Introduction

Multiple sclerosis (MS) is the archetypal inflammatory demyelinating disease of the central nervous system (CNS). It is widely believed to be an autoimmune disease in which the immune system attacks specific elements of the CNS after breakdown of immune tolerance. The major targets for this immune system assault are thought to be components of the myelin sheath, or the oligodendrocytes themselves. A complex interaction of genetic and environmental factors leads to disease onset in affected individuals, but the etiology of the disease remains unknown (Compston and Coles, 2002).

For several decades before the 1990s, pathological investigations into CNS tissue damage in MS focused on the mech anisms of damage to the oligodendrocyte and myelin sheath by cells of the immune system. Relatively little attention was paid to axon damage despite the fact that axon injury had been described as early as the 1880s (Korneck and Lassmann, 1999). Whatever the influences that resulted in the relative neglect of axon pathology in MS, it is now abundantly clear that axon injury occurs early in the disease process and that it is a significant part of the pathology. It seems possible, as suggested by Kornek and Lassmann (1999), that the recent studies added a new dimension to the understanding of this problem by providing accurate quantitative data of the timing and extent of axon injury. Critical data that have triggered this renascence of interest in axon injury have come from a number of different lines of investigation.

Tissue loss and white matter damage can be detected in vivo in patients with MS by imaging modalities including magnetic resonance imaging (MRI) (Loseff et al., 1996), magnetic resonance spectroscopy (Davie et al., 1994), and magnetization transfer imaging (Filippi, 2003). The early studies applying these techniques provided a clear impetus for the application of modern histopathologi-cal techniques to reinvestigate axon injury in MS. Evidence of ongoing axon injury can be detected in MS postmortem tissue samples using sensitive immunocytochemical detection of axon end-bulbs (Fig. 1), a hallmark of axon injury.

Figure 1 Axon end-bulbs as revealed by immunocytochemistry for amyloid precursor protein present in (A) a rat EAE lesion 30 days after the initiation of disease, (C) in fiber tracts of brain tissue from an MS patient. (B) End-bulbs after a traumatic transection injury to rat spinal cord. Scale bar = 50 |m.

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Figure 1 Axon end-bulbs as revealed by immunocytochemistry for amyloid precursor protein present in (A) a rat EAE lesion 30 days after the initiation of disease, (C) in fiber tracts of brain tissue from an MS patient. (B) End-bulbs after a traumatic transection injury to rat spinal cord. Scale bar = 50 |m.

The number of injured axons, many presumed to be actual transections, was correlated with the intensity of the inflammatory response (Ferguson et al., 1997; Trapp et al., 1998). There were large numbers of injured axons in acute and chronic acute lesions, although few in chronic lesions.

The degree of axon injury has now been quantified in several major fiber tracts and is extensive in the corpus cal-losum (Evangelou et al., 2000) and spinal cord (Bjartmar et al., 2003). Axon injury is also present in animal models of MS (Korneck et al., 2000; Bjartmar et al., 2003). Furthermore, imaging studies have shown that there is significant loss of tissue and/or axons from the brains of person with MS and the loss of tissue correlates with clinical disability (Brex et al., 2002).

In short, it is now apparent that axon injury occurs early in the evolution of MS pathology, continues throughout the evolution of the disease, is a significant part of the pathology, and likely contributes to the irreversible accumulation of neurological deficits. These observations raise many important new questions in MS research, and indeed the outcomes of this research will likely impact on other neurological diseases. We need to understand the cellular and molecular events by which inflammation in the CNS leads to axon injury. We need to identify the secondary consequences of axon injury distal to the site of injury. Our understanding of the events of axon injury in MS are rudimentary and indeed axon injury has been somewhat neglected in many neurological diseases (Coleman and Perry, 2002; Medana and Esiri, 2003). In stroke, for example, after many years of research focused on protection of the neuronal cell soma, there is now recognition that preservation of axons injured by the ischemic insult is one of the major challenges (Dewar et al., 1999).

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