Cortical remyelination: a new target for repair therapies in multiple sclerosis

Ann Neurol. 2012 Dec;72(6):918-26. doi: 10.1002/ana.23693. Epub 2012 Oct 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Adult Stem Cells / metabolism
  • Adult Stem Cells / pathology
  • Aged
  • Antigens / metabolism
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology*
  • Demyelinating Diseases / complications
  • Demyelinating Diseases / pathology
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism
  • Male
  • Middle Aged
  • Multiple Sclerosis / pathology*
  • Myelin Proteolipid Protein / metabolism
  • Myelin Sheath / pathology
  • Nerve Fibers, Myelinated / pathology
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Postmortem Changes
  • Proteoglycans / metabolism
  • RNA, Messenger / metabolism
  • Regeneration / physiology*


  • Adaptor Proteins, Signal Transducing
  • Antigens
  • Glial Fibrillary Acidic Protein
  • Hyaluronan Receptors
  • Myelin Proteolipid Protein
  • Proteoglycans
  • RNA, Messenger
  • chondroitin sulfate proteoglycan 4