NEW ORLEANS—Despite a consensus that the repair capacity of the adult human brain decreases with age, cortical remyelination appears to continue in patients with multiple sclerosis (MS) into the eighth decade of life, according to research presented at the 2013 Annual Meeting of the American Neurological Association. Depending on the region of the brain, the environment may affect remyelination, said Bruce Trapp, PhD, Chair of the Department of Neurosciences at the Lerner Research Institute of the Cleveland Clinic. Sulfate proteoglycans inhibit the differentiation of oligodendrocyte progenitor cells (OPCs) and are highly expressed in chronic white-matter lesions, but not in gray-matter lesions.
These findings have “therapeutic implications because we’re at the cusp of designing clinical trials for remyelinating therapies,” said Dr. Trapp. “Therapeutic enhancement of white-matter remyelination may be more efficacious for acute lesions in early stages of MS. Cortical remyelination should be considered as a primary outcome measure in clinical trials that test remyelination because it may be a more amenable target for enhancement,” he added.
Oligodendrocytes Were More Common in Gray Matter
Cortical lesions are not inflamed to the same extent as white-matter lesions and consequently are difficult to detect by standard MRI techniques in living patients. Active white-matter lesions, however, can be identified by an abundance of immune cells within the lesion. Immune cells may be involved in cortical lesions, too, albeit in significantly lower numbers, said Dr. Trapp.
He and his colleagues studied 19 brains from patients with MS to determine whether remyelination occurred in cortical lesions. Patients’ age ranged between 27 and 77, and the investigators examined 147 subpial lesions and 65 leukocortical lesions. Approximately 75% of the subpial lesions had evidence of remyelination, and about 25% of them had no remyelination. “We were really quite surprised by how often remyelination was occurring in these subpial lesions,” said Dr. Trapp.
Confocal microscopy indicated that processes sent by oligodendrocytes attached to the ends of inner nodes, not to the center of the internodes. The finding likely will change myelin biologists’ understanding of how remyelination occurs, said Dr. Trapp.
The researchers also identified 65 leukocortical lesions in the study, seven of which were active and had no remyelination in the white or gray matter. Of 58 chronic lesions, 27 had active remyelination, and 24 of these had significantly greater remyelination in the gray matter than in the white matter.
The investigators found 37 remyelinating oligodendrocytes/mm2 of tissue in the gray-matter portion of the leukocoritcal lesions, compared with four oligodendrocytes/mm2 of tissue in the white-matter portion. The oligodendrocytes in the gray-matter lesions were forming 10 to 30 myelin sheaths each, while the oligodendrocytes in the demyelinated white matter were forming few myelin internodes. Two patients with extensive, ongoing cortical remyelination were age 77. The data provide “compelling evidence that remyelination in the cortex is much more apparent than it is in the white matter in aged patients,” said Dr. Trapp.
Hyaluronan May Inhibit Remyelination in White Matter
One reason that cortical remyelination continues throughout a patient’s life may be that little inflammation occurs during demyelination of gray matter. “This inflammatory response sets up certain aspects of the microenvironment of the brain in white matter, but not in gray matter,” said Dr. Trapp.
Another possible explanation is the fact that cortical lesions have normal densities of OPCs, which make new remyelinating oligodendrocytes. White-matter lesions have reduced densities of OPCs. Investigators also suggest that white-matter lesions have molecules that inhibit remyelination, while gray matter does not have these molecules. One such molecule, hyaluronan, inhibits oligodendrocyte differentiation in vitro and remyelination in vivo.
To test whether these molecules are present in white-matter lesions, Dr. Trapp and colleagues examined leukocortical lesions that contain both gray- and white-matter demyelination. They observed that astrocytes in the white-matter portion of leukocoritcal lesions, but not in gray-matter portions, significantly upregulated CD44, hyaluranon, and versican. The group also found a “significant” increase in glial fibrillary acidic protein in the white-matter lesion, but not in the gray-matter lesion.
“These molecules form complexes that can reduce oligodendrocyte maturation and remyelination,” said Dr. Trapp. “These [molecules] are similar to molecules that inhibit axon regeneration in spinal cord injury, so there’s a huge amount of literature on them. Reducing or disrupting this complex may increase remyelination for white-matter lesions.”