Cortical demyelination and diffuse white matter injury in multiple sclerosis
Abstract
Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyel…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Autopsy studies of patients with long-lasting disease show extensive cortical demyelination with severe reduction in oligodendrocyte lineage cells.
“autopsy studies of patients with long-lasting disease show extensive cortical demyelination with severe reduction in oligodendrocyte lineage cells.41,46,68”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [46]
Demyelination of cortical grey matter is an important characteristic of MS, and in many patients the proportion of demyelinated grey matter outweighs that of demyelinated white matter.
“Demyelination of the cortical grey matter is an important characteristic of MS, and the proportion of demyelinated grey matter outweighs that of demyelinated white matter in many patients.46,47”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [46]
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Axonal transection in the lesions of multiple sclerosis
Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mörk, S., & Bö, L. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801293380502 · Cited by 4,029 · see citing works
Peterson, J. W., Bö, L., Mörk, S., Chang, A., & Trapp, B. D. (2001) · Annals of Neurology · doi:10.1002/ana.1123 · Cited by 1,403 · cited 5× · see citing works
“Keywords: multiple sclerosis; cortical demyelination; normal-appearing white matter; PPMS; SPMS Abbreviations: AMS = acute multiple sclerosis; NAWM = normal-appearing white matter; PLP = proteolipid protein; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary-…”
BackgroundInfluential
Flagged first, then by citations
Cited by
Sorted by citations
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
Inflammatory cortical demyelination in early multiple sclerosis.
Lucchinetti, C. F., Popescu, B. F. G., Bunyan, R. F., Moll, N. M., Roemer, S. F., Lassmann, H., Brück, W., Parisi, J. E., Scheithauer, B. W., Giannini, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1100648 · Cited by 1,103 · see citing works
Self-citationProgressive multiple sclerosis: pathology and pathogenesis
Lassmann, H., van Horssen, J., & Mahad, D. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.168 · Cited by 1,033 · see citing works
Self-citationPrimary-progressive multiple sclerosis
Miller, D. H., & Leary, S. M. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70243-0 · Cited by 818 · see citing works
Remyelination is extensive in a subset of multiple sclerosis patients
Patrikios, P., Stadelmann, C., Kutzelnigg, A., Rauschka, H., Schmidbauer, M., Laursen, H., Sorensen, P. S., Bruck, W., Lucchinetti, C., & Lassmann, H. (2006) · Brain · doi:10.1093/brain/awl217 · Cited by 807 · see citing works
Self-citationAn updated histological classification system for multiple sclerosis lesions
Kuhlmann, T., Ludwin, S., Prat, A., Antel, J., Brück, W., & Lassmann, H. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1653-y · Cited by 692 · see citing works
Self-citationMultiple sclerosis progression: time for a new mechanism-driven framework
Kuhlmann, T., Moccia, M., Coetzee, T., Cohen, J. A., Correale, J., Graves, J., Marrie, R. A., Montalban, X., Yong, V. W., Thompson, A. J., et al. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00289-7 · Cited by 667 · see citing works
Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations.
Müller, N. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby024 · Cited by 648 · see citing works
Fischer, M. T., Sharma, R., Lim, J. L., Haider, L., Frischer, J. M., Drexhage, J., Mahad, D., Bradl, M., van Horssen, J., & Lassmann, H. (2012) · Brain · doi:10.1093/brain/aws012 · Cited by 507 · see citing works
Self-citationNylander, A., & Hafler, D. A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58649 · Cited by 495 · see citing works
Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging
Dal-Bianco, A., Grabner, G., Kronnerwetter, C., Weber, M., Höftberger, R., Berger, T., Auff, E., Leutmezer, F., Trattnig, S., Lassmann, H., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1636-z · Cited by 463 · see citing works
Self-citationProgressive multiple sclerosis: from pathophysiology to therapeutic strategies
Faissner, S., Plemel, J. R., Gold, R., & Yong, V. W. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0035-2 · Cited by 459 · see citing works
Exploring the origins of grey matter damage in multiple sclerosis
Calabrese, M., Magliozzi, R., Ciccarelli, O., Geurts, J. J. G., Reynolds, R., & Martin, R. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3900 · Cited by 414 · see citing works
The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain
Haider, L., Zrzavy, T., Hametner, S., Höftberger, R., Bagnato, F., Grabner, G., Trattnig, S., Pfeifenbring, S., Brück, W., & Lassmann, H. (2016) · Brain · doi:10.1093/brain/awv398 · Cited by 400 · see citing works
Self-citationMeningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis.
