Multiple Sclerosis (MS) is defined as a chronic inflammatory disease of the central nervous system (CNS) secondary to an immune-mediated destruction of the myelin sheath. Diagnosis of MS is based on neural pathology as the presence of multifocal inflammatory demyelinated plaques within the CNS. Its mechanism(s) has not been fully understood and there are still some discrepancies on the primary mechanism responsible for occurrence and progression of MS. Some investigators suggested that MS is a demyelinating disease induced by the subjectâ€™s own immune system activity against myelin sheath. Axonal damage has also been shown as an independent and prominent pattern of MS followed by demyelination (1). In contrast, others showed a reverse feature. Furthermore, another proposal is based on the concurrent axon and myelin damage (2). However, the precise correlation between demyelination and axonal injury is still unknown. It is not clear whether demyelination is essential for axonal injury or axonal damage leads to myelin destruction or whether both factors occur independently during MS progression. In this paper I will discuss the role of axonal damage as the main pathological mechanism in MS.
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The development and introduction of new axonal staining techniques in recent years have led to the recognition of some axonal changes in MS such as axonal swelling, axonal transection, and Wallerian degeneration (3). As a result, the independent role of axonal damage and neuronal injury is now considered as the primary pathological mechanism in the early phase of the disease (4, 5).
Axonal loss has been described as an important pathological component of MS. Based on these findings, axonal loss is now noted as an early and persistent phenomenon in the progression of MS pathology (3). Kornek et al. described that permanent neurological problems in MS patients are more related to axonal loss than to demyelination (6).
Evidence suggests that although inflammation directly induces demyelination and axonal loss in MS, it is not the only factor that leads to neurodegeneration over disease evolution (2). Lassmann (2010) reported the presence of axonal injury and loss in all demyelinated MS lesions with variable extent (4).
Acute axonal injury are represented as axonal spheroids (4,6,7) and end bulbs (4) and can be detected with immunohistochemistry for the amyloid precursor protein (APP) (8) which goes through the axon by axonal transport. This pattern of axonal injury is clearly observed in actively demyelinating lesions (4).
According to the studies done by Kutzelnigg (9) and Frischer (10), axonal injury is not only observed in focal demyelinated sites, but also is seen in the normal appearing white matter (NAWM). If one takes into consideration the fact that the MS inflammatory process is not limited to focal white substance lesions but also can involve the entire brain of a patient, one would expect that the axonal injury in the NAWM occurs separately from focal lesions (4). Therefore, two patterns of axonal involvement in MS could be proposed. The first one happens in demyelinated lesions as a result of primary demyelination and its intensity depends on lesional activity (Fig. 2B), and the other one occurs in the entire brain and spinal cord and is correlated with inflammation. The latter form seems to take place in non-demyelinated axons.
The involvement of the gray matter (GM) in MS which is characterized by neuronal loss and dendritic atrophy (11) is considered as a supporting evidence for others non-demyelinating mechanisms in the pathogenesis of axonal damage and loss during the progression of MS (6). It has been reported that GM lesions which estimate the level of disability in MS patients, are associated with cortical thinning (12) and cognitive impairment in these patients (13). Cortical and subcortical GM volume depletion at the earliest phases of MS disease which are shown with Magnetic Resonance Imaging (MRI), propose that axonal injury probably evolves independently of demyelination (14).
Huizinga revealed that neuronal cell death can be imitated with the injection of Neurofilament light chain (NF-L) into mice, which produces a GM pathology associated with axonal loss and depleted myelin sheaths (Fig.1) (15). He demonstrated that autoimmunity to the cytoskeletal protein NF-L of axon and neuron can leads to primary axonal damage and secondary involvement of myelin (15). In this experiment the severity of axonal degeneration was explained by a higher level of activated macrophages and microglia (Fig. 2C).
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Mathey et al. in an animal model illustrated that neurofascin-specific antibodies attached to the nodes of Ranvier which are devoid of myelin, induced axonal damage, destroyed neuronal conduction, and intensified the clinical signs of MS (16). Therefore, the presence of autoantibodies opposed to the neuronal proteins such as NF-L, Neurofilament medium chain (17), as well as neurofascin, suggest that autoimmunity in MS pathogenesis is not limited to the myelin.
Some studies have supported the concept of axonal injury as a distinct mechanism in MS by showing increased levels of axonal cytoskeletal proteins including actin, tubulin, tau, and NF-L in the cerebral spinal fluid (CSF) of MS patients (15). Lycke et al. revealed the level of NF-L in CSF as an indicator of disease activity in MS which strongly relates to Expanded Disability Status Scale (EDSS) score of patients (18). By detecting this protein at all stages of disease progression, it was concluded that axonal damage is not restricted to the late stage secondary to long-term demyelination (6).
From a clinicopathological point of view, an additional study that demonstrates independency of axonal involvement from demyelination in MS is based on different effects of immunoregulatory medications on the natural history of MS. Although immunomodulatory therapies can reduce the number of relapses, debilitating symptoms such as fatigue, cognitive dysfunction, memory impairment, and clinical condition tend to progress over time (6).
A neuronal metabolite named N-acetyl aspartate (NAA) is known as a marker of mitochondrial activity and is exclusively found in neurons and axons of adult brains (8). Bjartmar implied a precise correlation between diminished NAA level and decreased axonal numbers in patients with Secondary Progressive MS (SPMS) (19). Detection of decreased level of NAA in both lesions and NAWM which is performed by Proton Magnetic Resonance Spectroscopy (H-MRS), suggests that mitochondrial dysfunction and axonal damage can take place in sectors free of active demyelination (6).
The excitatory neurotransmitter glutamate is defined as another metabolite involved in MS pathogenesis that elevates in acute MS lesion and NAWM (6). In cultured neurons, high amount of glutamate destroyed neurofilament transportation and led to cytoskeletal protein aggregation at the swelling part of a damaged axon. Axonal transport impairment seems to provoke Wallerian degeneration of distal axons and axonal transection which has been noted a symbol of irreversible axonal damage (20).
Since the late 1990s, with the introduction of new technical approaches such as MRI, immuno-histo-chemistry, and neuropathological studies, it is now well documented that axonal and neuronal degeneration and loss in an inflammatory and immunological process are a remarkable pattern of MS pathology in both early and late phases of disease which has a close correlation with its persisting progressive functional disabilities and deficits. According to this novel concept, demyelinated lesions are not a prerequisite event in MS. It is supposed that axonal loss and injury as a primary lesion can involve in initial stages of disease and be followed by demyelination during its Relapsing- remitting phase. However, there are still some evidence suggesting axonal loss secondary to demyelination. Further investigations are needed to provide more specific evidence of underlying pathogenesis of MS.