MS Abstracts 01c-2g5

  1. IL-10 promoter HaploType influence on Interferon treatment response in Multiple Sclerosis
    Eur J Neurol 2005 Mar;12(3):171-5

  2. Gray and White Matter volume changes in early RRMS: a 2-year longitudinal study
    Neurology 2005 Mar 22;64(6):1001-7

  3. No Evidence for Production of Intrathecal ImmunoGlobulin G against Acinetobacter or Pseudomonas in Multiple Sclerosis
    Eur Neurol 2005 Feb 1;53(1):27-31

  4. The expression of MicroFilament-associated cell-cell contacts in Brain Endothelial Cells is modified by IFN-ß-1a (Rebif)
    J Interferon Cytokine Res 2004 Dec;24(12):711-6

  5. MR Spectroscopic evidence for Glial increase but not for NeuroAxonal damage in MS Normal-Appearing White Matter
    Magn Reson Med 2005 Feb;53(2):256-66

  6. Lesion mechanism dependent, differential changes in NeuroFilaments and MicroTubules: a pathological and experimental study
    Rev Neurol (Paris) 2005 Jan;161(1):55-60

  7. Two genes encoding Immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to Multiple Sclerosis
    Genes Immun 2005 Jan 27

  8. Short-term accrual of Gray Matter pathology in patients with Progressive Multiple Sclerosis: an in vivo study using diffusion tensor MRI
    NeuroImage 2005 Feb 15;24(4):1139-46

  9. The role of Edema and DeMyelination in chronic T1 black holes: a quantitative Magnetization Transfer study
    J Magn Reson Imaging 2005 Feb;21(2):103-10

  10. Quantification of Cervical Cord pathology in Primary/Progressive MS using Diffusion Tensor MRI
    Neurology 2005 Feb 22;64(4):631-5

  11. Intrathecal sICAM-1 production in Multiple Sclerosis Correlation with triple dose Gd-DTPA MRI enhancement and IgG index
    J Neurol 2005 Feb;252(2):146-150

  12. AntiEpileptic medications in Multiple Sclerosis: adverse effects in a three-year follow-up study
    Neurol Sci 2005 Feb;25(6):307-10


IL-10 Promoter HaploType Influence On Interferon Treatment Response In Multiple Sclerosis

Wergeland S, Beiske A, Nyland H, Hovdal H, Jensen D, Larsen JP, Maroy TH, Smievoll AI, Vedeler CA, Myhr KM
Eur J Neurol 2005 Mar;12(3):171-5
The Multiple Sclerosis National Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway
PMID# 15693804

The level of InterLeukin-10 (IL-10) expression is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 Gene, which constitute three Haplotypes, GCC, ATA, and ACC.

The ATA (a non-GCC) haplotype, which is associated with low IL-10expression, has been shown to improve Interferon (IFN) treatment response in Hepatitis C.

We analyzed the distribution of IL-10 promoter HaploType combinations to determine whether they could influence initial IFN treatment response in 63 patients with Relapsing/Remitting Multiple Sclerosis (MS).

The patients were grouped into non-GCC or GCC HaploTypes, and the clinical and Magnetic Resonance Imaging (MRI) disease activity was compared in the two groups.

During the first 6 months of treatment, MS patients with non-GCC HaploTypes experienced fewer new MRI T1-contrast enhancing lesions [0.77 +/- 0.36 (SEM)] than patients with the GCC HaploType (2.45 +/- 0.57) (P = 0.05, Mann-Whitney U test).

No differences were detected on clinical disease activity. The results suggest an influence of IL-10 promoter Polymorphisms on IFN treatment response in MS.


Gray And White Matter Volume Changes In Early RRMS: A 2-Year Longitudinal Study

Tiberio M, Chard DT, Altmann DR, Davies G, Griffin CM, Rashid W, Sastre-Garriga J, Thompson AJ, Miller DH
Neurology 2005 Mar 22;64(6):1001-7
NMR Research Unit, Department of NeuroInflammation, Institute of Neurology, London WC1N 3BG, UK
PMID# 15781816

Brain Atrophy, in excess of that seen with normal aging, has been observed early in the clinical course of Relapsing/Remitting Multiple Sclerosis (RRMS).

