Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 165-171, 15 February 2003

Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA

Article Outline

Abstract 

Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing–remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view—the axonal hypothesis—is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15–30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.

Keywords:  Multiple sclerosis, Axon, Pathology, Transection, Disability

 

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1. Introduction 

Patients with multiple sclerosis (MS) typically exhibit an initial relapsing–remitting (RR-MS) phase that subsequently transforms into a secondary progressive (SP-MS) disease, the latter characterized by increasing irreversible functional decline. What are the histopathological correlates to this disease course, that is most common among patients with MS? Demyelination and inflammation are hallmarks of active MS lesions. However, most MS lesions also contain various degrees of reactive astrogliosis, phagocytic activity, oligodendroglial loss, and axonal pathology. In addition, there is a local response from oligodendrocyte progenitor cells and, at least at initial stages of the disease, some remyelination. Hence, the histopathology of MS is complex and many characteristics vary between lesions and within individual lesions over time [1], [2], [3].

Axonal pathology in MS has been noted in the literature for more than a century [4], [5]. Recently, new insights regarding the timing and functional consequences of axonal loss in MS have generated renewed attention to this issue. This review discusses current data on axonal pathology in MS, obtained through morphological and magnetic resonance techniques, or through studies on animal models of MS, which are relevant for our understanding of the progressive functional impairment experienced by most MS patients. Together, the data provide evidence that cumulative loss of axons constitutes a key aspect of MS pathogenesis, and suggests that axonal degeneration is the major determinant of progressive neurological disability in patients with MS.

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2. Axonal injury begins at disease onset 

Several studies have demonstrated a positive correlation between axonal damage and degree of inflammation in active cerebral MS lesions. Ferguson et al. [6] described accumulation of axonal amyloid precursor protein (APP), a marker for axonal dysfunction or injury, in active lesions and at the border of chronic active lesions. Many APP-immunoreactive structures resembled axonal ovoids, characteristic of newly transected axons. These observations were extended by a quantitative morphological investigation on lesions from MS brains with various degree of inflammation and disease duration [7]. Axonal ovoids were identified through confocal microscopy as terminal ends of transected axons immunostained for non-phosphorylated neurofilaments. On average, 11,236 terminal ends per mm3 were found in active lesions, 3138/mm3 were found at the edge of chronic active lesions and 875/mm3 were found in the core of chronic active lesions. In contrast, control white matter contained less than one transected axon per mm3. Kornek et al. [8] reported a similar correlation between activity of MS lesions and density of APP-positive axons. The occurrence of terminal ends in active lesions, detected in patients with short disease duration, supports axonal transection from onset of MS.

The mechanisms of early axonal injury in MS are poorly understood. Positive correlations with lesion activity, however, support the idea that inflammatory mediators produced by immune or glial cells play a role [6], [7], [8] (Fig. 1). Oxidative damage to mitochondrial DNA and impaired activity of mitochondrial enzyme complexes in MS lesions suggest that inflammation can affect energy metabolism, ATP synthesis, and viability of affected cells [9]. Treatment with the AMPA/kaniate glutamate receptor antagonist NBQX resulted in increased oligodendrocyte survival and reduced axonal damage in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, indicating that glutamate is involved in tissue damage in acute lesions [10]. Data suggesting that cytotoxic CD8+ T cells may mediate axonal transection in inflammatory lesions have been provided in MS tissue [11], in EAE mice [12], and in vitro [13]. In addition, it was recently proposed that axons exposed to nitric oxide at sites of inflammation are particularly vulnerable to degeneration when electrically active [14]. Also, genes involved in axonal responses to inflammation and demyelination could influence the extent of axonal injury in individual patients [3]. Finally, inflammatory edema may cause increased extracellular pressure that results in axonal damage, particularly in anatomical locations of the CNS where space for tissue expansion is limited such as the spinal cord [15]. In support of this hypothesis, the spinal cord cross-sectional area of relapsing–remitting EAE mice increased by 9% at first attack, but returned to normal at end-stage disease [16].

