Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions

Abstract

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

Cortical pathology in multiple sclerosis detected by the T1/T2‐weighted ratio from routine magnetic resonance imaging

“…Such evidence exists. Although not surrounded by oligodendrocytes, transected dendrites occur in both demyelinated and myelinated cortex 11. A recent study revealed a widespread and pronounced loss of dendritic spines in MS cortex independent of cortical demyelination and axon loss 2.…”

“…However, cortical pathology seems to extend beyond the area of demyelinated lesions. Histological studies demonstrated transected neurites not only in axons within demyelinated lesions but also in dendrites within the myelinated cortex,11 and a recent study demonstrated loss of dendritic spines independent of cortical demyelination and axon loss 2…”

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

“…In fact, GM atrophy has been found to be associated with changes in all cognitive domains in MS (Morgen et al., 2006). This is not surprising as several pathological (Kutzelnigg et al., 2005; Peterson, Bo, Mork, Chang, & Trapp, 2001) and MRI (Calabrese, Atzori, et al., 2007; Calabrese, De Stefano, et al., 2007; De Stefano et al., 2003) studies have shown that the cerebral cortex is profoundly affected in MS. Indeed, cortical atrophy has been proposed as one of the major underlying substrates of cognitive impairment in MS (Amato et al., 2004; Benedict et al., 2004; Tekok‐Kilic et al., 2007).…”

Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability

“…However, more recent studies have demonstrated the presence of gray matter (GM) lesions (Peterson et al, 2001;Geurts et al, 2005) and brain atrophy (Chard et al, 2002;Anderson et al, 2006). Total brain atrophy can be viewed as a surrogate marker of the destructive pathological processes taking place in MS and can be observed with magnetic resonance imaging (MRI) by measuring the brain parenchymal fraction, a normalized measure that represents the sum of both gray matter (GM) and WM atrophy (Chard et al, 2002).…”