Previous work has suggested that at this stage of the disease, Gray Matter (GM) Atrophy progresses more rapidly than the White Matter (WM) Atrophy.

To characterize the evolution of GM and WM Volumes over 2 years, and their associations with lesion loads in a cohort of patients with clinically early RRMS.

Twenty-one patients with RRMS (mean age 37.5 years, mean disease duration from symptom onset 2.1 years) and 10 healthy control subjects (mean age 37.1 years) were studied.

Tissue Volumes, as Fractions of Total Intracranial Volumes, were estimated at baseline and 1- and 2-year follow-up. Brain Parenchymal Fractions (BPF), GM Fractions (GMF), and WM Fractions (WMF) were estimated.

In subjects with MS, Brain Lesion Loads were determined on conventional T2-weighted along with pre- and post-Gadolinium (Gd) enhanced T1-weighted images at each timepoint.

A decrease in GMF was observed in subjects with MS vs normal controls over the 2 years of the study (mean -2.1% vs -1.0%, p = 0.044), while no change was seen in WMF over the same period (mean -0.09% vs +0.09%, p = 0.812).

However, when the MS cohort was divided in half, dependent upon change in Gd-enhancing lesion load over 2 years (n = 20), a decrease in WMF was seen in the group (n = 10) with the largest decline in Gd volume.

Whereas, WMF increased in the other half (n = 10) concurrent with a net increase in volume of Gd-enhancing lesions (difference between groups: p = 0.034).

Increasing Gray Matter but not White Matter (WM) Atrophy was observed early in the clinical course of Relapsing/Remitting Multiple Sclerosis. Fluctuations in inflammatory WM lesions appear to be related to volume changes in WM over this time period.


No Evidence For Production Of Intrathecal ImmunoGlobulin G Against Acinetobacter Or Pseudomonas In Multiple Sclerosis

Chapman MD, Hughes LE, Wilson CD, Namnyak S, Thompson EJ, Giovannoni G
Eur Neurol 2005 Feb 1;53(1):27-31
Institute of Neurology, Department of NeuroImmunology, Queen Square, London, UK
PMID# 15687729

The production of OligoClonal, polyspecific ImmunoGlobulin G is characteristic of Multiple Sclerosis (MS), yet no pathogen has been identified as an infectious agent.

Recent studies have proposed Acinetobactercalcoaceticus and Pseudomonas Aeruginosa as candidate organisms, on the basis of a sequence homology between a Bacterial Enzyme and bovine Myelin Basic Protein.

To investigate this, we looked for specific, high-affinity ImmunoGlobulin G against these pathogensin paired Serum and CerebroSpinal Fluid from MS patients compared to other Neurological Diseases.

We found no greater incidence of high-affinity AntiBodies against the organisms studied in MS vs. other Neurological Diseases, and so conclude that A. Calcoaceticus and P. Aeruginosa are unlikely to be implicated in the pathogenesis of MS.

Copyright (c) 2005 S. Karger AG, Basel.


The Expression Of MicroFilament-Associated Cell-Cell Contacts In Brain Endothelial Cells Is Modified By IFN-ß-1a (Rebif)

Harzheim M, Stepien-Mering M, Schroder R, Schmidt S
J Interferon Cytokine Res 2004 Dec;24(12):711-6
University of Bonn, Department of Neurology, Germany
PMID# 15684738

In Multiple Sclerosis (MS), a crucial step in the induction phase of the inflammatory process in the Central Nervous System (CNS) is the disruption of the Endothelial Blood-Brain Barrier (BBB).

Its permeability depends on the expression of InterCellular Adhesion Molecules, such as Vinculin and N-Cadherin in Endothelial Cells.

