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June 02, 2009; 72 (22) Articles

Remyelination capacity of the MS brain decreases with disease chronicity

T. Goldschmidt, J. Antel, F. B. König, W. Brück, T. Kuhlmann
First published June 1, 2009, DOI: https://doi.org/10.1212/WNL.0b013e3181a8260a
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Abstract

Objective: To analyze and compare the extent of remyelination in lesions from patients with multiple sclerosis (MS) who have a short (early MS lesions) or a long (chronic MS lesions) disease duration and to determine the influence of anatomic localization on the extent of remyelination. In early MS lesions, remyelination has been described as a relatively frequent event, in contrast to chronic MS lesions, where remyelination is absent or limited to the lesion border in the majority of lesions. However, no studies have been published that have quantified and compared the extent of remyelination in early and chronic MS lesions.

Methods: We analyzed the occurrence of remyelination in 52 biopsies from 51 patients (early MS) and in 174 lesions from 36 autopsy cases (chronic MS) by immunohistochemistry for myelin proteins, and correlated our findings with anatomic localization, sex, age, and disease duration.

Results: Significantly more lesions were remyelinated in early than in chronic MS (80.7% vs 60%). In chronic MS, subcortical lesions showed more extensive remyelination than periventricular lesions. The majority of cerebellar lesions were completely demyelinated.

Conclusion: In summary, our data demonstrate that remyelination is a frequent event in early multiple sclerosis lesions. Furthermore, the anatomic localization of a lesion might influence the extent of remyelination.

CNPase = 2,3-cyclic nucleotide 3-phosphodiesterase; LFB = Luxol fast blue; MBP = myelin basic protein; MOG = myelin oligodendrocyte protein; MS = multiple sclerosis; OPC = oligodendrocyte progenitor cell;PAS = periodic acid-Schiff; PBS = phosphate-buffered saline; PLP = proteolipid protein.

Histopathologically, multiple sclerosis (MS) is characterized by inflammation, demyelination, axonal loss, and astrogliosis. Besides these destructive mechanisms, endogenous repair mechanisms such as remyelination that contribute to axonal protection occur.1 Remyelination has been described as a frequent phenomenon in acute or early MS lesions.2–5 However, relatively little is known about the frequency and time course with which remyelination occurs in early vs chronic disease stages. A recent imaging study using voxel-based magnetization transfer ratio indicated that remyelination is most prominent in the first 7 months after gadolinium enhancement.6

Remyelinated lesion areas are also present in chronic MS lesions.7 Frequently, remyelination is found in a rim at the border of chronic MS lesions. Completely remyelinated lesions, called shadow plaques, are less frequently observed. Previous studies describe the presence of extensive remyelination in approximately 20% of chronic MS lesions.8,9 However, somewhat conflicting results exist regarding the heterogeneity of remyelination within the same patient. One study described a more homogenous pattern of remyelination in different lesions from the same patient,8 whereas another study demonstrated a heterogeneous extent of remyelination (ranging from 0 to 89%) between lesions from the same patient.9

In our study, we systematically examined the extent of remyelination in 52 early (51 patients) and 174 chronic (36 patients) MS lesions. We found signs of remyelination in 80.7% of early and 60% of chronic MS lesions. In the majority of patients, we observed a heterogeneous pattern of remyelination. Additionally, the location of a lesion apparently influences the likelihood of extensive remyelination. While 44.4% of the subcortical lesions were characterized by marked remyelination, only 22% of periventricular lesions showed significant remyelination. The majority of cerebellar lesions were completely demyelinated. These findings indicate that the anatomic localization influences the extent of remyelination in chronic MS lesions.

METHODS

Material.

We retrospectively investigated paraffin-embedded brain tissues from 140 patients with MS. Early MS lesions were derived from biopsies (104 patients) that were performed in different centers all over Germany. This biopsy material had been sent to the Department of Neuropathology in Göttingen after completion of routine diagnostic analyses to exclude neoplastic or infectious diseases. Informed consent had been obtained from each patient. None of the study authors were involved in decision making with respect to biopsy. Additionally, 36 autopsies (chronic MS lesions) from the Montreal Neurological Institute, McGill University, Canada, were analyzed. The study was approved by the Ethics Committee of the University of Göttingen.

Criteria for and quantitative analysis of remyelination.

