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PubMed2000

Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis.

Previous imaging studies have suggested that there is substantial axonal loss in the normal-appearing white matter (NAWM) of brains from multiple sclerosis patients and that this axonal loss may be an important determinant of disability. Recently, substantial axonal loss in the NAWM has been confirmed directly in post-mortem tissue. Whether the NAWM changes occur as a consequence of damage to axons traversing lesions or to a more diffuse injury process is uncertain. Using formalin-fixed brains of eight multiple sclerosis patients and eight age-matched controls, we examined the relationship between demyelinating lesion load in three volumes of the cerebral white matter and the loss of axons in NAWM of the corresponding three projection regions (anterior, middle, posterior) in the corpus callosum (CC). There was a significant loss of calculated total number of axons crossing the CC in each of the three regions relative to the non-multiple sclerosis controls. Strong correlations were found between the regional lesion load and both the axonal density (r = -0.673, P: = 0.001) and the total estimated number of axons crossing the corresponding projection area in the CC (r = -0. 656, P: = 0.001) for the patients. This suggests that Wallerian degeneration of axons transected in the demyelinating lesions makes a major contribution to the substantial, diffuse loss of axons in the NAWM in multiple sclerosis. These findings emphasize the need to consider the consequences of multiple sclerosis lesions in terms of both local and distant effects in functionally connected regions of the brain.

Adult↗
PubMed2000

Aberrant T cell migration toward RANTES and MIP-1 alpha in patients with multiple sclerosis. Overexpression of chemokine receptor CCR5.

Trafficking of inflammatory T cells into the central nervous system (CNS) plays an important role in the pathogenesis of multiple sclerosis. The directional migratory ability of peripheral T cells is associated with interactions of chemokines with their receptors expressed on T cells. In this study, transmigration of peripheral T cells toward a panel of chemokines was examined in patients with multiple sclerosis and healthy individuals using Boyden chemotactic transwells. A significantly increased migratory rate preferentially toward RANTES and MIP-1alpha, but not other chemokines, was found in T cells obtained from multiple sclerosis patients as opposed to healthy individuals (P: < 0.001). The migratory T-cell populations represented predominantly Th1/Th0 cells while non-migratory T cells were enriched for Th2-like cells. The study demonstrated further that aberrant migration of multiple sclerosis-derived T cells toward RANTES and MIP-1 alpha resulted from overexpression of their receptors (CCR5) and could be blocked by anti-CCR5 antibodies. These findings have important implications for our understanding of the mechanism underlying aberrant T cell trafficking in multiple sclerosis.

Cell Movement↗
PubMed2001

Visual and motor evoked potentials in the course of multiple sclerosis.

While evoked potentials are sensitive tools for diagnosing multiple sclerosis, little is known about their prognostic value and their role in determining the course of the disease. To validate the visual and motor evoked potentials (VEP and MEP) as measures for the course of multiple sclerosis, we examined prospectively 30 patients with relapsing-remitting or secondary progressive multiple sclerosis. The Expanded Disability Status Scale (EDSS), VEP and MEP were measured at entry and after 6, 12 and 24 months. The Spearman rank correlation was used for statistical analysis. Applying multiple regression in 15 randomized patients allowed derivation of a formula for predicting changes in EDSS score based on changes in MEP and VEP. Validation was done by comparing the predicted with the real changes in EDSS in the other 15 patients. The number of pathological VEP and MEP results correlated at all four measurement points with the EDSS (rho > or = 0.6, P < or = 0.01). When the latencies of VEP and MEP were combined using the sum of their Z scores, correlation with the EDSS was even more significant (rho > or = 0.6, P < 0.001). Changes over time of electrophysiological data and EDSS were also correlated (rho = 0.43, P < 0.05). Moreover, VEP and MEP at baseline correlated with the EDSS after 2 years (rho = 0.43,P = 0.03). Reliable prediction of the course of multiple sclerosis for individual patients is not possible from VEP and MEP data. However, we conclude that, for groups of patients with secondary progressive or relapsing-remitting multiple sclerosis the combined testing of VEP and MEP yields numerical data that allow objective estimation of the course and prognosis of the disease.

