Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis

Abstract

Recent pathological studies have re-emphasized that axonal injury is present in patients with multiple sclerosis, the most common demyelinating disease of the CNS in humans. However, the temporal profile of demyelination and axonal loss in multiple sclerosis patients and their independent contributions to clinical and electrophysiological abnormalities are not completely understood. In this study, we used the Theiler's murine encephalomyelitis virus model of progressive CNS inflammatory demyelination to demonstrate that demyelination in the spinal cord is followed by a loss of medium to large myelinated fibres. By measuring spinal cord areas, motor-evoked potentials, and motor coordination and balance, we determined that axonal loss following demyelination was associated with electrophysiological abnormalities and correlated strongly with reduced motor coordination and spinal cord atrophy. These findings demonstrate that axonal loss can follow primary, immune-mediated demyelination in the CNS and that the severity of axonal loss correlates almost perfectly with the degree of spinal cord atrophy and neurological deficits.

Assessment of hindlimb gait as a powerful indicator of axonal loss in a murine model of progressive CNS demyelination

“…1A). This is a time point characterized by a substantial loss of medium and large normally myelinated axons in infected SJL/ J mice [8]. Reductions in the width of stride were not observed in the forelimbs of SJL/ J mice (Fig.…”

“…The virus is cleared from the gray matter within 20 days and establishes chronic persistence in the brainstem and spinal cord white matter. We have demonstrated previously that medium and large axons are lost during the late, chronic stage (~180 days post-infection) of this demyelinating disease [8], and we have hypothesized that this fiber loss contributes significantly to disruptions in motor coordination at this time point.Because both demyelination and axonal loss can contribute independently to neurologic dysfunction during the course of a progressive CNS demyelinating disease, it is important to * Corresponding author. Tel.…”

“…Analysis of footprints in rodents has provided a useful functional assay for determining the effects of peripheral nerve injury / repair [9][10][11][12], experimental allergic neuritis [13], spinal cord injury / repair [14][15][16], drug-induced motor impairment [17], and x-irradiation [18]. We have demonstrated previously that reductions in forelimb and hindlimb stride length are progressive through the first 100 days of TMEV infection in susceptible mice [19], which coincides with the demyelinating phase of the disease [8]. However, no reductions in forelimb or hindlimb stride width were observed during this time period [19].…”

“…The spinal cords were removed, sectioned into 1-mm transverse blocks, post-fixed with 1% osmium tetroxide (in 0.2 M phosphate buffer), and embedded in Araldite (Polysciences; Warrington, PA, USA). Quantification of axonal loss in the normal-appearing white matter was performed on randomly selected sham-infected (n=7) and infected (n=6) SJL/ J mice, as described previously [8,20]. Sections (1 μm) were cut from the 1-mm block corresponding to T6 in each mouse.…”

Evaluation of corticospinal axon loss by fluorescent dye tracing in mice with experimental autoimmune encephalomyelitis

“…Thus axon loss must exceed a threshold before progressive un-remitting clinical symptoms appear (Trapp et al, 1999). Only in models with a chronic disease phase is the accumulated structural damage translated into measurable clinical deficits (McGavern et al, 2000). On the other hand, a primary intrinsic limitation of conventional MRI studies as an indirect method to measure the axonal change is the difficulty to identify the particular underlying pathology due to image contrast, since it can be affected by many factors (Arnold, 1999).…”