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At least 847 records · Page 47Linked to original sources
PubMed1996

Glial transforming growth factor (TGF)-beta isotypes in multiple sclerosis: differential glial expression of TGF-beta 1, 2 and 3 isotypes in multiple sclerosis.

We studied glial transforming growth factor (TGF)-beta isotype expression in 14 cases of multiple sclerosis. Acute active lesions exhibited selective TGF-beta 2 immunoreactivity of lesion encircling ramified microglia. In contrast, astrocytes within chronic active white matter lesions expressed all three isotypes. Chronic active lesions which extended into cortex exhibited selective cortical astrocyte TGF-beta 2 expression. This isotype was also selectively expressed by astrocytes in apparently normal white matter. A similar pattern of glial TGF-beta expression was seen in the pathological control, progressive multifocal leukoencephalopathy. The results suggest that TGF-beta cytokines are locally expressed in demyelination and that the beta 2 isotype may be uniquely regulated.

Humans↗
PubMed1998

Hypointense multiple sclerosis lesions on T1-weighted spin echo magnetic resonance images: their contribution in understanding multiple sclerosis evolution.

The predictive value of T2-weighted imaging in multiple sclerosis is only moderate, due to low specificity of high signal on such images. Among new MR techniques with acclaimed higher pathological specificity, hypointense lesions on moderately T1-weighted spin echo images show improved correlation with disability. The degree of hypointensity of so called black holes correlates with loss of magnetisation transfer, a marker of matrix destruction. Severe tissue loss is also shown histopathologically in a post-mortem MR study of black holes. In this review unresolved issues regarding black holes are discussed including standardisation of sequences, definition of hypointensity, interobserver variation in measuring lesion load with this technique, and significance of acute black holes. The role of black holes in monitoring treatment efficacy is as yet unexplored.

Brain↗
PubMed2004

Targeting experimental autoimmune encephalomyelitis lesions to a predetermined axonal tract system allows for refined behavioral testing in an animal model of multiple sclerosis.

In multiple sclerosis (MS) the structural damage to axons determines the persistent clinical deficit patients acquire during the course of the disease. It is therefore important to test therapeutic strategies that can prevent or reverse this structural damage. The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in the central nervous system, which leads to a clinical deficit that cannot be directly attributed to a defined tract system. For this reason we have developed a localized EAE model, in which large inflammatory lesions are targeted to the dorsal columns of the spinal cord, an area including the corticospinal tract. These lesions show the pathological hallmarks of MS plaques and lead to reproducible and pronounced deficits in hindlimb locomotion. Because of the anatomical specificity of this technique we can now use highly sensitive behavioral tests that assess the functional integrity of specific axonal tracts. We show that these tests are predictive of the site and extent of a given lesion and are more sensitive for assessing the clinical course than the scales commonly used for disseminated EAE models. We believe that this targeted EAE model will become a helpful new tool for the evaluation of therapeutic approaches for MS that attempt to protect axons or support their repair.

Animals↗
PubMed2002

Gender issues in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is primarily a disease of premenopausal women. Interactions between the disease and the reproductive cycle are important to consider for optimal patient management. REVIEW SUMMARY: Sex hormones are potent immunomodulators, and their actions may help explain the gender distribution seen in MS and other immune-mediated diseases. Preliminary data suggest that immune function may vary cyclically as a function of hormonal milieu. MS does not affect fertility or the ability to bear children, and pregnancy generally has a salutary effect on the disease. Possible teratogenic actions of drugs used for symptom management and prophylactic treatment must be reviewed when managing patients. CONCLUSIONS: Additional studies are needed to delineate the roles of sex hormones as etiologic (and possibly therapeutic) agents in MS. Pharmacologic treatment of MS may impact reproductive function. Neurologists need to be familiar with these issues to assist their patients in choosing therapies and family planning.

Journal Article↗
PubMed1998

Improving the quality of life of patients with multiple sclerosis: diagnosis.