Adult↗
PubMed2001

Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disease of the CNS with, as yet, an unknown aetiology. Temporal profile, intensity and treatment responses are highly variable in multiple sclerosis suggesting pathogenetic heterogeneity. This hypothesis has been supported by histopathological studies disclosing at least four different subtypes of acute demyelinating lesions. Although stratification of multiple sclerosis patients into these categories would be extremely helpful for clinical studies, this approach is impractical as it requires brain biopsy. In this study we investigated CSF cytology from 60 multiple sclerosis patients by flow cytometry. We identified different patterns of CSF cytology, which were independent of immunological parameters in the peripheral blood. The most variable CSF parameter was the B cell to monocyte ratio, which remained stable during different phases of disease in selected patients. The ratio correlated with disease progression but not with disability or disease duration in a retrospective, consecutive analysis. A high ratio (predominance of B cells) was associated with more rapid disease progression, whereas a low ratio (predominance of monocytes) was found in patients with slower progression. Our study demonstrates the existence and potential clinical relevance of different CSF cytology patterns. We hypothesize that CSF cytology patterns may reflect the heterogeneity in the pathogenesis of multiple sclerosis.

Adolescent↗
PubMed2001

Proton MR spectroscopy with metabolite-nulling reveals elevated macromolecules in acute multiple sclerosis.

Proton magnetic resonance spectroscopy has shown elevated signals in the spectral region of lipids in acute multiple sclerosis lesions. The metabolite-nulling technique allows the separation of macromolecules from other metabolites, such as lactate, N-acetyl-aspartate, creatine, choline and myo-inositol. Using this technique in studies on multiple sclerosis patients, we were able to differentiate macromolecules biochemically in acute and chronic multiple sclerosis lesions. Ten patients with acute, contrast-enhancing multiple sclerosis lesions, 10 patients with chronic lesions and 10 healthy control subjects were investigated with a 1.5 T whole body system, using a stimulated echo acquisition mode (STEAM) sequence with metabolite-nulling and outer volume saturation. Metabolites and macromolecules were quantitated absolutely. The 0.9 and 1.3 parts per million (p.p.m.) resonances of the macromolecules were significantly elevated in acute lesions compared with chronic lesions and healthy controls (P < 0.001 for 0.9 p.p.m., P < 0.05 for 1.3 p.p.m.). The macromolecular resonances at 2.1 and 3.0 p.p.m. in acute and chronic lesions were normal. N-acetyl-aspartate was significantly reduced in acute and chronic lesions compared with controls (P < 0.05 and P < 0.01, respectively). Choline was significantly elevated in acute lesions compared with controls (P < 0.05). Up to now, elevated resonances at 0.9 and 1.3 p.p.m. in acute lesions have been interpreted as lipids. In metabolite-nulled spectra, the macromolecular resonances did not fit those of lipids and might have been due to proteins or polypeptides containing the amino acids alanine, threonine, valine, leucine and isoleucine. These account for approximately 40% of the amino acids of myelin proteolipid protein and for approximately 20% of myelin basic protein. The increased macromolecular resonances at 0.9 and 1.3 p.p.m. may be interpreted as biochemical markers of myelin fragments and may be used as reliable markers of acute multiple sclerosis lesions as they provide clear discrimination among acute and chronic lesions and controls.

Acute Disease↗
PubMed2001

Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions.