Interferon-gamma (IFN-γ), as a ProInflammatory Cytokine, decreases the expression of both Adhesion Molecules in Epithelial and Astrocytic Cells.

Whereas IFN-ß-1a, an established treatment for MS, increases the expression of N-Cadherin and Vinculin in Astrocytic Cells.

And, is postulated to preserve Endothelial Cell barrier function and to inhibit TransEndothelial migration of activated Leukocyte.

We analyzed the expression of N-Cadherin and Vinculin in a murine Brain Endothelial Cell line by ImmunoFluorescence Staining and Western Blot.

To study the presumed reversal effects of IFN-ß-1a (Rebif, Serono Pharma, Unterschleissheim, Germany) and IFN-γ on the formation of InterCellular contacts.

Vinculin and N-Cadherin expression in Brain Endothelial Cells was decreased after treatment with IFN-γ, whereas stimulation with IFN-ß-1a caused increased expression of both Adhesion Molecules. Combined treatment with both IFNs did not affect Vinculin and N-Cadherin expression.

These data suggest that IFN-γ contributes to BBB disruption by decreasing and IFN-ß-1a restores the BBB by an upregulation of Vinculin and N-Cadherin expression in Brain Endothelial Cells. This action of IFN-ß-1a may contribute to its beneficial effects in MS therapy.


MR Spectroscopic Evidence For Glial Increase But Not For NeuroAxonal Damage In MS Normal-Appearing White Matter

Vrenken H, Barkhof F, Uitdehaag BM, Castelijns JA, Polman CH, Pouwels PJ
Magn Reson Med 2005 Feb;53(2):256-66
VU University Medical Center, MR Center for MS Research, Department of Radiology, Amsterdam, The Netherlands
PMID# 15678547

Quantitative single-Voxel, short Echo-Time (TE) MR Spectroscopy (MRS) was used to determine metabolite concentrations in the Cerebral Normal-Appearing White Matter (NAWM) of 76 patients with Multiple Sclerosis (MS), and the WM of 25 controls.

In NAWM of all MS disease types (Primary/Progressive, Relapsing/Remitting, and Secondary/Progressive), the concentration ratio of total N-AcetylAspartate (tNAA)/total Creatine (tCr) was decreased compared to controls.

Remarkably, this was entirely due to an increase of tCr in MS patients, whereas there was no difference in tNAA.

Separate quantification of the two tNAA components yielded no significant difference in NAA (N-AcetylAspartate), while the concentration of NAAG (N-AcetylAspartyl-Glutamate) was slightly-but significantly-elevated in MS patients.

Myo-inositol (Ins) was strongly increased in MS patients, and Choline-containing compounds (Cho) were mildly increased.

There were no metabolite differences between disease types, and no correlations with disability scores. The results are supported by measures of Spectral quality, which were identical for patients and controls.

PeriLesional tissue is characterized by increased Glial Cell numbers (increase of Ins and tCr) without evidence of Axonal dysfunction (normal NAA).

Further studies should elucidate the mechanism underlying increased NAAG in MS NAWM.


Lesion Mechanism Dependent, Differential Changes In NeuroFilaments And MicroTubules: A Pathological And Experimental Study

Fressinaud C, Jean I, Dubas F
Rev Neurol (Paris) 2005 Jan;161(1):55-60
UPRES EA 3143, CHU, Departement de Neurologie, Angers
PMID# 15678001

The consequences of Axonal or DeMyelinating injuries on the Axonal CytoSkeleton have rarely been described.

We have compared the density of fibers labeled by Anti-NeuroFilaments (NF) and Anti-ß Tubulin (TUB) to the density of total Fibers:

  • In nine patients with Axonal Neuropathies of undetermined Etiology (AUE)
  • Six with Necrotizing Angeitis with Neuropathy (NAN)
  • Seven with Chronic Inflammatory DeMyelinating Neuropathy (CIDP)
  • In five controls, as well as in six patients with chronic Multiple Sclerosis (MS)

    We also studied DeMyelinated rat Corpus Callosum after LysoPhosphatidyl (LPC) microinjection.