All lesions fulfilled the generally accepted criteria for the diagnosis of MS.10,11 In biopsies and autopsies, a semiquantitative score was used to assess the extent of remyelination. In biopsies, remyelination was identified as thin, irregularly formed myelin sheaths in 2,3-cyclic nucleotide 3-phosphohydrolase (CNPase) staining, and remyelinating lesion areas were infiltrated by numerous macrophages and T cells. Because biopsy samples are small and show only parts of the lesion, we quantified the extent of remyelination using the following categories: 0 = no remyelination, 1 = single remyelinated fibers, 2 = patchy remyelination, and 3 = remyelination throughout the sampled lesion area (figure 1, A, C, and E).

Figure1

Figure 1 Remyelination scores in early and chronic multiple sclerosis

Depending on the extent of remyelination, lesions were scored from 0 to 3. In early multiple sclerosis lesions (A, C, and E), remyelination could be found diffusely within the samples lesion area. Lesions lacking remyelination completely were scored as 0 (A). Score 1 lesions were characterized by few remyelinated axons (indicated by arrows) (C). Lesions demonstrating patchy remyelination throughout the lesion area were scored as 2. Lesions displaying remyelination within the total lesion area were scored as 3 (E). In the majority of chronic multiple sclerosis lesions (B, D, and F), remyelination was found in a rim adjacent to the lesion border. Score 0 lesions were characterized by a complete absence of remyelination (A). In score 1 lesions, remyelination was found in less than 50% of the lesion area (B), whereas in score 2 lesions, more than 50% of the lesion area was remyelinated. Completely remyelinated lesions (shadow plaques) were scored as 3 (C). A, C, and E: Immunohistochemistry for 2,3-cyclic nucleotide 3-phosphodiesterase. B, D, and F: Luxol fast blue–periodic acid-Schiff staining.

In autopsy cases, regions of remyelination were identified by pale staining in the Luxol fast blue (LFB)–periodic acid-Schiff (PAS) staining, located at the lesion border or as complete focal areas. The lesions displayed a sharp border. In contrast to the biopsy cases, the chronic MS lesions were characterized by scant inflammatory infiltrates. In a subset of chronic MS lesions, a rim of activated microglial cells was observed at the lesion border. For autopsies, in which complete lesions were sampled in the majority of cases, we classified the lesions depending on the percentage of lesion area that was remyelinated: 0 = no remyelination, 1 = less than 50% remyelination, 2 = more than 50% remyelination, and 3 = complete remyelination (shadow plaque) (figure 1, B, D, and F).

Immunohistochemistry.

Tissues specimens were fixed in 4% paraformaldehyde and embedded in paraffin. Biopsy and autopsy tissues were cut in 4-μm-thick sections that were stained with hematoxylin and eosin, LFB, and Bielschowsky silver impregnation. Immunohistochemical staining was performed with an avidin–biotin technique. After deparaffinization, intrinsic peroxidase activity was blocked by incubation with 5% H2O2 in phosphate-buffered saline (PBS) for 20 minutes. Nonspecific antibody binding was inhibited with 10% fetal calf serum in PBS for 25 minutes. Microwave pretreatment for better antigen retrieval was performed for CNP, proteolipid protein (PLP), and myelin oligodendrocyte protein (MOG). The primary antibodies were rabbit anti-myelin basic protein (1:1,000; Boehringer Mannheim, Mannheim, Germany), mouse anti-PLP (1:500; Biozol, Eching, Germany), mouse anti-CNPase (1:200; Sternberger Monoclonals, Baltimore, MD), anti-MOG (1:1,000), and rabbit anti-MAG (1:1,000) (kindly provided by C. Richter Landsberg). Secondary antibodies were anti-mouse or anti-rabbit biotinylated immunoglobulin (1:200; Amersham Biosciences, Freiburg, Germany).

Statistical analysis.

For statistical analysis, Student t tests or the Mann–Whitney U test was performed. All tests were classified as significant if the p value was less than 0.05. GraphPad PRISM™ software (Graph Pad Software, Inc., San Diego, CA) was used for these analyses.

RESULTS

Remyelination is a frequent phenomenon in early MS lesions.

We analyzed 105 biopsies from 104 patients. Samples smaller than 0.12 cm2 were excluded from the analysis, resulting in 52 biopsies from 51 patients (36 women, 15 men) being included in the present study. One patient was biopsied twice within 6 years. For 13 patients (8 women, 5 men), the time period between onset of symptoms and biopsy was available (range 6–93 days, mean 36 days; table). For 13 patients, separate tissue samples from the same biopsy were available. In these cases, we assumed that the same lesion was always biopsied and we selected the tissue sample with most prominent remyelination for the analysis.