Macroscopic sampling of multiple sclerosis lesions in the brain tends to find chronic lesions. For a better understanding of the dynamics of the multiple sclerosis disease process, research into new and developing lesions is of great interest. As MRI in vivo effectively demonstrates lesions in multiple sclerosis patients, we have applied it to unfixed post-mortem brain slices to identify abnormalities, in order to obtain a higher yield of active lesions. The Netherlands Brain Bank organized the rapid autopsy of 29 multiple sclerosis patients. The brain was cut in 1 cm coronal slices. One or two slices were subjected to T(1)- and T(2)-weighted MRI, and then cut at the plane of the MRI scan into 5 mm thick opposing sections. Areas of interest were identified based on the MRI findings and excised. One half was fixed in 10% formalin and paraffin-embedded, and the corresponding area in the adjacent half was snap-frozen in liquid nitrogen. In total, 136 out of 174 brain tissue samples could be matched with the abnormalities seen on T(2)-weighted MRIs. The stage of lesional development was determined (immuno) histochemically. For 54 MRI-detectable samples, it was recorded whether they were macroscopically detectable, i.e. visible and/or palpable. Histopathological analysis revealed that 48% of the hyperintense areas seen on T(2)-weighted images represented active lesions, including lesions localized in the normal appearing white matter, without apparent loss of myelin but nevertheless showing a variable degree of oedema, small clusters of microglial cells with enhanced major histocompatibility complex class II antigen, CD45 and CD68 antigen expression and a variable number of perivascular lymphocytes around small blood vessels [designated as (p)reactive lesions]. From the macroscopically not-visible/not-palpable MRI-detected abnormalities, 58% were (p)reactive lesions and 21% contained active demyelinating lesions. In contrast, visible and/or palpable brain tissue samples mainly contained chronic inactive lesions. We conclude that MRI-guided sampling of brain tissue increases the yield of active multiple sclerosis lesions, including active demyelinating and (p)reactive lesions.

Adult↗
PubMed2001

The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis.

In multiple sclerosis, matrix metalloproteinases (MMPs) are effectors of crucial pathogenetic steps, such as blood-brain barrier breakdown, invasion of brain parenchyma by immune cells and demyelination. However, only limited data are available on the types of MMPs induced in the course of multiple sclerosis, and on the role of their endogenous antagonists, the tissue inhibitors of metalloproteinases (TIMPs). We quantified the transcriptional expression of six MMPs and the four TIMPs in lesions and in normal appearing white matter (NAWM) from post-mortem multiple sclerosis brain tissue by real-time polymerase chain reaction, and compared levels with those in brain tissue from six control patients without neurological disease. The mRNA expression of MMP-7 and -9, but not of other metalloproteinases [MMP-2 and -3, and tumour necrosis factor (TNF)-alpha-converting-enzyme] was equally upregulated throughout all stages of lesion formation with active inflammation, and in most of matched NAWM tissue. The transcription of cytokines TNF-alpha/beta and IL (interleukin)-2, known modulators of MMPs, was upregulated only in distinct stages of lesion formation, while their receptors were not induced at all, which suggests that additional signalling molecules participate in the sustained upregulation of MMP-7 and -9 in multiple sclerosis. None of the TIMPs showed a significant induction over baseline expression of controls. We hypothesize that an imbalance between MMP and TIMP expression may cause a persistent proteolytic overactivity in multiple sclerosis, that may be a factor for continuous tissue destruction, and hence for secondary disease progression.

ADAM Proteins↗
PubMed2003

Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.

Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan-Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing-remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.

Adolescent↗
PubMed2003

A new paraclinical CSF marker for hypoxia-like tissue damage in multiple sclerosis lesions.

Recent studies on the immunopathology of multiple sclerosis revealed a heterogeneity in the patterns of demyelination, suggesting interindividual differences in the mechanism responsible for myelin destruction. One of these patterns of demyelination, characterized by oligodendrocyte dystrophy and apoptosis, closely mimics myelin destruction in acute white matter ischaemia. In the course of a systematic screening for virus antigen expression in multiple sclerosis brains, we identified a monoclonal antibody against canine distemper virus, which detects a cross-reactive endogenous brain epitope, highly expressed in this specific subtype of actively demyelinating multiple sclerosis lesions with little or no immunoreactivity in other active multiple sclerosis cases. The respective epitope, which is a phosphorylation-dependent sequence of one or more proteins of 50, 70 and 115 kDa, is also expressed in a subset of active lesions of different virus-induced inflammatory brain diseases, but is present most prominently and consistently in acute lesions of white matter ischaemia. Its presence is significantly associated with nuclear expression of hypoxia-inducible factor-1 alpha within the lesions of both inflammatory and ischaemic brain diseases. The respective epitope is liberated into the CSF and, thus, may become a useful diagnostic tool to identify clinically a defined multiple sclerosis subtype.

