Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 181-185, 15 February 2003

Remyelination in multiple sclerosis

Institut für Neuropathologie, Charité, Campus Virchow-Klinikum, Humboldt-Universität, Augustenburger Platz 1, 13353 Berlin, Germany

Article Outline

Abstract 

Remyelination in multiple sclerosis (MS) lesions has been described in several studies. It depends on the presence of myelinating oligodendrocytes and a functional interaction between these myelinating cells and axons. The imaging signal of remyelination in magnetic resonance imaging or spectroscopy is not yet defined. The present review will focus on the morphological appearance of remyelinating MS lesions, their correlation with oligodendrocyte pathology, and possible markers for remyelination in imaging.

Keywords:  Multiple sclerosis, Remyelination, Oligodendrocytes, MRI

 

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1. Introduction 

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by the morphological hallmarks of inflammation, demyelination, gliosis, and axonal loss [1], [2], [3]. The pathogenesis and etiology of MS are yet unknown and recent detailed studies on the immunopathology revealed a profound heterogeneity of the lesions with respect to the composition of the inflammatory infiltrate, immunological effector mechanisms, extent and mode of oligodendrocyte death, and occurrence of remyelination [4], [5]. These data suggest that multiple effector mechanisms of myelin, oligodendrocyte or axon damage may be present in MS lesions leading to this heterogenous pathology of the plaques.

Remyelination is a phenomenon that has already been described in the very early morphological descriptions of the disease [6]. More recent studies consistently revealed the presence of remyelination in MS lesions, either restricted to the lesion edge or even extending through the entire plaque area, then being designated as shadow plaques [7], [8], [9], [10], [11]. These remyelinated lesions may even become the target of new demyelinating attacks [12]. Remyelination of MS lesions may have different important functions, including lesional repair, protection of axons, and restoration of conduction velocity. Clinically, induction of remyelination may have significant implications for improvement of disability in MS patients. There are, however, only few data available on the frequency, time course and extent of remyelination in MS. Additionally, the imaging correlate of remyelinating lesions is completely unknown. However, identifying the presence or absence of oligodendrocytes and axons in MS patients in vivo is a prerequisite for the establishment of therapeutic strategies to induce remyelination. These strategies may include, e.g. application of growth factors [13], [14] or remyelinating autoantibodies [15], and the transplantation of oligodendrocyte precursor cells or stem cells [16], [17], [18], which all have been shown to successfully induce remyelination in different immune-mediated, toxic, or genetic animal models of demyelination or dysmyelination.

The present review will therefore focus on the morphology of remyelination in MS lesions, the correlation of remyelination with oligodendrocyte pathology, and the possibility of detecting remyelination with different imaging methods.

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2. Morphology of remyelination 

The characteristic signs of oligodendrocyte remyelination are best recognized ultrastructurally; they have mainly been defined in experimental models (e.g. toxic demyelination using lysolecithin or cuprizone) and were also detected in MS lesions [19]. The hallmarks are a shortened internode distance and a decreased myelin thickness to axonal diameter ratio (Fig. 1a) [8], [9], [20]. Light microscopically, short internodes are impossible to detect, whereas thin, irregularly formed myelin sheaths are readily identifiable in cross or longitudinal sections by using conventional myelin stains or immunocytochemistry for myelin proteins [11].

  • View full-size image.
  • Fig. 1. 

    (a) Remyelinated lesion in the dorsal funiculus of adult rat spinal cord 3 weeks after induction of demyelination with 1% lysolecithin. Uniformly thin myelin sheaths are detectable with a decreased myelin thickness to axon diameter ratio. (b) Late remyelinated shadow plaque with myelin pallor and a sharp border to the normal appearing white matter (immunocytochemistry for MBP). (c) Early remyelinating lesion with irregularly arranged thin myelin sheaths that surround clusters of axons. Note the high cellularity in the lesion at this stage of early remyelination (immunocytochemistry for MBP).

Remyelination of demyelinated plaques may be complete or incomplete; if incomplete, it mostly occurs at the plaque edge, forming a transition zone between normal appearing white matter and the demyelinated plaque center [9], [11]. Completely remyelinated plaques in MS cases, the so-called shadow plaques, appear as sharply circumscribed areas of myelin pallor in the normal appearing white matter (Fig. 1b). Remyelination at the edge of a demyelinated plaque also forms a sharp border to the normal appearing white matter. Remyelination in MS lesions is mostly correlated with the presence of high numbers of oligodendrocytes expressing myelin proteins or myelin protein mRNA in their cytoplasm [21], [22].