View this table:

Table Sex, age, disease duration, and extent of remyelination in early multiple sclerosis lesions

View this table:

Table Continued

We compared the extent of detectable remyelination in LFB-PAS staining with the staining signals of myelin basic protein (MBP), PLP, and CNPase immunohistochemistry to determine which of the myelin stainings were the most sensitive method to detect early remyelination in human biopsy samples. LFB-PAS staining was less sensitive in detecting early remyelination than immunohistochemistry for MBP, CNPase, or PLP (figure 2, A–D, and table). Similar findings were observed in the toxic demyelinating–remyelinating cuprizone mouse model. These parallel experiments were performed because remyelination in this model always follows the same timeline. Early during the remyelination process in the cuprizone model, the re-expression of myelin proteins such as MBP and CNPase precedes the reappearance of LFB-PAS staining in the corpus callosum (see appendix e-1 and figure e-1 on the Neurology® Web site at www.neurology.org). During later remyelination stages (e.g., 28 days after cessation of cuprizone treatment), a similar extent of remyelination was observed in myelin protein and LFB-PAS stainings. Therefore, we focused on the CNPase immunohistochemistry to estimate the presence of remyelination in early MS lesions using a semiquantitative score. Of 52 biopsies, 42 (80.7%) showed signs of remyelination. Four lesions (7.6%) were characterized by the presence of few remyelinated fibers, whereas 12 (23.1%) and 26 lesions (50%) showed patchy remyelination or marked remyelination throughout the sampled lesion area (figure 3). More women than men showed extensive remyelination (score 3) (women 56.8%, men 33.14%); however, the difference observed between women and men did not reach significance (p = 0.2, Fisher exact test). Additionally, no correlation between age or disease duration and the extent of remyelination was found.

Figure2

Figure 2 Staining for LFB-PAS was less sensitive in detecting remyelination than immunohistochemistry for myelin proteins

The same lesion was stained for Luxol fast blue–periodic acid-Schiff (LFB-PAS; A), 2,3-cyclic nucleotide 3-phosphodiesterase (CNP; B), myelin basic protein (MBP; C), and proteolipid protein (PLP; D). Remyelination was obvious in the sections stained for MBP, CNP, and PLP, whereas no significant signs of remyelination were detected in the LFB-PAS staining.

Figure3

Figure 3 Extent of remyelination in early multiple sclerosis lesions

In early multiple sclerosis lesions, 80.7% of the lesions showed signs of remyelination. In 7.6% of the lesions, only single fibers were remyelinated (score 1), whereas 23.1% of the lesions showed patchy remyelination (score 2). Fifty percent of the lesions displayed remyelination throughout the entire sampled tissue area (score 3).

Remyelination is limited in the majority of chronic MS lesions.

To determine the extent of remyelination in chronic MS lesions, we analyzed 174 lesions from 36 autopsy cases (17 women, 19 men; disease duration between 3 and 41 years, mean 17 years). Of the 174 lesions, 69 (39.6%) were completely demyelinated, 60 (34.5%) showed less than 50% remyelination, and 22 (12.6%) were characterized by remyelination of more than 50%. Only 23 lesions (13.2%) showed complete remyelination (figure 4A). We observed significantly more demyelinated lesions in chronic than in early MS lesions (39.7% vs 19.7; p = 0.008, Fisher exact test). In women, the percentage of lesions with a high extent of remyelination (score 2 or 3) was slightly higher than in men (women, score 2 or 3: 17 or 16%; men, score 2 or 3: 9 or 11%); however, there was no significant correlation between female sex and higher extent of remyelination. No correlation between disease duration or age at death and remyelination was observed.

Figure4

Figure 4 Remyelination in chronic multiple sclerosis

In chronic multiple sclerosis, 40% of the lesions were completely demyelinated (score 0), and only 13.2 of the lesions were completely remyelinated (A). Among subcortical lesions (B) a higher percentage of lesions (44.4%) showed marked remyelination (score 2 or 3) compared with periventricular (22.2%) (C) and cerebellar lesions (11.2%) (D). The extent of remyelination in different lesions from the same individual was heterogeneous in the majority of patients (E and F, black circles). Among the women (E), one patient showed marked remyelination in all sampled lesions (open circles), and three patients showed only minor remyelination (plus signs). In men (F), remyelination was either heterogeneous in different lesions of the same patients (black circles) or limited/absent (plus signs).

To determine whether the extent of remyelination is heterogeneous in different lesions from the same patient, we selected patients from whom we had five or more lesions available. Of 19 patients, 12 showed a variable extent of remyelination ranging from score 0 or 1 to score 2 or 3. In 7 of the 19 patients, we found a somewhat more homogenous pattern of remyelination; in these patients, the lesions were scored either as score 0 or 1 or as score 2 or 3 (figure 4, E and F).