Multiple sclerosis (MS) is the commonest neurological cause of disability in young adults. The clinical course is extremely variable, but typically a relapsing-remitting phase of variable duration is followed by a gradual progression in disability. However, the diagnosis of MS may have an impact that reaches beyond the physical disabilities into many other aspects of life, including career and family. The time of diagnosis is one of the most important in the course of the illness and the way in which investigations are conducted, the timing and manner of imparting the diagnosis, and subsequent support and education may have far-reaching consequences. The diagnostic phase thus presents a difficult management challenge for the neurologist and other health workers attempting to address these issues. This review considers the steps involved in reaching the diagnosis, together with ways in which the overall quality of life of the patient may be maximized during this period.

Journal Article↗
PubMed2005

Recombinant erythropoietin down-regulates IL-6 and CXCR4 genes in TNF-alpha-treated primary cultures of human microvascular endothelial cells: implications for multiple sclerosis.

In multiple sclerosis (MS), disruption of the blood-brain barrier might lead to new gadolinium-enhanced lesion formation in the brain and cause acute relapses. Current therapeutic options for acute relapses in MS are limited. The effect of recombinant erythropoietin (rEPO) on cytokine gene expression in TNF-alpha-treated human brain microvascular endothelial cells was studied. The cells were controls (untreated), exposed for either 6 or 24 h to TNF-alpha or TNF-alpha/rEPO. Of the 96 genes studied, interleukin-6 (IL-6), IL-1beta, CXCR4, and IL-1alpha genes were down-regulated when treated with TNF-alpha/rEPO for 6 h as compared with TNF-alpha alone. At 24 h, IL-6 and CXCR4 gene expression was 4.24 and 2.98, respectively. Quantitative RT-PCR analysis showed down-regulation by 3.86 and 1.9 for IL-6 and CXCR4 genes, respectively. Our findings suggest that further studies are warranted to evaluate the use of EPO in minimizing acute relapses in MS.

Blood-Brain Barrier↗
PubMed2025

GWAS highlights the neuronal contribution to multiple sclerosis susceptibility.

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the brain and spinal cord. Genetic studies have identified many risk loci, that were thought to primarily impact immune cells and microglia. Here, we performed a multi-ancestry genome-wide association study with 20,831 MS and 729,220 control participants, identifying 236 susceptibility variants outside the Major Histocompatibility Complex, including four novel loci. We derived a polygenic score for MS and, optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 genes affected by MS risk variants. Notably, while T cells showed the strongest enrichment, inhibitory neurons emerged as a key cell type. The expression of IL7 and STAT3 are affected only in inhibitory neurons, highlighting the importance of neuronal and glial dysfunction in MS susceptibility.

Journal Article↗
PubMed1996

The effects of interference on verbal learning in multiple sclerosis.

Thirty multiple sclerosis (MS) patients were compared with 30 matched (age and education) controls and were asked to learn and recall 20 target words that were placed among 24 distracter words. Targets and distracters were printed on different colored cards, and the subjects were asked to read each word aloud and recall the target words. This task was repeated four times. The MS patients recalled significantly fewer words across the four trials. A second list without distracters was presented for two trials, and there were no significant differences between the groups' recall. Subsequent recall (short delay and long delay) for List 1 revealed significantly poorer recall for the MS group and significantly poorer cued recall but not recognition memory. Retrieval processes were implicated such as source memory, or contextual stamping, rather than encoding mechanisms.

Journal Article↗
PubMed1987

Multiple sclerosis: II. Effects of prothymosin alpha on the autologous and allogeneic MLR in patients with multiple sclerosis.

