Reich DS, Azevedo CJ; North American Imaging in Multiple Sclerosis Cooperative (NAIMS). Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement. Brain. 2021 Aug 17;144(7):1974-1984. doi: 10.1093/brain/awab132. PMID: 33757115; PMCID: PMC8370433.

Mahajan KR, Amin M, Poturalski M, Lee J, Herman D, Zheng Y, Androjna C, Howell M, Fox RJ, Trapp BD, Jones SE, Nakamura K, Ontaneda D. Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages. Mult Scler. 2021 Dec;27(14):2159-2169. doi: 10.1177/1352458521999651. Epub 2021 Mar PMID: 33749379; PMCID: PMC8455719.

Amin M, Ontaneda D. Thalamic Injury and Cognition in Multiple Sclerosis. Front Neurol. 2021 Feb 5;11:623914. doi: 10.3389/fneur.2020.623914. PMID: 33613423; PMCID: PMC7892763.

Conway DS, Planchon SM, Oh SH, Nakamura K, Thompson NR, Sakaie K, Ontaneda Measures of Thalamic Integrity are Associated with Cognitive Functioning in Fingolimod-treated Multiple Sclerosis Patients. Mult Scler Relat Disord. 2021 Jan;47:102635. doi: 10.1016/j.msard.2020.102635. Epub 2020 Nov 22. PMID: 33260053.

Galioto R, Berenholz O, Wang Z, Conway DS, Planchon SM, Rao SM. Does obesity exacerbate brain lesion volume and atrophy in patients with multiple sclerosis? Mult Scler Relat Disord. 2020 Nov;46:102502. doi: 10.1016/j.msard.2020.102502. Epub 2020 Sep 10. PMID: 32932165.

Uchida A, Pillai JA, Bermel R, Jones SE, Fernandez H, Leverenz JB, Srivastava SK, Ehlers JP. Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases. PLoS One. 2020 Sep 3;15(9):e0237078. doi: 10.1371/journal.pone.0237078. PMID: 32881874; PMCID: PMC7470418.

Bagnato F, Gauthier SA, Laule C, Moore GRW, Bove R, Cai Z, Cohen-Adad J, Harrison DM, Klawiter EC, Morrow SA, Öz G, Rooney WD, Smith SA, Calabresi PA, Henry RG, Oh J, Ontaneda D, Pelletier D, Reich DS, Shinohara RT, Sicotte NL; NAIMS Cooperative. Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy. J Neuroimaging. 2020 May;30(3):251-266. doi: 10.1111/jon.12700. PMID: 32418324.

Ontaneda D, Tallantyre EC, Raza PC, Planchon SM, Nakamura K, Miller D, Hersh C, Craner M, Bale C, Chaudhry B, Gunzler DD, Love TE, Gerry S, Coles A, Cohen JA, Evangelou N. Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol. Contemp Clin Trials. 2020 Aug;95:106009. doi: 10.1016/j.cct.2020.106009. Epub 2020 Apr 19. PMID: 32320842.

Mahajan KR, Nakamura K, Cohen JA, Trapp BD, Ontaneda D. Intrinsic and Extrinsic Mechanisms of Thalamic Pathology in Multiple Sclerosis. Ann Neurol. 2020 Jul;88(1):81-92. doi: 10.1002/ana.25743. Epub 2020 May 1. PMID: 32286701; PMCID: PMC8291218.

Evangelou N, Ontaneda D. Detection of central vein should be part of MS diagnostic criteria - Yes. Mult Scler. 2020 Apr;26(4):405-406. doi: 10.1177/1352458520908176. Epub 2020 Mar 3. PMID: 32125247.

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