Research Focus Overview

Research Focus Overview

Magnetic Resonance Imaging (MRI) has provided an exquisite opportunity to see inside the brain of people living with multiple sclerosis (MS). However, it’s often unclear which pathological processes are represented on MRI. Cleveland Clinic's brain and spinal cord donation program has been active for over 20 years collecting brain and spinal cord from post-mortem donors with MS to help understand the underlying pathology of MS. The program involves obtaining an MRI shortly after death (typically within 6 hours), conducting a 3-Tesla MRI of the brain and upper cervical cord, followed by removal of the brain and spinal cord.

Portions of the brain and spinal cord are either flash frozen or placed in fixative for RNA and immunohistochemistry analysis. The program accepts tissues from patients followed at the Mellen Center and from patients who pass away within about a 75 mile radius of Cleveland Clinic. In total, over 160 subjects’ brains and spinal cord have been collected.

The MRI data and tissue obtained has been used by a multidisciplinary research team including neurologists, pathologists, basic science researchers, imaging engineers, and biomedical engineers to conduct transformative research evaluating the connection between MRI and pathology in MS. The brain and spinal cord donation program is directed by neurologist Daniel Ontaneda, MD, PhD and basic neuroscientist Bruce Trapp, PhD.

The Imaging/Pathology Correlation program has enabled several discoveries in the field of MS including:

  • Distinct spinal cord pathologies in MS
  • Axonal transection in early MS
  • Identification and classification of cortical lesions
  • Role of premyelinating oligodendrocytes in chronic MS lesions
  • Mechanisms of axonal degeneration in MS
  • Hippocampal pathology in MS
  • Thalamic pathology in MS
  • Identification of an MS subtype with normal brain white matter myelin content

Currently, multiple research studies use tissue from the MS brain and spinal cord donation program.

Contact

Kedar Mahajan, MD, PhD
mahajak@ccf.org

Funding

NIH R35NS097303, Pathogenesis of neurological disability in primary diseases of myelin, Trapp (PI) 12/2016 – 11/2024.

NIH K23NS109328. Thalamic MRI, histopathologic, and clinical correlations in multiple sclerosis, Mahajan (PI) 9/15/18 – 6/30/23.

NIH R21NS123546-01A1. Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis, Dutta (PI) 2/1/22 – 1/31/24.

NIH R01NS123532. Understanding role of circadian disruption in pathogenesis of MS, Dutta (PI). 3/1/22 – 2/28/27.

DOD W81XWH-22-1-0492. Characterization of the Underlying Pathophysiology of Myelinated Cerebral White Matter MRI Lesions in Multiple Sclerosis, Holloman (PI). 07/01/2022- 06/30/2024.

NIH R01NS119178-2. The role of the astrocyte immunoproteasome during chronic CNS autoimmunity, Williams (PI). 12/1/20 – 11/30/25.

DOD W81XWH-21-1-0787. Pathology of Slowly Enlarging Lesions in Multiple Sclerosis, Nakamura (PI) 8/15/21 – 8/14/24.

Publications

Publications

Tripathi A, Pandit I, Perles A, Zhou Y, Cheng F, Dutta R. Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures. Ann Clin Transl Neurol. 2021 Jun;8(6):1279-1291. doi: 10.1002/acn3.51365. Epub 2021 May 12. PMID: 33978322; PMCID: PMC8164853.

Chomyk A, Kucinski R, Kim J, Christie E, Cyncynatus K, Gossman Z, Chen Z, Richardson B, Cameron M, Turner T, Dutta R, Trapp B. Transcript Profiles of Microglia/Macrophage Cells at the Borders of Chronic Active and Subpial Gray Matter Lesions in Multiple Sclerosis. Ann Neurol. 2024 May;95(5):907-916. doi: 10.1002/ana.26877. Epub 2024 Feb 12. PMID: 38345145; PMCID: PMC11060930.

Kihara Y, Zhu Y, Jonnalagadda D, Romanow W, Palmer C, Siddoway B, Rivera R, Dutta R, Trapp BD, Chun J. Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod. Front Cell Neurosci. 2022 Jun 17;16:918041. doi: 10.3389/fncel.2022.918041. PMID: 35783097; PMCID: PMC9247150.

Rai NK, Singh V, Li L, Willard B, Tripathi A, Dutta R. Comparative Proteomic Profiling Identifies Reciprocal Expression of Mitochondrial Proteins Between White and Gray Matter Lesions From Multiple Sclerosis Brains. Front Neurol. 2021 Dec 24;12:779003. doi: 10.3389/fneur.2021.779003. PMID: 35002930; PMCID: PMC8740228.

The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis. Mult Scler J 2015;21(14):1794-801. KA, Sakaie KE, Lowe MJ, Lin J, Stone L, Bermel RA, Beall EB, Rao SM, Trapp BD, Phillips MD. PMID: 26106010.

Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015;14(2):183-93. DH, Trapp BD, Lassmann H. PMID: 25772897.

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

DNA methylation in demyelinated multiple sclerosis hippocampus. Sci Rep 2017;7(1):8696. AM, Volsko C, Tripathi A, Deckard SA, Trapp BD, Fox RJ, Dutta R. PMID: 28821749.

Much, if not all, of the cortical damage in MS can be attributed to the microglial cell – No. Dutta, R., Trapp, B.D., 2018. Mult. Scler. J. 24, 897–899. https://doi.org/10.1177/1352458517743094.

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.

The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis. Koenig, K.A., Rao, S.M., Lowe, M.J., Lin, J., Sakaie, K.E., Stone, L., Bermel, R.A., Trapp, B.D., Phillips, M.D., 2019. Mult. Scler. 25, 574–584. https://doi.org/10.1177/1352458518760716.

Brain fibrinogen deposition plays a key role in MS pathophysiology - Yes. Davalos, D., Mahajan, K.R., Trapp, B.D., 2019. Mult. Scler. 25, 1434–1435. https://doi.org/10.1177/1352458519852723.

Identifying a new subtype of multiple sclerosis. Neurodegener. Trapp, B.D., Ontaneda, D., 2018. Dis. Manag. 8, 367–369. https://doi.org/10.2217/nmt-2018-0032.

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.

Oligodendrocyte Intrinsic miR-27a Controls Myelination and Remyelination. Tripathi, A., Volsko, C., Garcia, J.P., Agirre, E., Allan, K.C., Tesar, P.J., Trapp, B.D., Castelo-Branco, G., Sim, F.J., Dutta, R., 2019. Cell Rep. 29, 904-919.e9. https://doi.org/10.1016/j.celrep.2019.09.020.

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

Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages. 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. Mult Scler. 2021 Dec;27(14):2159-2169. doi: 10.1177/1352458521999651. PMID: 33749379.

 

Members & Collaborations

Members & Collaborations

Cleveland Clinic

External Relationships and Collaborations

Susie Huang, MD, PhD, Athinoula A Martinos Center, Massachusetts General Hospital, Boston, MA.