To analyze whether the localization of the lesions influences the extent of remyelination, we grouped the lesions into the following categories: periventricular (n = 83), subcortical (n = 18), hemispheric (neither periventricular nor subcortical) (n = 45), or cerebellar (n = 18). In contrast to periventricular lesions, subcortical lesions showed a higher proportion of lesions with marked remyelination (score 2 or 3) (subcortical 44.4%, periventricular 22.9%), indicating that either periventricular location is a negative or subcortical location a positive factor for remyelination. The percentage of hemispheric lesions showing marked remyelination was 31.1%. Of the cerebellar lesions, the majority of plaques (72.2%) were characterized by complete demyelination, indicating that cerebellar lesions are less likely to remyelinate (figure 4, B–D).

DISCUSSION

Here, we demonstrate that remyelination is a frequent event in early stages of lesion formation. However, in chronic MS lesions, the extent of remyelination is limited in the majority of patients. In our collection of autopsies, the extent of remyelination of different lesions from the same patient was heterogeneous in the majority of patients with MS. Additionally, we found that certain brain regions, such as the subcortical lesions, showed more extensive remyelination than periventricular lesions or lesions in the cerebellum. These data indicate that local factors besides systemic effects (genetics, sex, age) may influence the extent of remyelination in MS lesions.

So far, no study exists that attempts to estimate the extent of remyelination in early MS lesions. Single reports exist that describe that remyelination is a frequent phenomenon in early MS. In our study, we observed signs of remyelination in approximately 80% of the lesions. However, LFB staining is not a suitable marker to detect these early signs of remyelination. Similar to our findings in the cuprizone model, the re-expression of myelin proteins precedes the presence of lipids detectable by LFB staining. We saw comparable findings in early MS lesions. Myelin sheaths were labeled in the CNPase or MBP staining, whereas the LFB-PAS staining was completely negative. In contrast, in chronic MS lesions, similar staining results were obtained by MBP and LFB staining (data not shown). These data suggest that ongoing/early remyelination is characterized by the presence of myelin proteins such as CNPase or MBP and the absence of lipids detectable by LFB, whereas inactive/long-lasting remyelination may be identified by myelin sheaths that are detectable in myelin protein stainings as well as in LFB staining.

The percentage of completely demyelinated lesions was significantly higher in chronic than in early MS lesions. A potential explanation for this phenomenon is that repeated waves of demyelination occur within the same lesions, leading to an exhaustion of the oligodendroglial progenitor pools.12,13 However, in demyelinating animal models, only extended periods of demyelination but not repeated waves of demyelination resulted in a depletion of oligodendroglial progenitor cells and reduced remyelination.14–16 In rodent animal models, remyelination efficiency decreases with the age of the animals.17–19 This phenomenon is associated with a delay in the recruitment and differentiation of oligodendroglial progenitor cells,20 which may be explained by an inefficient recruitment of histone deacetylases, which down-regulate oligodendroglial differentiation inhibitors (such as HES1, Hes5, Id2, and Id4) in demyelinated, old rodent brains.21 Similar mechanisms may contribute to limited remyelination in chronic MS lesions in which a differentiation block of oligodendroglial progenitor cells has been observed, as in the rodent animal models.22,23

Previous animal studies have demonstrated more extensive remyelination in females compared with males in older adult rats.24 We also found a slight but not significant tendency for more pronounced remyelination in women compared with men. These data might indicate that women are more prone to remyelination than men are. Furthermore, the extent and composition of the inflammatory infiltrates in MS lesions may influence the capability of remyelination. One major difference between early and chronic MS lesions is the reduced inflammatory reaction in chronic MS lesions. Early MS lesions are invaded by numerous foamy macrophages and a marked number of lymphocytes, whereas significant inflammatory infiltrates are rare or absent in chronic MS lesions. Only a subgroup of chronic lesions shows a hypercellular rim at the lesion border caused by microglia. It is well established that inflammation is required for remyelination. Macrophage depletion, lack of pro-inflammatory factors such as tumor necrosis factor or interleukin 1β, or treatment with immunosuppressants reduces the extent of remyelination in experimental animal studies.25–30

In our study, complete remyelination (shadow plaques) was found in 13.8% of chronic lesions. These results are comparable to those of earlier studies in which complete remyelination in 22% or 23%, of the analyzed lesions was observed.9,31 Compared with earlier studies, we found a higher percentage (40%) of completely demyelinated lesions.9 However, one of the previous studies described an even higher percentage of completely demyelinated lesions (58%). The underlying cause for the differences in the percentage of lesions with complete demyelination observed between these studies is unclear, because all studies used LFB staining to quantify the extent of remyelination.