During plaque development, remyelination may occur very rapidly and occasionally, ongoing myelin breakdown may coexist with signs of remyelination [7], [8], [10]. Generally, active remyelination occurs in lesions that still contain large numbers of macrophages. This lesion type may be designated as early remyelinating lesion [23]. Clusters of axons are observed surrounded by thin myelin sheaths that are irregularly arranged (Fig. 1c) and complete remyelination of a total plaque area often does not occur at this stage of plaque development. In later stages, remyelination of plaques may be complete or, as described above, restricted to the plaque edge. In these late remyelinating lesions or shadow plaques, the number of macrophages is significantly reduced and only few of these cells are still present [23]. These shadow plaques are sharply demarcated lesions in the white matter with reduced myelin density (pale staining in LFB or immunocytochemistry for myelin proteins) (Fig. 1b), uniformly thin myelin sheaths, profound fibrillary gliosis, and reduced axonal density. Their shape and topographical distribution is the same as that of classical demyelinated plaques. These lesions have to be distinguished from active lesions with incomplete demyelination (edema, myelin sheaths in the process of dissolution, massive infiltration of the tissue with macrophages, containing early myelin degradation products) and from areas of secondary Wallerian Degeneration (areas with ill-defined borders, reduced density of myelin and axons, the preserved myelin showing similar thickness compared to that in the normal white matter, diffuse fibrillary gliosis and macrophages containing large myelin granules in the absence of T cells). Remyelinated lesions may undergo active demyelination [12]. In this situation, a typical shadow plaque contains numerous macrophages with early degradation products and shows signs of acute myelin disintegration.

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3. Oligodendrocytes in MS 

Demyelination in MS could in part result from destruction of oligodendrocytes. The fate of the oligodendrocyte in the evolution and repair of the demyelinating lesion is uncertain and a matter of debate. Oligodendrocytes are susceptible to damage via a number of immune or toxic mechanisms present within the MS lesion. These factors include cytokines such as TNF-α or IFN-γ, the generation of reactive oxygen or nitrogen species, the production of excitatory amino acids such as glutamate, the activation of complement components, the release of proteolytic and lipolytic enzymes, T-cell-mediated injury via T-cell products (perforin/lymphotoxin), the interaction of Fas antigen with Fas-ligand, CD8+ class I MHC-mediated cytotoxicity, or persistent viral infection (for review, see Ref. [24]).

Pathological studies have reported preserved oligodendrocytes in actively demyelinating lesions [21], [22], [25], [26]. These cells may either be myelinating oligodendrocytes that have not been affected by the demyelinating process, mature oligodendrocytes that have survived the loss of their myelin-forming processes, or cells that are rapidly recruited from the progenitor pool and express markers of mature oligodendrocytes. In contrast, oligodendrocyte injury has also been described as an early event in MS lesion formation [27], supporting the hypothesis of a heterogeneous pathology of demyelination and oligodendrocyte destruction or preservation within the lesions.

Recently, a systematic analysis of oligodendrocyte pathology in 113 MS cases demonstrated two principal patterns of oligodendrocyte pathology in MS lesions [28]. The first pattern revealed a variable destruction of oligodendrocytes during active demyelination. Oligodendrocytes, however, reappeared within inactive or remyelinating areas of the same lesions with an increased number of PLP mRNA-expressing cells compared to those expressing myelin oligodendrocyte glycoprotein (MOG). Although markers for the identification of immature oligodendrocytes have not been applied in this study, the presence of cells expressing PLP mRNA but not more mature oligodendrocyte markers such as MOG suggests that these cells may have been derived from the progenitor pool. In other studies, immature, presumably newly generated oligodendrocytes that are at a much earlier differentiation stage have directly been visualized [25], [29], [30], [31]. Remyelinating areas were frequently found in this first pattern of oligodendrocyte pathology. The remyelinating process itself is associated with the reexpression of developmental genes by oligodendrocytes [32] and an increased expression of cell death inhibitory proteins such as bcl-2 [33].

The second pattern of oligodendrocyte pathology is characterized by extensive destruction of oligodendrocytes in areas of active myelin breakdown. Remyelination is sparse or absent in these cases. The failure of recruiting myelinating oligodendrocytes in this pattern may have different reasons: (1) surviving progenitor cells fail to differentiate into oligodendrocytes, (2) the local progenitor population is destroyed together with the differentiated oligodendrocytes and the lesions are not repopulated by progenitor cells from the vicinity of the plaque, or (3) immature oligodendrocytes die very shortly after their generation.

Several recent studies revealed the presence of premyelinating oligodendrocytes or oligodendrocyte precursor cells in some chronic MS plaques in the absence of remyelination [29], [30], [34], [35], [36]. This quiescent cell population may be a reservoir for remyelinating oligodendrocytes and the potential to generate new myelinating oligodendrocytes may be more likely and pronounced in those lesions with large numbers of progenitor cells. The numbers of progenitor cells tends to decrease with lesion progression and lesion age, indicating that the time window for lesion repair may be limited. Additionally, these observations indicate that there is a failure in generating myelinating oligodendrocytes in these chronic stages of lesion development. The reasons for the lack of differentiation should be clarified since these cells may represent interesting targets for therapy regimens aiming to induce remyelination. Different hypotheses exist for the differentiation failure of these oligodendrocytes precursors. There may be either a lack of the right sequence of growth factor stimulation that is necessary for the development of oligodendrocytes [37], an impaired axon–oligodendrocyte interaction, or the glial scar that hinders remyelination [29].