    In AUE and NAN NF positive fibers decreased together with total Fiber Density, whereas TUB increased.

    In DeMyelinating lesions TUB was not altered (CIDP) or strongly decreased (MS, LPC); NF were strongly reduced in MS (where Axon Loss was prominent) and in LPC lesions (despite the lack of fiber degeneration) and for fiber densities< 3900/mm2 in CIDP.

    The initial mechanism of a disease, either Axonal Degeneration or DeMyelination, could result into a specific pattern of Axonal CytoSkeleton alterations.


    Two Genes Encoding Immune-Regulatory Molecules (LAG3 And IL7R) Confer Susceptibility To Multiple Sclerosis

    Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J, Anvret M
    Genes Immun 2005 Jan 27
    AstraZeneca R&D Sodertalje, Department of Molecular Sciences, Section for Genetics and Bioinformatics, Sodertalje, Sweden
    PMID# 15674389

    Multiple Sclerosis (MS) is a T-Cell-mediated disease of the Central Nervous System, characterized by damage to Myelin and Axons, resulting in progressive Neurological disability.

    Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA Class II HaploTypes.

    Whole-Genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility Genes.

    In this two-stage analysis, we determined GenoTypes, in up to 672 MS patients and 672 controls, for 123 Single-Nucleotide Polymorphisms (SNPs) in 66 genes. Genes were chosen based on their Chromosomal positions or biological functions.

    In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P < 0.08) between patients and controls.

    After additional GenoTyping in stage two, two Genes-each containing at least three significantly (P < 0.05) associated SNPs-conferred susceptibility to MS: LAG3 on Chromosome 12p13, and IL7R on 5p13.

    LAG3 inhibits activated T-Cells, while IL7R is necessary for the maturation of T and B-Cells.

    These results imply that germline Allelic variation in genes involved in Immune homeostasis-and, by extension, derangement of Immune homeostasis-influence the risk of MS.

    Genes and Immunity advance online publication, 27 January 2005; doi:10.1038/sj.gene.6364171.


    Short-term Accrual Of Gray Matter Pathology In Patients With Progressive Multiple Sclerosis: An In Vivo Study Using Diffusion Tensor MRI

    Rovaris M, Gallo A, Valsasina P, Benedetti B, Caputo D, Ghezzi A, Montanari E, Sormani MP, Bertolotto A, Mancardi G, Bergamaschi R, Martinelli V, Comi G, Filippi M
    NeuroImage 2005 Feb 15;24(4):1139-46
    Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Milan, Italy
    PMID# 15670691

    The mechanisms underlying the Progressive course of Multiple Sclerosis (MS) are not fully understood yet.

    The present study investigated the value of DT MRI-derived measures for the assessment of the short-term accumulation of White and Gray Matter (GM) pathology in patients with Primary/Progressive (PP) and Secondary/Progressive (SP) MS.

    Since Diffusion Tensor (DT) MRI can provide quantitative estimates of both MRI-visible and MRI-occult Brain damage related to MS.

    Fifty-four patients with PPMS and 22 with SPMS were studied at baseline and after a mean follow-up of 15 months.

    Dual-echo, T1-weighted, and DT MRI scans of the Brain were acquired on both occasions. Total Lesion Volumes (TLV) and Percentage Brain Volume Changes (PBVC) were computed.

    Mean Diffusivity (MD) and Fractional Anisotropy (FA) maps of the Normal-Appearing White (NAWM) and Gray Matter (NAGM) were produced, and Histogram analysis was performed.

    In both patient groups, a significant increase of average lesion MD (P = 0.01) and of average NAGM MD (P = 0.007) was found at follow-up.

    No significant differences between PPMS and SPMS patient groups were found for the on-study changes of any MRI-derived measure.

    No significant correlations were found between the percentage changes of DT MRI-derived measures and those of TLV and PBVC.