Choi, S. R., Howell, O. W., Carassiti, D., Magliozzi, R., Gveric, D., Muraro, P. A., Nicholas, R., Roncaroli, F., & Reynolds, R. (2012) · Brain · doi:10.1093/brain/aws189 · Cited by 386 · see citing works
Sankowski, R., Mader, S., & Valdés-Ferrer, S. I. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00028 · Cited by 351 · see citing works
Disease-specific molecular events in cortical multiple sclerosis lesions
Fischer, M. T., Wimmer, I., Höftberger, R., Gerlach, S., Haider, L., Zrzavy, T., Hametner, S., Mahad, D., Binder, C. J., Krumbholz, M., et al. (2013) · Brain · doi:10.1093/brain/awt110 · Cited by 311 · see citing works
Self-citationKamiya, K., Hori, M., & Aoki, S. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2020.108908 · Cited by 283 · see citing works
“This is thought to be due, at least partly, to the limited sensitivity of conventional MRI to histologically confirmed pathology (Kutzelnigg et al., 2005; Weinstein et al., 2015).”
BackgroundInflammation, demyelination, and degeneration — Recent insights from MS pathology
Stadelmann, C., Wegner, C., & Brück, W. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.007 · Cited by 276 · see citing works
Self-citationCortical lesions in multiple sclerosis
Calabrese, M., Filippi, M., & Gallo, P. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.93 · Cited by 269 · see citing works
Brambilla, R. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01980-7 · Cited by 246 · see citing works
Zirngibl, M., Assinck, P., Sizov, A., Caprariello, A. V., & Plemel, J. R. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00538-8 · Cited by 233 · see citing works
Cortical remyelination: A new target for repair therapies in multiple sclerosis
Chang, A., Staugaitis, S. M., Dutta, R., Batt, C. E., Easley, K. E., Chomyk, A. M., Yong, V. W., Fox, R. J., Kidd, G. J., & Trapp, B. D. (2012) · Annals of Neurology · doi:10.1002/ana.23693 · Cited by 216 · see citing works
Microglia in multiple sclerosis: Friend or foe
Guerrero, B. L., & Sicotte, N. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00374 · Cited by 215 · see citing works
Review: Mitochondria and disease progression in multiple sclerosis
Mahad, D., Lassmann, H., & Turnbull, D. (2008) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2008.00987.x · Cited by 193 · see citing works
Self-citationMechanisms of white matter damage in multiple sclerosis
Lassmann, H. (2014) · Glia · doi:10.1002/glia.22597 · Cited by 191 · see citing works
Self-citationFocal demyelination in Alzheimer’s disease and transgenic mouse models
Mitew, S., Kirkcaldie, M. T. K., Halliday, G. M., Shepherd, C. E., Vickers, J. C., & Dickson, T. C. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0657-2 · Cited by 186 · see citing works
The blood-brain barrier in cortical multiple sclerosis lesions
van Horssen, J., Brink, B. P., de Vries, H. E., van der Valk, P., & Bø, L. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318040b2de · Cited by 187 · see citing works
Increased PK11195 PET binding in the cortex of patients with MS correlates with disability
Politis, M., Giannetti, P., Su, P., Turkheimer, F., Keihaninejad, S., Wu, K., Waldman, A., Malik, O., Matthews, P. M., Reynolds, R., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182635645 · Cited by 176 · see citing works
The Cuprizone Model: Dos and Do Nots
Zhan, J., Mann, T., Joost, S., Behrangi, N., Frank, M., & Kipp, M. (2020) · Cells · doi:10.3390/cells9040843 · Cited by 171 · see citing works
“Diffuse white matter damage [76,79] Demyelination of white matter tracts, especially in the corpus callosum [78,80]”
BackgroundMechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis
Correale, J., Marrodan, M., & Ysrraelit, M. C. (2019) · Biomedicines · doi:10.3390/biomedicines7010014 · Cited by 167 · see citing works
The role of glial cells in multiple sclerosis disease progression
Healy, L. M., Stratton, J. A., Kuhlmann, T., & Antel, J. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00624-x · Cited by 152 · see citing works
Patejdl, R., Penner, I. K., Noack, T. K., & Zettl, U. K. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2015.11.005 · Cited by 141 · see citing works
Multiple sclerosis and Alzheimer's disease
Dal Bianco, A., Bradl, M., Frischer, J., Kutzelnigg, A., Jellinger, K., & Lassmann, H. (2008) · Annals of Neurology · doi:10.1002/ana.21240 · Cited by 123 · see citing works
Self-citationImaging of microglia in patients with neurodegenerative disorders
Politis, M. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00096 · Cited by 111 · see citing works
DNA damage in the oligodendrocyte lineage and its role in brain aging
Tse, K.-H., & Herrup, K. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.05.006 · Cited by 108 · see citing works
