Cortical remyelination: A new target for repair therapies in multiple sclerosis
Open accessAbstract
OBJECTIVE: Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter. METHODS: Postmortem brain tissue from 22 patients with MS (age 27-77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination. RESULTS: New oligodendrocytes that were actively forming myelin sheaths were identified in 30 of 42 remyelinated subpial cortical lesions, including lesions from 3 patients in their 70s. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes, and fewer reactive astrocytes. Astrocytes in the white matter, but not in cortical portions of these lesions, significantly upregulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination. INTERPRETATION: Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
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Although OPCs represent an available pool to replace lost oligodendrocytes and myelin, replacement is limited, particularly in cortical lesions.
“Although OPCs represent an available pool to replace lost oligodendrocytes and myelin, replacement is limited, particularly in cortical lesions (Chang et al. 2012).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Chang et al. 2012
The Results section, “Oligodendrocyte Progenitor Cell Density is Not Decreased in Cortical Lesions,” supports the availability of OPCs in cortical lesions. But the Discussion reports significantly greater oligodendrocyte generation and remyelination in cortex than in adjacent white matter—the opposite of the claim that replacement is particularly limited in cortical lesions. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredRemyelination after a demyelinating insult is more efficient in the cerebral cortex compared to the white matter.
“Previous studies in human post-mortem tissue and experimental models suggested that remyelination after a demyelinating insult is more efficient in the cerebral cortex compared to the white matter.”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [15]
The Results section reports that remyelination was more extensive in the cortical than the white-matter portion of 24 of 28 remyelinated leukocortical lesions, supporting the comparison in human postmortem tissue. The paper’s Methods describe human tissue analysis, not an experimental-model comparison, so it does not support that part of the citing sentence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn multiple sclerosis, remyelination occurs in both white and grey matter and is more efficient in the cortex than in white matter lesions in the same patient.
“In patients with multiple sclerosis, remyelination has been observed in both white and grey matter and found to be more efficient in the cortex.”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [15]
Numerical and functional differences in oligodendrocyte lineage cells, and the phenotype of reactive astrogliosis including lower expression of CD44, versican and hyaluronan in the cortex, may play a role in cortical remyelination.
“Studies in human tissue and experimental models suggest that numerical and functional differences in oligodendrocyte lineage cells, as well as e.g. the phenotype of reactive astrogliosis, including a lower expression of CD44, versican and hyaluronan in the cortex, may play a role.15”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [15]
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- Authors
- 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.
- Affiliations
- Cleveland Clinic (US)
- University of Calgary (CA)
- Corresponding author
- Trapp, Bruce D.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2012-10-17
- Volume
- 72
- Issue
- 6
- Pages
- 918-926
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3535551
- OpenAlex
- W2061522969
- Cited by
- 216
- References
- 42
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 10 · 2023: 19 · 2022: 22 · 2021: 16 · 2020: 18 · 2019: 23 · 2018: 16 · 2017: 11 · 2016: 16 · 2015: 16 · 2014: 13 · 2013: 13 · 2012: 2
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Multiple Sclerosis Society
- Cleveland Clinic
- National Institutes of Health (UL1TR000439)
- University of California, Davis
- National Institute of Neurological Disorders and Stroke (NS38867, P50NS038667)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- multiple sclerosis, demyelination, oligodendrocyte precursor cells, reactive astrocytes, CD44, hyaluronic acid, versican, oligodendrocyte maturation, white matter lesions, remyelination therapy
- MeSH terms
- Chondroitin Sulfate Proteoglycan 4, Adult, Aged, Antigens, Cerebral Cortex, Demyelinating Diseases, Female, Glial Fibrillary Acidic Protein, Humans, Male, Middle Aged, Multiple Sclerosis, Myelin Sheath, Nerve Fibers, Myelinated, Oligodendroglia, Postmortem Changes, Proteoglycans, Regeneration, RNA, Messenger, Hyaluronan Receptors, Myelin Proteolipid Protein, Adaptor Proteins, Signal Transducing, Adult Stem Cells
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