    No significant changes of DT MRI-derived measures were observed in age-matched healthy controls over the same study period.

    Over a 1-year period of follow-up, DT MRI can detect tissue changes beyond the resolution of conventional MRI in the NAGM of patients with Progressive MS.

    The accumulation of DT MRI-detectable Gray Matter damage does not seem to merely depend upon the concomitant increase of T2-visible lesion load and the reduction of Brain Volume.

    These observations suggest that Progressive NAGM damage might yet be an additional factor leading to the accumulation of disability in Progressive MS.


    The Role Of Edema And DeMyelination In Chronic T1 Black Holes: A Quantitative Magnetization Transfer Study

    Levesque I, Sled JG, Narayanan S, Santos AC, Brass SD, Francis SJ, Arnold DL, Pike GB
    J Magn Reson Imaging 2005 Feb;21(2):103-10
    McGill University, Montreal Neurological Institute, McConnell Brain Imaging Centre, Montreal, H3A 2B4 Quebec, Canada
    PMID# 15666408

    To use quantitative Magnetization Transfer Imaging (qMTI) in an investigation of T1-weighted HypoIntensity observed in clinical Magnetic Resonance Imaging (MRI) scans of Multiple Sclerosis (MS) patients,.

    Which has previously been proposed, as a more specific indicator of tissue damage than the more commonly detected T2 HyperIntensity.

    Materials And Methods
    A cross-sectional study of 10 MS patients was performed using qMTI. A total of 60 MTI measurements were collected in each patient at a resolution of 2 x 2 x 7 mm, over a range of saturation pulses.

    The observed T1 and T2 were also measured. qMT model parameters were estimated using a Voxel-by-Voxel fit.

    A total of 65 T2-HyperIntense lesions were identified; 53 were also T1 HypoIntense.

    In these black holes, the qMTI-derived semisolid pool fraction F correlated negatively with T(1,obs) (r2 = 0.76; P < 0.0001).

    The water pool absolute size (PDf) showed a weaker correlation with T(1,obs) (positive, r2 = 0.53; P < 0.0001). The Magnetization Transfer Ratio (MTR) showed a similarly strong correlation with F and a weaker correlation with PDf (r2 = 0.18; P < 0.04).

    T1 increases in chronic Black Holes strongly correlated with the decline in semisolid pool size.

    And, somewhat less to the confounding effect of Edema. MTR was less sensitive than T(1,obs) to liquid pool changes associated with Edema.

    (c) 2005 Wiley-Liss, Inc.


    Quantification Of Cervical Cord Pathology In Primary/Progressive MS Using Diffusion Tensor MRI

    Agosta F, Benedetti B, Rocca MA, Valsasina P, Rovaris M, Comi G, Filippi M
    Neurology 2005 Feb 22;64(4):631-5
    Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Via Olgettina, 60, 20132 Milan, Italy
    PMID# 15728283

    To investigate the extent and severity of Cervical Cord damage using Diffusion Tensor MRI (DT-MRI) and Histogram analysis in patients with Primary/Progressive MS (PPMS).

    Diffusion-weighted Sensitivity-Encoded (SENSE) Echo Planar images of the Cervical Cord and Brain Dual-Echo and Diffusion-weighted scans were acquired from 24 patients with PPMS and 13 healthy controls.

    Cord and Brain Mean Diffusivity and Fractional Anisotropy Histograms were produced. An analysis of variance model, adjusting for Cord volume, was used to compare Cord DT-MRI parameters from controls and patients.

    Compared to healthy controls, PPMS patients had reduced Cervical Cord Cross-Sectional Area and average Cord Fractional Anisotropy (p = 0.007), and increased Cord Mean Diffusivity (p = 0.024).

    No correlations were found between DT-MRI metrics of the Cord and quantities obtained from conventional and DT-MRI of the Brain.

    DT-MRI of the Cervical Cord can quantify the extent of diffuse Cord pathology in patients with PPMS.

