BACKGROUND: Recent pathologic investigations have shown that neocortical lesions are frequent in multiple sclerosis (MS). Structural MRI has shown that neocortical atrophy occurs early and can be substantial, but the specific substrate for this atrophy has not been defined quantitatively. OBJECTIVE: To investigate cortical thickness as well as neuronal, glial, and synaptic densities in MS. METHODS: We studied brain samples from 22 patients with MS and 17 control subjects. Neocortical lesions and cortical thickness were assessed on sections stained for myelin basic protein. Neuronal, glial, and synaptic densities were measured in type I leukocortical lesions, nonlesional neocortex, and non-MS control cortex. Immunoautoradiography was used to quantify synaptic densities. RESULTS: Neocortical lesions were common in patients with MS. Subpial type III (44%) and leukocortical type I (38%) lesions were more abundant than intracortical type II (18%) lesions. An overall relative neocortical thinning of 10% (p = 0.016) was estimated for the patients. Within the type I lesions, we found evidence for substantial cell (glial, 36%, p = 0.001; neuronal, 10%, p = 0.032) and synaptic (47% decrease in synaptophysin, p = 0.001) loss. Nonlesional neocortex did not show significant relative changes in neuronal, glial, or synaptic density. CONCLUSIONS: Neocortical neuronal and glial degeneration is significant in multiple sclerosis. Synaptic loss was particularly striking in the neocortical lesions, which should make a major independent contribution to the expression of pathology. New therapies should be directed toward limiting this damage.
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