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  • Fig. 1. 

    Axonal injury caused by inflammatory demyelination in an active MS lesion. Substances produced by activated immune and glial cells may mediate tissue damage, including axonal transection. Axons degenerate rapidly distal to the site of transection. In contrast, CNS myelin can persist for a long time and form empty tubes, or later degenerating ovoids. The white matter distal to the lesion may appear normal on conventional MRI images or routine histological examination. Denervation of target neurons causes functional loss and possibly downstream effects.

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3. Axonal degeneration in non-lesion white matter 

Axons degenerate rapidly distal to the site of transection, whereas CNS myelin can persist for a long time after proximal fiber transection. Histologically, such remaining myelin sheaths will form empty tubes, or later degenerating ovoids (Fig. 1). The white matter, however, may appear normal on conventional MRI images and routine histological examination by luxol fast blue. Recent postmortem studies have quantified the extent of axonal loss in MS normal appearing white matter (NAWM). Ganter et al. [17] reported reductions in axonal density by 19–42% in the lateral corticospinal tract of MS patients with lower limb weakness. Lovas et al. [18] found reductions in axonal density up to 57% in spinal cord NAWM from SP-MS patients. An average total axonal loss of 53% was found in normal appearing corpus callosum in MS patients with disease durations between 5 and 34 years and various degrees of functional impairment [19]. Together, these reports indicate that white matter that appears normal histologically or on MRI scans might contain a considerable loss of axons, particularly in patients with long disease duration.

Morphological evidence for axonal degeneration in NAWM distal to an acute lesion was described in a patient with a 9-month history of RR-MS [20]. Postmortem analysis of the spinal cord demonstrated a 22% axonal loss in descending tracts distal to a terminal brain stem lesion, in spite of grossly normal immunostaining for myelin. Confocal microscopy, however, revealed empty myelin sheaths, myelin ovoids, and signs of myelin degradation by activated microglia. There were no signs of primary demyelination and adjacent axons were morphologically intact, findings characteristic for fiber degeneration caused by proximal transection. Other descending and ascending fiber tracts exhibited normal axon numbers. These data suggest that irreversible axonal loss with retention of slowly degenerating myelin occurs early in disease and is one histopathological correlate to NAWM abnormalities observed in MS patients by some MR techniques [20], [21].

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4. Extensive axonal loss in long-term MS 

Axonal loss can be substantial over time in MS (Fig. 2). In order to quantify long-term axonal loss, total axon numbers were quantified in 10 chronic inactive spinal cord lesions from five paralyzed MS patients (EDSS≥7.5) with disease durations from 12 to 39 years [22]. These lesions contained a 45–84% (mean 68%) loss of axons, whereas average axonal density (number of axons per unit area) was decreased by 58%. A similar reduction in axonal density, 61%, was found in spinal cord lesions from patients with secondary progressive MS (SP-MS) [18]. Given the considerable disability of these patients, these results support axonal degeneration as the main cause of irreversible neurological impairment during progressive stages of MS.

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  • Fig. 2. 

    Loss of axons in a spinal cord lesion from a paralyzed patient with secondary progressive MS and long disease duration. Neurofilament staining demonstrates axonal density in control (A) and in a demyelinated area in the gracile fasciculus of MS cervical spinal cord (B). This chronic MS lesion exhibits significant axonal loss. Scale bar=25 μm (from Bjartmar et al. [25]).

Extensive axonal loss and progression of disability, even in the absence of overt inflammatory activity, indicate that mechanisms other than inflammatory demyelination contribute to disease progression in patients with SP-MS [23], [24]. A number of myelin related proteins such as myelin-associated glycoprotein (MAG), proteolipid protein (PLP), peripheral myelin protein 22 (PMP22), P0 and connexin 32, contribute to long-term viability of axons [25], [26]. Late onset axonal pathology such as atrophy or swelling, cytoskeleton alterations, organelle accumulation and degeneration was observed in mice lacking MAG [27] or PLP [28]. In PLP-null mice, the axonal pathology was accompanied with progressive clinical disability including impaired gait, tremor and spasticity. These observations indicate that chronically demyelinated axons may undergo degeneration due to lack of trophic support from myelin or myelin forming cells. Finally, it has been proposed that abnormal expression of sodium channel subtypes—maladaptive responses to demyelination—may render axons vulnerable to degeneration, conforming with the interesting possibility that MS may involve an acquired channelopathy [29].

