Research: Repair of grey matter lesions

Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, Yong VW, Fox RJ, Kidd GJ, Trapp BD.  Cortical remyelination: A new target for repair therapies in multiple sclerosis. Ann Neurol. 2012  doi: 10.1002/ana.23693. [Epub ahead of print]

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: Post-mortem 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 CD44hyaluronan, 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.

MS is a chronic inflammatory-demyelinating disease of the white matter (WM) of central nervous system. In addition studies have shown that a large number of lesions are located in the cortical and deep gray matter.  The available MRI data obtained on large cohorts of MSers, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment. Remyelination in the white matter occurs but this is hampered by loss of immature oligodendrocyte (myelin-forming cell) surrounding the lesions and the production of an astrocytic scar. This study shows that in lesions in the grey matter there is evidence of robust remyelination and no loss of the immature oligodendrocyte cells. This indicates that there is nothing inherently wrong with the repair mechanism. This suggests that if we could change the environment in the white matter such that it is not hostile to repair, then it may be feasible to promote repair. Also DoctorKlaus pointed out to me that the repairing cells are lining the lesions and this will help repair the lesions.This is going to be a more difficult task than in the grey matter. If we are looking for drugs to promote repair, then it may be best to look at grey matter lesions for evidence of efficacy.

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