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


CONCLUSIONS
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.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Ansi
A
Chang
Susan M
SM
Staugaitis
Ranjan
R
Dutta
Courtney E
CE
Batt
Kathryn E
KE
Easley
Anthony M
AM
Chomyk
V Wee
VW
Yong
Robert J
RJ
Fox
Grahame J
GJ
Kidd
Bruce D
BD
Trapp
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000941:Antigens / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000150:complications / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D011180:Postmortem Changes; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D005904:Glial Fibrillary Acidic Protein; D018960:Hyaluronan Receptors; D018991:Myelin Proteolipid Protein; D011509:Proteoglycans; D012333:RNA, Messenger; D000099216:Chondroitin Sulfate Proteoglycan 4