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5. The axonal hypothesis—cumulative axonal loss causes irreversible disability during progressive MS 

Episodes of reversible clinical symptoms during RR-MS are primarily associated with acute inflammatory lesions in articulate parts of the CNS. Resolution of the inflammation, redistribution of axolemmal sodium channels, remyelination, and/or compensatory cortical adaptation contribute to clinical remission [30], [31]. A recent combined functional MRI and MRS study of RR-MS patients without overt permanent functional disability demonstrated a fivefold increase in sensorimotor cortex activation after simple hand movements when compared with control individuals [32]. These data indicate that adaptive cortical changes, possibly involving reorganization of functional pathways, contribute to maintained motor function after axonal damage during early stages of MS.

Most MS patients develop progressive irreversible functional impairment 8–15 years after disease onset. The extent of axonal loss in progressive patients with long disease duration [18], [22], the temporal reduction of levels of the neuronal/axonal marker N-acetyl aspartate (NAA) in MS brains over time [33], and the correlations between NAA levels and functional impairment [34], [35], all support the hypothesis that permanent neurological disability develops when a threshold of axonal loss is reached and the CNS compensatory resources are exhausted [30], [31], [36], [37]. The time-point when a patient reaches this threshold varies among individuals, and probably reflects a number of factors such as location of lesions, disease activity, medication and genetic susceptibility.

An initial silent stage of neuronal cell loss is characteristic for all neurodegenerative diseases. For example, in amyotrophic lateral sclerosis (ALS) and in Parkinson's disease, it has been estimated that 50% to 80% of target neurons, respectively, may be lost before these patients present with neurological symptoms [38], [39]. These figures beg the question of how many axons can be destroyed in the CNS of patients with MS before permanent functional disability occurs? With the exception for in vivo measurements of NAA [36], quantitative correlations between tract specific axonal loss and disability are difficult to obtain in MS patients. In addition, such correlations may not be straightforward since axonal loss threshold levels probably vary between different CNS tracts. However, direct experimental support for the hypothesis that cumulative loss of axons determines disability in patients with MS was recently described in a chronic relapsing–remitting EAE mouse model of MS [16].

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6. In EAE spinal cords, axonal loss above a threshold determines the extent of neurological disability 

Female mice of the SWXJ strain immunized with the p 139–151 peptide of PLP develop consistent progression from relapsing disease to chronic disability [40]. Since most inflammatory lesions in this EAE model occur in the spinal cord, neurological disability (clinical score) was correlated with spinal cord inflammation and axonal loss at first attack and at end-stage disease [16]. The spinal cord area occupied by cells expressing the pan-leukocyte marker CD45 [41] was used as an indication of overall inflammatory activity. At initial attack, clinical score correlated with the extent of spinal cord inflammation but not with axonal loss, indicating that acute reversible disability in relapsing EAE results from mechanisms other than axonal transection. At a chronic end-stage of disease (Fig. 3), however, clinical score was highly correlated with axon loss in both cervical (ρ=0.75; p=0.0001) and lumbar spinal cords (ρ=0.63; p=0.004). Total axonal loss in end-stage mice with permanent limb paralysis (clinical score=4) averaged 59% and 43% at cervical and lumbar levels, respectively. In contrast, disability did not correlate with inflammation in these chronic mice. The number of symptomatic EAE attacks ranged from one to five. Regression analysis demonstrated a significant correlation between number of attacks and axonal loss. This relationship was stronger in the cervical cord (ρ=0.72; p=0.0004) than in the lumbar cord (ρ=0.45; p=0.05). As predicted from the relationship between attack number and axonal loss, the number of relapses for each mouse was significantly related to clinical score (ρ=0.59; p=0.007).

