Axonal Degeneration in Chronically Demyelinated MS Lesions

Ten chronically demyelinated inactive spinal cord lesions, from five paralyzed patients with MS (EDSS >7.5) with disease duration ranging from 12 to 39 years, were analyzed to quantify total axon numbers and axonal density (Bjartmar et al., 2000). Substantial axonal loss was identified in these lesions (Fig. 7A, B). In one lesion, axonal loss was as great as 84%, with a mean axonal loss of 68% (range 45-84%) for all the lesions analyzed (Fig. 7C). Measures of the average axonal density for these lesions identified decreases in axon densities by 58%, corroborating the substantial axonal loss determined by quantification of axons. In another study, similar reductions in average axonal density of 61% were found in spinal cord lesions from patients with SP-MS (Lovas et al., 2000). These studies analyzed patients with considerable disability; therefore, these results support axonal degeneration as the main cause of irreversible neurological impairment during chronic progressive stages of MS. The observations on these lesions suggest that axonal loss in SP-MS may result from chronic demyelination (Bjartmar et al., 1999; Trapp et al., 1999a). Thus, loss of axon-myelin and axon-oligoden-

Figure 6 Pathology precedes axonal degeneration in myelinated nerve fibers from mice expressing myelin protein gene defects. By electron microscopy, paranodal axonal caliber is much greater in control (A) than in MAG-deficient (B) fibers. In transverse orientation, thick redundant myelin (C, arrowheads) partially surrounds an axon (C, arrow) with remarkably small caliber. Schematic representation of myelin and axonal pathology in MAG-, PLP-, and CNP-deficient fibers (D-I). In MAG-deficient mice, paranodes develop normally (D, G), but with time, they develop late-onset axonal degeneration preceded by paranodal axon atrophy with reduced neurofilament spacing (E, H), resulting in myelin sheath collapse and tomacula formation (F, H). PLP-, and CNP-deficient mice develop late-onset paranodal axonal swellings caused by apparent defects in axonal transport (I). (Reproduced from Yin et al., 1998 (A-F) and Trapp et al., 1999a (G-I), with permission.)

Figure 6 Pathology precedes axonal degeneration in myelinated nerve fibers from mice expressing myelin protein gene defects. By electron microscopy, paranodal axonal caliber is much greater in control (A) than in MAG-deficient (B) fibers. In transverse orientation, thick redundant myelin (C, arrowheads) partially surrounds an axon (C, arrow) with remarkably small caliber. Schematic representation of myelin and axonal pathology in MAG-, PLP-, and CNP-deficient fibers (D-I). In MAG-deficient mice, paranodes develop normally (D, G), but with time, they develop late-onset axonal degeneration preceded by paranodal axon atrophy with reduced neurofilament spacing (E, H), resulting in myelin sheath collapse and tomacula formation (F, H). PLP-, and CNP-deficient mice develop late-onset paranodal axonal swellings caused by apparent defects in axonal transport (I). (Reproduced from Yin et al., 1998 (A-F) and Trapp et al., 1999a (G-I), with permission.)

drocyte interactions is another pathological aspect responsible for inducing changes that may cause axonal degeneration.

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