Magnetic resonance imaging (MRI) studies in patients with MS have demonstrated only a weak correlation between lesion load and clinical deficits (Stevens et al., 1986). Moreover, pathological studies have demonstrated that some lesions observed by MRI are indeed demyelinated and frequently involve areas of CNS that should have resulted in neurological deficits, but do not (Bruck et al.,
1997). Likewise, autopsy analysis has demonstrated that demyelination, sufficient to make the pathological diagnosis of MS, can be observed in individuals who during life remained normal in neurological function (Mews et al.,
1998). These observations have suggested that demyelina-tion may be required but not sufficient for the development of permanent neurological deficits.
Further challenge to the demyelination hypothesis is provided by studies that use magnetic resonance spectroscopy to sensitively and quantitatively measure axon-specific metabolites such as ^-acetyl aspartate (NAA). These studies found that active lesions are significantly reduced in NAA, and that as the disease progresses from the relapsing-remitting phase to the chronic-progressive phase, a reduction in NAA can be measured even in normal-appearing white matter (Matthews et al., 1996). This finding suggests that a reduction in NAA may reflect both acute, but potentially reversible, axonal dysfunction associated with temporary demyelination, as well as chronic, irreversible loss of axons as a result of degeneration beyond the scope of any given demyelinated lesion. The
mechanisms by which demyelination induces axon dysfunction and axon degeneration remain unclear (Trapp et al., 1998), but a number of recent studies suggest that multiple factors may be involved, ranging from increased accessibility of inflammatory mediators and immune effector cells, to a loss of trophic support. For example, CD8+ cytotoxic T-cells have been observed in contact with demyelinated axons in active MS lesions (Neumann et al., 2002), and the terminal swellings of transected axons have been found to be engulfed by macrophages and microglia (Trapp et al., 1998). Likewise, myelination is known to provide trophic and maintenance cues to axons, controlling axon caliber, and neurofilament phosphorylation and spacing (Sanchez et al., 1996; Windebank et al., 1985). Finally, changes in NAA associated with MS may reflect defects or dysregulation of axonal energy-storage mechanisms, as NAA-derived metabolic products such as acetyl coenzyme A may function to meet the high energy demands of axonal electrochemical conduction (Mehta and Namboodiri, 1995). This idea is particularly intriguing in light of evidence that both lesion load and Expanded Disability Status Score (EDSS) are negatively correlated with levels of NAA found in normal-appearing white matter of patients with MS (Sarchielli et al., 1999), suggesting that axonal loss, axonal metabolic dysfunction, or both, are primarily responsible for neurological deficit in MS.
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