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  • Fig. 3. 

    Loss of spinal cord axons correlate with irreversible neurological disability in mice with chronic EAE. (A–D) Neurofilament stained axons in the dorsolateral spinal cord from control (A) and EAE mice with clinical scores of 0 (B), 2 (C) and 4 (D). (E) Density of axons in cervical (white bars) and lumbar (black bars) spinal cord, expressed as percent axonal loss relative to controls. Axonal loss increased significantly for each higher clinical score (Spearman's rank correlation test; cervical cord: ρ=0.75; p=0.0001, and lumbar cord: ρ=0.63; p=0.004). Scale bars (A–D)=10 μm (from Wujek et al. [16]).

These data support a causal relationship between number of inflammatory attacks, axonal loss and permanent neurological disability in mice with relapsing EAE [16]. In end-stage mice lacking observable symptoms (clinical score 0), axonal loss compared to controls was 30% and 15% in the cervical and lumbar spinal cord, respectively. Strikingly, this axonal loss was significantly greater than in first attack mice with a reversible clinical score of 4 (limb paralysis). The 45% and 60% axonal loss in irreversibly paralyzed end-stage mice approaches the 68% axonal loss in spinal cord lesions of paralyzed MS patients [22]. Axonal loss in mice with a clinical score 2 (poor righting reflex) was intermediate between that found in mice with scores of 0 and 4 (Fig. 3). Therefore, the data also support the hypothesis that a threshold of axonal loss must be surpassed before irreversible neurological disability occurs.

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7. What happens after EDSS 4? Does a threshold of axonal loss trigger pre-programmed progressive neurodegeneration 

Most patients with MS exhibit progressive functional decline from moderate to severe disability, even in the absence of overt inflammatory disease activity [24]. This observation supports the concept that different mechanisms cause axonal loss at different stages of the disease course. Axonal transection caused by inflammatory demyelination is the main cause of initial moderate disability in most MS patients. In addition, chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support (see above) [25], [26]. Axonal and neuronal degeneration caused by these two mechanisms will have cumulative effects on remaining neurons due to withdrawal of pre- and/or postsynaptic trophic signals. We hypothesize that lack of such trans-synaptic support induces triggering of neurodegenerative pathways in some neurons. An epidemiologic study by Confavreux et al. [42] showed that although the time from onset of MS to EDSS score 4 varied between 1 and 33 years, the time course from EDSS scores 4 to 7 was similar among the patients. These observations support the possibility that most MS patients eventually develop a final common pathway of pre-programmed neuronal degeneration once a clinical/pathological threshold is surpassed. While the extent of inflammatory demyelination and tissue damage may influence the time to EDSS 4, neurodegenerative mechanisms other than axonal transection in inflammatory lesions therefore most likely contribute to neuronal decline at more severe stages of disease [3], [31], [37], [42]. Such pre-programmed neurodegenerative mechanisms dissociate acute inflammatory damage observed early in the disease from progressive tissue degeneration during chronic stages of MS. The illumination of these mechanisms may provide new opportunities for therapeutic designs in MS.

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8. MS lesions involving gray matter 

The data reviewed above support loss of white matter axons as the prime determinant of disability in patients with MS. However, other mechanisms of axonal and neuronal loss may contribute to neurological decline in MS patients. Although MS traditionally is regarded a white matter disease, it is well demonstrated that demyelinated lesions can occur also in gray matter [43], [44], [45], [46]. Indeed, many axons originating from and terminating on cortical neurons are myelinated. Compared to white matter lesions, however, cortical MS lesions are less obvious macroscopically, histologically, and on conventional T2-weighted MRI scans. Consequently, the significance of cortical lesions may not have been fully appreciated previously [45], [47], although involvement of cerebral cortex in MS has attracted interest recently [48]. Kidd et al. [45] reported that the use of gadolinium-enhancement increased the detection of cortical lesions on MRI scans by 140%. Of all active brain lesions examined in this study, 26% arose within or adjacent to the cerebral cortex. This report also indicated that MRI underestimates the presence of small cortical lesions, when compared to subsequent neuropathological analysis of the same tissue.