Acute Disease↗
PubMed2003

Focal thinning of the cerebral cortex in multiple sclerosis.

Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm (SD 0.15) versus 2.95 mm (SD 0.11)] brain regions was observed, even early in the course of the disease or in patients with mild disability. Patients with longstanding disease or severe disability, however, presented additionally with focal thinning of the motor cortex area [2.35 mm (SD 0.19) versus 2.74 mm (SD 0.15)]. We conclude that in vivo measurement of cortical thickness is feasible in patients suffering from multiple sclerosis. The data provide new insight into the cortical pathology in multiple sclerosis patients, revealing focal cortical thinning beside an overall reduction of the cortical thickness with disease progression.

Adult↗
PubMed2003

Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis.

Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.

Adult↗
PubMed2004

Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.

While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.

Adolescent↗
PubMed2004

Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population.

Twin, family and adoption studies suggest that susceptibility to multiple sclerosis is substantially mediated by genetic factors. Linkage to human chromosome 17q, homologous to a locus linked to experimental animal models of multiple sclerosis, has been widely replicated and the region likely to harbour a multiple sclerosis susceptibility gene has recently been refined to a 2.5 Mb region of 17q22-24. The candidate multiple sclerosis susceptibility gene, protein kinase C alpha (PRKCA), maps within this interval and association with 35 single-nucleotide polymorphism (SNP) markers, spanning the gene with a median spacing of 7.8 kb, was tested using a case-control approach. Single-marker genotype and estimated haplotype frequencies were compared in UK unrelated cases with multiple sclerosis (n = 184) and healthy controls (n = 340) in order to investigate association with susceptibility to disease. A haplotype of two SNPs mapping to the proximal region of the gene showed evidence for association with susceptibility (Bonferroni-corrected P value = 1.1 x 10(-5)). These findings suggest that further investigation of the PRKCA gene is warranted, particularly in cohorts with evidence of linkage to 17q22. Most of the SNPs investigated in this study were intronic and screening to identify disease-associated functional mutations is now required. Our results suggest that the promoter and proximal gene region should be not only included but prioritized in any screening strategy.

Adult↗
PubMed2005

Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter.

Multiple sclerosis is an inflammatory demyelinating disease of the CNS, the aetiology of which is believed to have both genetic and environmental components. We have investigated one of the candidate viruses for the environmental component of multiple sclerosis, the neurotropic human herpesvirus 6 (HHV-6). Utilizing fluorescent in situ hybridization (FISH) techniques, we have examined human post-mortem tissues for the presence of immediate early and late viral gene expression in multiple sclerosis patient normal appearing white matter (NAWM), lesional tissue and normal control brain samples. HHV-6 gene transcription was detected in all tissue samples and was restricted to oligodendrocytes, as determined by double mRNA FISH analysis. Quantitative analysis of viral mRNA expression indicated that both NAWM and lesional multiple sclerosis samples exhibited significantly higher levels of HHV-6 expression compared with the normal control samples. Lesional samples exhibited the highest levels of viral gene expression, with NAWM exhibiting an intermediate level between lesional and control tissues. Immunofluorescence against early and late HHV-6 proteins verified active translation of HHV-6 viral mRNA in oligodendrocytes. Southern blot analysis of nested polymerase chain reactions using extracted genomic DNA and cDNA confirmed the presence of the HHV-6 genome in all individuals, with the active expression profile mirroring the FISH results. The frequent high level of HHV-6 infection in multiple sclerosis samples suggests a possible role in pathogenesis.