    Such Cord Diffusivity changes in patients with PPMS are likely to reflect irreversible Axonal Injury and reactive Gliosis and seem to be independent of Brain damage.


    Intrathecal sICAM-1 Production In Multiple Sclerosis Correlation With Triple Dose Gd-DTPA MRI Enhancement And IgG Index

    Acar G, Idiman F, Kirkali G, Ozakbas S, Oktay G, Cakmakci H, Idiman E
    J Neurol 2005 Feb;252(2):146-150
    Karsiyaka Neurology Outpatient Clinic, Dokuz Eylul University, Izmir, Turkey
    PMID# 15729518

    In this study the aim was to evaluate the Intrathecal sICAM-1 production in Multiple Sclerosis (MS) patients during relapse and remission.

    In addition to this, we assessed whether there is a correlation between Intrathecal sICAM-1 production and other disease activity markers such as IgG index and Gadolinium enhancement in Magnetic Resonance Imaging (MRI).

    Twenty four Relapsing/Remitting MS patients were included in the study. Serum and CerebroSpinal Fluid (CSF) samples were obtained both during relapse and remission.

    The soluble form of ICAM (sICAM) was measured by the ELISA method in Serum and CSF. Cranial MRI with triple dose Gadolinium injection was performed for each patient both during relapse and remission.

    Serum levels of sICAM-1 (245.23+/-92.88 ng/ml) were higher during relapse than those in remission (219.90+/-110.94 ng/ml), but the difference was not statistically significant.

    In relapse periods CSF levels of sICAM-1 (1.304+/-0.92 ng/ml) were higher than those in remission (1.06+/-0.86 ng/ml), but this was not significant.

    However, during relapse periods patients had significantly higher sICAM-1 index values (1.76+/-0.60) than those found during remission periods (1.01+/-0.44) (p < 0.05). The IgG index values were higher in relapse periods than in remission (0.88+/-0.37 vs. 0.67+/-0.28) (p < 0.005).

    On T1 weighted images following triple dose Gd injection, at least two or more enhancing lesions were present in 22/24 of the patients (91 %) in relapse and 4/24 of the patients (19 %) in remission.

    There was strong correlation both between the sICAM-1 index and Gd enhancement (r=0.72 p < 0.05) and sICAM-1 index and IgG index in relapse (r=0.69 p < 0.05).

    In conclusion, there is association between high sICAM-1 and IgG indices, as well as between high sICAM-1 index and Gd enhancing MRI lesions in Relapsing MS patients.


    AntiEpileptic Medications In Multiple Sclerosis: Adverse Effects In A Three-Year Follow-Up Study

    Solaro C, Brichetto G, Battaglia MA, Messmer Uccelli M, Mancardi GL
    Neurol Sci 2005 Feb;25(6):307-10
    P. A. Micone Hospital, Department of Neurology, Via D. Oliva 22, Genoa, Sestri Ponente, Italy
    PMID# 15729492

    Neuropathic Pain and paroxysmal symptoms are common in Multiple Sclerosis (MS) patients, although no double-blind clinical trial has been conducted to support AntiEpileptic Medications (AED) use in MS.

    The aim of the study was to evaluate the frequency of AED utilization and reported adverse events, in a cohort of MS patients.

    For a period of 3 years the rationale for prescribing AED, adverse effects, treatment duration and reasons for discontinuation were recorded in a database.

    Carbamazepine (CBZ) was prescribed in 36 patients, with adverse effects reported in 20 cases, of which 12 mimicked a relapse.

    Gabapentin (GBP) was prescribed in 94 patients, with adverse effects reported in 16 cases and in one case mimicked a relapse. Lamotrigine (LMT) was prescribed in 22 patients, with adverse effects reported in 4 cases, none mimicking a relapse.

    The present study found a significantly higher incidence of adverse effects in patients treated with CBZ, with a high rate of discontinuation at low dosages and episodes of evident worsening of Neurological functioning compared to GBP or LMT.

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