Remyelination alters the pattern of myelin in the cerebral cortex
Orthmann-Murphy, J., Call, C. L., Molina-Castro, G. C., Hsieh, Y. C., Rasband, M. N., Calabresi, P. A., & Bergles, D. E. (2020) · eLife · doi:10.7554/elife.56621 · Cited by 111 · see citing works
Maki, T., Liang, A. C., Miyamoto, N., Lo, E. H., & Arai, K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00275 · Cited by 99 · see citing works
Vainchtein, I. D., Vinet, J., Brouwer, N., Brendecke, S., Biagini, G., Biber, K., Boddeke, H. W. G. M., & Eggen, B. J. L. (2014) · Glia · doi:10.1002/glia.22711 · Cited by 92 · see citing works
Teo, W., Caprariello, A. V., Morgan, M. L., Luchicchi, A., Schenk, G. J., Joseph, J. T., Geurts, J. J. G., & Stys, P. K. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016897118 · Cited by 92 · see citing works
White matter microglia heterogeneity in the CNS
Amor, S., McNamara, N. B., Gerrits, E., Marzin, M. C., Kooistra, S. M., Miron, V. E., & Nutma, E. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02389-x · Cited by 89 · see citing works
Diagnosis and Management of Progressive Multiple Sclerosis
Macaron, G., & Ontaneda, D. (2019) · Biomedicines · doi:10.3390/biomedicines7030056 · Cited by 70 · see citing works
Gray, E., Thomas, T. L., Betmouni, S., Scolding, N., & Love, S. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318183d003 · Cited by 51 · see citing works
Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models
Zhan, J., Kipp, M., Han, W., & Kaddatz, H. (2021) · Immunology · doi:10.1111/imm.13395 · Cited by 49 · see citing works
Nylund, M., Sucksdorff, M., Matilainen, M., Polvinen, E., Tuisku, J., & Airas, L. (2022) · Brain Communications · doi:10.1093/braincomms/fcab301 · Cited by 48 · see citing works
Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models
Nack, A., Brendel, M., Nedelcu, J., Daerr, M., Nyamoya, S., Beyer, C., Focke, C., Deussing, M., Hoornaert, C., Ponsaerts, P., et al. (2019) · Cells · doi:10.3390/cells8020094 · Cited by 43 · see citing works
Cuprizone‐induced demyelination triggers a <scp>CD8</scp>‐pronounced T cell recruitment
Kaddatz, H., Joost, S., Nedelcu, J., Chrzanowski, U., Schmitz, C., Gingele, S., Gudi, V., Stangel, M., Zhan, J., Santrau, E., et al. (2021) · Glia · doi:10.1002/glia.23937 · Cited by 39 · see citing works
“…(Sen, Mahns, Coorssen, & Shortland, 2019; Zhan et al., 2020) including diffuse white matter injury (Goldberg, Clarner, Beyer, & Kipp, 2015; Kutzelnigg et al., 2005), minor BBB damage (Kirk, Plumb, Mirakhur, & McQuaid, 2003; Merkler et al., 2005), widespread cortical and subcortical…”
BackgroundInfluentialAnimal models to investigate the effects of inflammation on remyelination in multiple sclerosis
Gharagozloo, M., Mace, J. W., & Calabresi, P. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.995477 · Cited by 38 · see citing works
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Bergner, C. G., van der Meer, F., Franz, J., Vakrakou, A., Würfel, T., Nessler, S., Schäfer, L., Nau-Gietz, C., Winkler, A., Lagumersindez-Denis, N., et al. (2025) · Brain · doi:10.1093/brain/awae293 · Cited by 16 · see citing works
“41,46,68 Our data on the normal-appearing cortex in chronic MS, with morphologically inconspicuous myelination as assessed by MBP immunohistochemistry, revealed an important reduction of pre-differentiated BCAS1+ oligodendrocytes compared to age-matched controls.”
Self-citation
- Authors
- Kutzelnigg, A., Lucchinetti, C. F., Stadelmann, C., Brück, W., Rauschka, H., Bergmann, M., Schmidbauer, M., Parisi, J. E., & Lassmann, H.
- Affiliations
- Medical University of Vienna (AT)
- University of Göttingen (DE)
- Corresponding author
- Kutzelnigg, Alexandra
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-17
- Volume
- 128
- Issue
- 11
- Pages
- 2705-2712
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2047062145
- Cited by
- 1,836
- References
- 3
- Citations by year
- 2026: 40 · 2025: 60 · 2024: 82 · 2023: 57 · 2022: 90 · 2021: 103 · 2020: 108 · 2019: 83 · 2018: 96 · 2017: 102 · 2016: 102 · 2015: 104 · 2014: 101 · 2013: 118 · 2012: 110
- FWCI
- 44.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Austrian Science Fund
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- multiple sclerosis, cortical demyelination, normal-appearing white matter, diffuse axonal injury, microglial activation, meningeal inflammation, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, disease progression
- MeSH terms
- Acute Disease, Adult, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebral Cortex, Female, Humans, Male, Middle Aged, Multiple Sclerosis, Sex Factors, Time Factors, Case-Control Studies, Disease Progression, Multiple Sclerosis, Chronic Progressive, Multiple Sclerosis, Relapsing-Remitting
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