Adult↗
PubMed2005

Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T.

Histopathological reports of multiple sclerosis and its animal models have shown evidence of a link between axonal injury in active lesions and impaired glutamate metabolism. Mature oligodendrocytes play a role in glutamate uptake to maintain glutamate homeostasis but in multiple sclerosis white matter the loss of expression of glutamate transporters in the lesion vicinity results in ineffective glutamate removal. Using a magnetic resonance spectroscopy technique that isolates the glutamate resonance at 3 T, we compared glutamate levels between normal subjects and multiple sclerosis patients in different brain areas. Metabolite concentrations (glutamate, glutamine, N-acetyl-aspartate, myo-inositol, choline, creatine) were derived from LCmodel and corrected for T1 relaxation time. Glutamate concentrations were found to be elevated in acute lesions (P = 0.02) and normal-appearing white matter (P = 0.03), with no significant elevation in chronic lesions (P = 0.77). The N-acetyl-aspartate level in chronic lesions was significantly lower (P < 0.001) than in acute lesions and normal-appearing white matter. The choline level in acute lesions was significantly higher (P < 0.001) than in chronic lesions. Evidence was also found for increased glial activity in multiple sclerosis, with significantly higher (P < 0.001) myo-inositol levels in acute lesions compared with control white matter. These in vivo results support the hypothesis that altered glutamate metabolism is present in brains of multiple sclerosis patients.

Acute Disease↗
PubMed2005

CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis.

Subsequent to demyelination in multiple sclerosis, myelin repair occurs but, as lesions age, the ability to remyelinate diminishes. Molecular pathways underlying oligodendrocyte behaviour during CNS remyelination remain to be elucidated. In this study, we report for the first time constitutive expression of the CXC/alpha chemokine receptors, CXCR1, CXCR2 and CXCR3, on oligodendrocytes in normal adult human CNS tissue, the levels of which were upregulated in multiple sclerosis and other neurological diseases (OND). In addition, both immature (A2B5+/O4+) and more mature (CNPase+) human oligodendrocytes in vitro expressed the same three receptors. The respective ligands to CXCR1, CXCR2 and CXCR3 [i.e. CXCL8/IL-8, CXCL1/GRO-alpha and CXCL10/IP-10), were absent in CNS tissue from normals and subjects with OND, but were present at high levels on hypertrophic (reactive) astrocytes at the edge of active (but not silent) multiple sclerosis lesions. Astrocytes in vitro could be induced to express chemokines following stimulation with pro-inflammatory cytokines. CXCL8 and CXCL1 production by human astrocytes at both the RNA and protein levels could be induced by interleukin (IL)-1beta, while CXCL10 was induced by both IL-1beta and interferon-gamma. Since these cytokines are integral to inflammatory events occurring at the margins of active multiple sclerosis lesions, their upregulation in these regions may underlie the dynamics of chemokine expression observed herein. The simultaneous expression of different CXC chemokine receptors on oligodendrocytes, and their ligands on astrocytes around multiple sclerosis lesions, may bespeak novel functional roles for these immune system molecules in the recruitment of oligodendrocytes and remyelination.

Adult↗
PubMed2006

A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination.

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.

Animals↗
PubMed2006

Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years.

Reliable prognostic markers of primary progressive (PP) multiple sclerosis evolution are still needed. Diffusion tensor (DT) MRI can quantify normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis patients. We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP multiple sclerosis. In 54 PP multiple sclerosis patients, conventional and DT-MRI scans of the brain and T1-weighted scans of the cervical cord were acquired at baseline and after a median follow-up of 15 months. Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, brain and cord atrophy were obtained. Histograms of the mean diffusivity (MD) and fractional anisotropy (FA) values from the NAWM and GM were analysed. At follow-up, 35 patients (65%) experienced a confirmed disability progression. Baseline expanded disability status scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R2: 0.44; discriminating ability: 81%). A lower level of disability and a more severe GM damage identify PP multiple sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

Adult↗