We have recently demonstrated that peripheral blood monocytes from patients with multiple sclerosis (MS) have a defect in stimulating autologous and allogeneic T lymphocytes. This defect was found to correlate with disease activity. In this report we demonstrate that prothymosin alpha (ProT alpha), a rat thymus fraction 5 polypeptide, restores the MS monocyte stimulatory defect. The concentrations of ProT alpha which induced optimal enhancement of the mixed lymphocyte responses (MLR) were significantly higher when monocytes from patients with active disease were used as stimulators than when monocytes from patients with inactive disease were used. T4+ cells tested with autologous stimulatory monocytes harvested from an inactive stage of MS exhibited considerably higher proliferative responses than when stimulated with autologous monocytes obtained from an acute relapse. The decreased autologous proliferation of T4+ cells in MS patients was restored to normal levels after preincubation with ProT alpha in the environment of autologous monocytes. Our results demonstrate that ProT alpha is capable of fully restoring the deficient stimulatory function of MS monocytes and monocyte-associated functional defects of MS-derived T4+ cells.

Humans↗
PubMed2005

Apo E in multiple sclerosis and optic neuritis: the apo E-epsilon4 allele is associated with progression of multiple sclerosis.

OBJECTIVE: To investigate the association between apolipoprotein E (Apo E) genotype in multiple sclerosis (MS) and acute monosymptomatic optic neuritis (ON) in a genetically homogeneous population with a high frequency of the Apo epsilon4 allele. BACKGROUND: The association between heterozygosity of Apo epsilon4 and the development of MS is thoroughly investigated, while the association between homozygosity of Apo epsilon4 and the development of MS is insufficiently studied. The association between Apo E genotype and disease progression remains controversial. METHODS: 475 patients were included, 385 with MS and 90 with ON, consecutively seen in the MS clinic in the County of Copenhagen. Clinical data were obtained from medical records and degree of disability was determined prospectively using the Kurtzke expanded disability status scale (EDSS). Blood samples were used for Apo E genotyping. Disease progression was evaluated by the progression index (PI = EDSS/disease duration). Apo E genotype distribution was compared with 361 healthy controls. RESULTS: The Apo epsilon genotype distribution in the MS and ON groups was similar to the controls. The rate of disease progression in the group of MS patients with a disease duration of 10 years or less was significantly faster in the Apo epsilon4 positive group (heterozygosity and homozygosity for Apo epsilon4) (PI = 1.41) compared to the Apo epsilon4 negative group (PI =0.92) (P =0.009). Observing the MS subgroups, we found that the group of patients with RRMS had a faster rate of disease progression in the Apo epsilon4 positive group (PI =1.12) compared to the Apo epsilon4 negative group (P =0.77) (P =0.024). CONCLUSIONS: Apo E genotypes do not influence the development of MS and ON. The Apo epsilon4 allele seems to predispose carriers with MS to a faster progression of disease.

Adult↗
PubMed1996

Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group.

Evidence of diminution of therapeutic efficacy in 35% of interferon beta-1b (IFNB)-treated multiple sclerosis (MS) patients who developed neutralizing antibodies (NABs) led to extensive study of the effects of NABs on therapeutic benefits, side effects, and magnetic resonance imaging (MRI) data. First, we validated the IFNB NAB assay used in the multicenter trial by having representative stored serum samples reanalyzed by an independent laboratory. When NABs developed (as defined), usually in the first year, the exacerbation rates after 18 months resembled placebo rates, the numbers of enlarging MRI lesions significantly increased compared with those in NAB-negative patients, and there was increased new lesion formation in the MRI (p = 0.067). However, worsening of the mean Expanded Disability Status Scale score in the 8-MIU treatment arm was higher in patients who remained NAB-negative in the third year (p = 0.083). NAB-positive patients were not overrepresented among the noncompleters, or in five patients having at least one episode of skin-site necrosis. After 18 months, flu-like symptoms were about twice as common in NAB-negative as in NAB-positive patients, although the frequency did not exceed 21% in any semester. Decisions to discontinue IFNB therapy should be made individually based on clinical response and a positive titer of NABs in the serum with the use of a reliable assay. ELISA and Western blot techniques measure binding antibodies, not NABs specifically, and are unsuitable for use. Possible, but as yet unproven, means of dealing with NAB positivity should be studied in properly designed trials. IFNB-1b remains an effective therapy for a majority (65%) of MS patients having relapses. The annual exacerbation rates in NAB-negative patients receiving the 8-MIU dosage regimen are about 50% of those seen in untreated patients, a greater reduction than the one-third reduction earlier reported for the entire high-dose arm, and a meaningful treatment benefit.