The profound heterogeneity in extent and topography of oligodendrocyte destruction or preservation in MS lesions suggests that myelin and oligodendrocytes are differentially affected in different subgroups of MS patients. This heterogeneity of immunopathogenic mechanisms leading to plaque formation have been described recently [5]. These observations have significant consequences for the occurrence of spontaneous remyelination in vivo as well as for future therapeutic strategies. The identification of the different immunopathological subtypes defined in this study in vivo is prerequisite for the establishment of a therapy based on the underlying mechanisms of myelin destruction. First attempts to define such markers have been made [38].

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4. Imaging of remyelination 

If remyelination becomes a target for therapies in the future, its identification in imaging will be critical. At present, there is no marker for remyelination available by using the standard magnetic resonance imaging (MRI) techniques [39]. The T2 signal is nonspecific with respect to the underlying pathology and an abnormal T2 signal was attributed to remyelinating lesions in a primate model of multiple sclerosis [40]. However, newer MRI techniques will probably be helpful in defining myelin pathology. Experimental studies of the normal-appearing white matter suggested that the magnetization transfer ratio is a sensitive marker of physical changes to myelin whereas the short T2 component of the T2 relaxation is a more specific indicator of myelin content in the tissue [41]. The latter hypothesis was confirmed in a correlative pathologic–radiologic postmortem study. The short T2 component of the T2 relaxation distribution clearly corresponded to the anatomic distribution of myelin and chronic demyelinated plaques were shown to lack the short T2 component signal [42]. In an animal model for toxic demyelination, an increased magnetization transfer ratio (MTR) was observed during remyelination [43]. Whether certain metabolites in magnetic resonance spectroscopy are indicative of remyelination is not yet clear [44]. Additional useful information on the functional effects of demyelination and remyelination may be provided by the combination of MRI and electrophysiological measures such as visually evoked potentials (VEPs) [45]. Studies in optic nerves have associated the restoration of conduction with the occurrence of remyelination [46].

Hypointense lesions in T1-weighted MRI and a strongly decreased MTR ratio are indicators for severe tissue destruction in MS lesions [47], [48]. The extent of T1 hypointensity, however, is known to change over time [49]. In a recent study, we therefore analyzed changes of lesion hypointensity over time with initial histopathological changes in 14 patients who underwent brain biopsy for diagnostic reasons [50]. The longitudinal changes in T1 hypointensity were correlated with the initial stage of demyelinating activity. Lesions with early signs of remyelination showed a decrease in T1 hypointensity whereas inactive demyelinated plaques showed an increase. These observations may have several implications: (1) a decrease of T1 hypointensity over time may indicate the presence of remyelination, (2) the decision whether a lesion remyelinates or not takes place in an early phase of lesion development, and (3) inactive demyelinated lesions rarely become remyelinated again. In future studies, the evolution of decreasing or even resolving hypointensity could serve as a marker for remyelination, if our data are confirmed in a larger patient sample.

The decrease of hypointensity of a single lesion over time may be used as an indicator of remyelination in future therapeutic studies. Several attempts have been made to promote remyelination in MS. In animal models of MS, natural occurring autoantibodies or intravenous immunoglobulins have been shown to successfully induce remyelination [51], [52]. In the human disease, however, intravenous immunoglobulins failed to induce significant clinical improvement of a fixed deficit in a large multicenter trial [53]. Several other pharmaceutical approaches such as the application of growth factors have provided promising data in experimental models; however, it lack confirmation in MS [13], [54]. Transplantation of progenitor cells, stem cells, or Schwann cells may be interesting approaches for future therapy regimens inducing remyelination [16], [17], [55].

Remyelination is a consistent phenomenon in MS plaques and occurs early during plaque development. The presence of myelinating oligodendrocytes, mainly derived from the progenitor pool, is required to induce substantial remyelination. The detection of premyelinating oligodendrocytes in demyelinated plaques needs further clarification concerning the signaling failure of these cells. Imaging parameters that clearly show remyelination in vivo have to be defined and confirmed.

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Acknowledgements 

The present study was supported by grants from the Gemeinnützige Hertie-Stiftung. Christine Stadelmann is a postdoctoral fellow of the Schering Research Foundation. Fig. 1a was gratefully provided by Dr. Robin Franklin, Department of Clinical Veterinary Medicine, University of Cambridge, UK.

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Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 181-185, 15 February 2003

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