Inflammation and neuronal pathology in cortical MS lesions was recently characterized using immunohistochemistry and confocal microscopy [46]. Cortical lesions contained 13 times fewer lymphocytes and 6 times fewer microglia/macrophages than white matter lesions, indicating reduced inflammation in gray matter lesions. In addition, cortical lesions exhibited extensive neuronal injury including neuritic swellings, and dendritic or axonal transection. The density of transected neurites (axons and dendrites) was 4119/mm3 in active cortical lesions, 1107/mm3 in chronic active cortical lesions and 25/mm3 in chronic inactive cortical lesions. In contrast, myelinated MS cortex and control gray matter contained 8 and 1 transected neurite/mm3, respectively. Both active and chronic active cortical lesions exhibited activated microglia closely associated with neurites and neuronal perikarya. Finally, apoptotic neurons were significantly increased in cortical lesions compared to myelinated cortex [46].

The presence of cortical MS lesions may have several functional consequences. It is possible that neuronal damage in motor and sensory cortex contributes significantly to ambulatory decline. In addition, various aspects of cognitive deficits frequently occur in MS, affecting 40–70% of all diagnosed individuals [49], [50]. Most commonly affected are functions related to learning, memory and information processing [49]. Positron emission tomography (PET) studies demonstrated that decreased cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS [51]. Cognitive impairment in MS patients has generally been attributed to subcortical white matter lesions. However, considering the extent and nature of damage to cortical neurites in many MS brains, it is conceivable that injury to neurons in cortical lesions provides an additional biological substrate for this functional impairment.

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9. Conclusion 

Together, the data discussed in this review suggest that axonal injury begins at onset of disease and that cumulative axonal loss provides the pathological substrate for permanent disability in patients with MS. The concept of MS as an inflammatory neurodegenerative disease has several important implications. Since different mechanisms may contribute to axonal damage during different stages of disease, it is crucial to clarify the pathophysiology of neurodegeneration in MS. Inflammation may cause continuous tissue damage in the absence of clinical manifestations during RR-MS. Therefore, inflammation remains the major therapeutic target during early MS and anti-inflammatory therapies should be neuroprotective. Another possibility is the development of novel therapies that will spare axons from transection during various stages of MS. The development of neuroprotective drugs aimed for MS patients requires appropriate animal models. The relapsing EAE model discussed in this review resembles MS in many aspects and may be suitable for testing the efficacy of such drugs. First, the disease course is initially relapsing but subsequently progresses to chronic disability. Second, these mice respond to interferon beta treatment with milder symptoms and less frequent relapses [40]. Third, the magnitude of spinal cord axonal loss in chronic paralyzed mice [16] is comparable to that observed in lesions of severely disabled chronic MS patients [18], [22].

Importantly, tissue destruction begins at onset of MS and is clinically silent. Therefore, disease-modifying therapeutics should be started early and proactively in order to prevent or delay the development of functional disability. Promoting remyelination at an early stage of MS will restore conduction and, more importantly, may be neuroprotective since chronic demyelination can cause axonal degeneration. Possible avenues to obtain remyelination include enhancing endogenous CNS cells to repopulate and remyelinate lesions, or transplanting stem or progenitor cells into lesions. Bone marrow cells that can give rise to neuronal cells may provide an effective source of donor cells for transplantation that, in addition, will avoid controversial political issues associated with stem cells. Finally, the silent nature of early axonal loss and the lack of reliable surrogate markers of disease progression during RR-MS are major obstacles for testing future therapeutics. Surrogate markers of axonal loss are therefore needed to monitor patients with MS.

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Acknowledgements 

This work was supported by NIH grants NS35058, NS38667 and by a pilot study grant (B.D.T.) and a postdoctoral fellowship (C.B.) from the National Multiple Sclerosis Society.

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Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 165-171, 15 February 2003

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