Antibodies↗
PubMed1996

[EDMUS--a new European databank for multiple sclerosis. A brief introduction of ongoing and planned multicenter studies within the scope of the "European Concentrated Action for Multiple Sclerosis"].

EDMUS, the European Database for Multiple Sclerosis (MS), was established on the occasion of the first European Concerted Action for MS under the auspices of the European Community. The system is user-friendly and makes it possible to record and retrieve data relevant to MS. Within the framework of another European Concerted Action, several international multicenter trials are currently in progress. EVALUED, a validation of the EDMUS system, assesses the interrater variability; PRIMS examines the influence of pregnancy and the post-partum period on the course of MS; and PRESTIMUS investigates predictive factors in suspected MS. Further, planned studies include ERAZMUS (early azathioprine and interferon-beta treatment in MS) and AZASTOP, which is designed to evaluate the effect of stopping azathioprine treatment.

Azathioprine↗
PubMed1999

Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of interferon-alpha2a (IFN-alpha2a) in relapsing-remitting MS (RRMS). BACKGROUND: Several immune-modulating therapy regimens of IFN-alpha have shown varying results in MS. A recent pilot study suggested benefits from IFN-alpha2a. METHODS: Ninety-seven patients were randomized to receive subcutaneous injections of placebo (33 patients) or 4.5 million international units (mIU) (32 patients) or 9.0 mIU (32 patients) of IFN-alpha2a three times weekly for 6 months, with a further 6 months of follow-up. Monthly gadodiamide-enhanced MRI was the primary method of evaluating efficacy. RESULTS: IFN-alpha2a treatment resulted in fewer new MRI lesions during the treatment period (p < 0.003). The probability of no new lesions during treatment was >2.5 times higher with 9.0 mIU IFN-alpha2a than with placebo (p < 0.005). The median number of lesions at the end of treatment was lower with IFN-alpha2a treatment than with placebo (p = 0.0004), but the difference disappeared during follow-up. The total number of lesions (mean) increased by 4.78 with placebo, 0.86 with 4.5 mIU IFN-alpha2a, and 0.28 with 9.0 mIU IFN-alpha2a during treatment (p = 0.030). No treatment effect on exacerbation rate, progression of disability, or quality of life was detected. Nine patients discontinued treatment, five because of adverse events. CONCLUSIONS: IFN-alpha2a treatment significantly reduced disease activity as measured by MRI, but the efficacy disappeared within 6 months after discontinuation of treatment. A long-term study of more patients using disability as a primary outcome measure is needed to evaluate the clinical impact.

Adult↗
PubMed1986

The spectrum of multiple sclerosis lesions using a multiple spin echo pulse sequence and a high field strength.

Seventy-one patients having clinical laboratory findings consistent with multiple sclerosis (MS) were imaged with a 1.5 tesla MR instrument using multiple spin echo sequences (TR = 2,000 ms and TE = 30, 60, 90, 120 ms). Multiple spin echo is a sensitive method for detecting MS lesions. Sixty-seven patients (94%) demonstrated lesions consistent with MS. With the exception of those located in the cortex, optic nerve and chiasm the lesions detected correlated with pathologic data. Lesions of the cerebral hemispheres, corpus callosum and cerebellum were generally multiple while lesions of the brain stem and optic tracts were generally singular. The majority of the lesions were associated with the white matter tracts of the cerebral hemispheres and brain stem.

Brain↗