In our study, the extent of remyelination varied between different lesions from the same individual in the majority of patients. A subgroup of patients (7 of 19) was characterized by a more uniform pattern of remyelination with either extensive remyelination (n = 1) or remyelination of less than 50% of the lesion area (n = 6). In an earlier study, the majority of patients showed relatively homogenous patterns of either limited or extensive remyelination.8 The results of these two studies are difficult to compare because the authors of the earlier study presented the extent of remyelination of the total plaque area per patient. They also found a certain variability in the extent of remyelination between lesions from the same patient. Even patients with extensive remyelination, as determined by remyelination of the total lesion area, had completely demyelinated lesions.8 In both studies, absence of remyelination was observed in only a small subset of patients, indicating that in principle the majority of patients had the capability to remyelinate.

We found a higher extent of remyelination in subcortical lesions compared with periventricular and cerebellar lesions, indicating that the localization of a lesion influences the extent of remyelination. This result is in accord with recent studies describing more pronounced and faster remyelination within the cortex compared with white matter lesions.32,33 In animal studies, the activation stage of macrophages in cortical lesions has been found to differ from white matter lesions, indicating a different regulation of the immune response between white and gray matter. Similar mechanisms may contribute to the variability in remyelination that we observed in white matter lesions in different anatomic localizations. Alternatively, oligodendroglial precursor cells in different CNS regions may have a different capability for remyelination. It is well established that oligodendrocytes and oligodendrocyte progenitor cells (OPCs) originate from different CNS regions during development.34,35 In the adult rodent and human CNS, OPCs express different markers, suggesting either the presence of OPCs of heterogeneous differentiation stages or the existence of different subtypes of OPCs.36 The differentiation of progenitor cells may be influenced by the environment.37 In contrast to our findings, extensive and efficient remyelination has been observed in the cerebellar peduncles of adult rats.20 Additional studies are required to analyze systematically whether characteristics and the remyelination capabilities of oligodendroglial progenitors vary between different white matter CNS regions in rodents or humans. Another potential and simpler explanation for more extensive remyelination in subcortical compared with periventricular lesions might be a higher neuronal activity, which has been reported to contribute to the proliferation of OPCs. Because of the length of axons that may cross through multiple MS lesions, it is more likely that neuronal activity and transport is intact close to the neuronal cell bodies than, for example, in the hemisphere. Further experiments are required to determine which mechanism is the underlying cause for the more pronounced remyelination capacity of subcortical lesions. In contrast, periventricular lesions show less extensive remyelination. This might be explained by the presence of myelin reactive T cells and demyelinating antibodies in the CSF, which may enter the CNS via an ependyma with increased permeability due to the periventricular inflammatory process,38–40 and the resulting “milieu” might be less favorable for remyelination.

DISCLOSURE

T.G. was supported by a studentship of the Faculty of Medicine of the University Medical Center, Göttingen, and by the German National Academic Foundation. He reports no further disclosures. J.A. received grants from Novartis and TEVA Neuroscience for work unrelated to the current article. He has received honoraria for serving on data safety monitoring committees from Biogen Idec, Sanofi, Aventis, and BioMS/Lilly and for participating in symposia or workshops sponsored by Novartis, Serono Symposia, and TEVA Neuroscience. He has also been an invited guest of a number of American and Canadian Neurology departments; sponsorship if any of these programs is unknown to him. F.B.K. received honoraria from Biogen-Idec, Bayer Vital Health Care and Bergmann.consult (Teva). W.B. has received honoraria from BiogenIdec, Merck-Serono, Teva, Sanofi-Aventis, and Bayer Vital. He has received grants from Serono, BiogenIdec, and Teva and has served on the advisory board of Teva/Sanofi-Aventis and BiogenIdec. T.K. has received honoraria for participating in symposia sponsored by TEVA Neuroscience and Bayer HealthCare.

Footnotes

  • Received October 8, 2008. Accepted in final form March 2, 2009.

    Supplemental data at www.neurology.org

    *These authors contributed equally to this work.

    Supported by the Research Program and the Heidenreich von Siebold-Program from the Faculty of Medicine, Georg-August-University Göttingen (T.K.), the Hertie Foundation (T.K.), and the 6th Framework of the European Union, NeuroproMiSe, LSHM-CT-2005-018637 (W.B.). T.G. was supported by a studentship of the Faculty of Medicine of the University Medical Center, Göttingen.

    Disclosure: Author disclosures are provided at the end of the article.

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