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MS Abstracts 4c-2g

  1. Insulin-like growth factor II receptors in human Brain and their absence in AstroGliotic plaques in Multiple Sclerosis
    Brain Res 2000 Apr 28;863(1-2):282-288

  2. Nerve Growth Factor protects Oligodendrocytes from TNF-alpha - induced injury through Akt-mediated signaling mechanisms
    J Biol Chem 2000 Mar 15

  3. Visualization of Myelin Basic Protein (MBP) T-Cell Epitopes in Multiple Sclerosis lesions using a MonoClonal AntiBody specific for the human Histocompatibility Leukocyte Antigen (HLA)-DR2-MBP 85-99 complex
    J Exp Med 2000 Apr 17;191(8):1395-412

  4. Evaluation of the clinical utility of CerebroSpinal Fluid (CSF) indices of inflammatory markers in Multiple Sclerosis
    Acta Neurol Scand 2000 Apr;101(4):239-43

  5. Staging of Multiple Sclerosis (MS) lesions: Pathology of the time frame of MS
    Neuropathol Appl NeuroBiol 2000 Feb;26(1):2-10

  6. Serial Magnetic Resonance Imaging in Multiple Sclerosis: correlation with attacks, disability, and disease stage
    J NeuroImmunol 2000 May 1;104(2):164-73

  7. Linomide in the treatment of Multiple Sclerosis: MRI results from prematurely terminated Phase-III Trials
    Mult Scler 2000 Apr;6(2):99-104

  8. Kurtzke scales revisited: the application of psychometric methods to clinical intuition
    Brain 2000 May;123(Pt 5):1027-1040


Insulin-Like Growth Factor II Receptors In Human Brain And Their Absence In AstroGliotic Plaques In Multiple Sclerosis

Wilczak N, De Bleser P, Luiten P, Geerts A, Teelken A, De Keyser J
Brain Res 2000 Apr 28;863(1-2):282-288
Academisch Ziekenhuis Groningen, Dept of Neurology, PO Box 30.001, 9700 RB, Groningen, The Netherlands
PMID# 10773220

Insulin-like Growth Factor (IGF) II Receptors were studied in human adult Brain by using AutoRadiography with [125I]IGF-II. Receptors were found to be widely distributed throughout all Neuronal regions.

The highest densities were found in Plexus Choroideus, Granular layer of the Cerebellar Cortex, Gyrus Dendatus and Pyramidal layer of the Hippocampus, Striatum, and Cerebral Cortex.

White Matter was devoid of IGF-II Receptors. We also examined [125I]IGF-II binding in six plaques of Multiple Sclerosis, which were characterized by a dense network of Astrocytes.

We were unable to detect IGF-II Receptors in any of the AstroGliotic plaques, suggesting that IGF-II Receptors in human Brain are not involved in AstroGliosis.

The regional variations in Neuronal distribution of IGF-II Receptors suggest involvement of IGF-II in functions associated with specific Neuronal Pathways.


Nerve Growth Factor Protects Oligodendrocytes From TNF-alpha - Induced Injury Through Akt-Mediated Signaling Mechanisms

Takana R, Hisahara S, Namikawa K, Kiyama H, Okano H, Miura M
J Biol Chem 2000 Mar 15
Osaka University, Division of NeuroAnatomy (D12), Osaka 565-0871
PMID# 10748222

Tumor Necrosis Factor-alpha is thought to be one of the most important inflammatory Cytokines associated with the DeMyelinating Disease, Multiple Sclerosis.

We determined whether NeuroTrophins could protect Oligodendrocytes from Tumor Necrosis Factor-alpha mediated CytoToxicity.

Among the NeuroTrophins tested, Nerve Growth Factor was most effective at preventing cell death.

Nerve Growth Factor also prevented the Tumor Necrosis Factor-alpha induced loss of Mitochondrial membrane potential.

Overexpression of constitutively active Akt, a downstream target of phosphatidylinositol 3-kinase, but not of constitutively active MEK, protected Oligodendrocytes from Tumor Necrosis Factor-alpha induced injury.

Moreover, overexpression of dominant-negative Akt negated the protective effects of Nerve Growth Factor for Tumor Necrosis Factor -mediated Oligodendrocyte CytoToxicity.

These findings indicate that the Akt pathway is crucial in Nerve Growth Factor-mediated Oligodendrocyte protection.


Visualization Of Myelin Basic Protein (MBP) T-Cell Epitopes In Multiple Sclerosis Lesions Using A MonoClonal AntiBody Specific For The Human Histocompatibility Leukocyte Antigen (HLA)-DR2-MBP 85-99 Complex

Krogsgaard M, Wucherpfennig KW, Canella B, Hansen BE, Svejgaard A, Pyrdol J, Ditzel H, Raine C, Engberg J, Fugger L
J Exp Med 2000 Apr 17;191(8):1395-412
Royal Danish School of Pharmacy, Dept of Pharmacology, DK-2100 Copenhagen, Denmark
PMID# 10770805; UI# 20233885

Susceptibility to Multiple Sclerosis (MS) is associated with the human Histocompatibility Leukocyte Antigen (HLA)-DR2 haplotype, suggesting that Major Histocompatibility Complex Class II-restricted presentation of Central Nervous System-derived Antigens is important in the disease process.

AntiBodies specific for defined HLA-DR2-Peptide complexes may therefore be valuable tools for studying Antigen Presentation in MS.

We have used phage display technology to select HLA-DR2-Peptide-specific AntiBodies from HLA-DR2-TransGenic mice immunized with HLA-DR2 molecules complexed with an ImmunoDominant Myelin Basic Protein (MBP) Peptide (residues 85-99).

Detailed characterization of one clone (MK16) demonstrated that both DR2 and the MBP Peptide were required for recognition.

Furthermore, MK16 labeled intra- and ExtraCellular HLA-DR2-MBP Peptide complexes when Antigen-Presenting Cells (APCs) were pulsed with recombinant MBP. In addition, MK16 inhibited InterLeukin 2 secretion by two transfectants that expressed human MBP-specific T-Cell receptors.

Analysis of the structural requirement for MK16 binding demonstrated that the two major HLA-DR2 anchor residues of MBP 85-99 and the COOH-terminal part of the Peptide, in particular residues Val-96, Pro-98, and Arg-99, were important for binding.

Based on these results, the AntiBody was used to determine if the HLA-DR2-MBP Peptide complex is presented in MS lesions.

The AntiBody stained APCs in MS lesions, in particular Microglia/Macrophages but also in some cases HyperTrophic Astrocytes. Staining of APCs was only observed in MS cases with the HLA-DR2 haplotype but not in cases that carried other haplotypes.

These results demonstrate that HLA-DR2 molecules in MS lesions present a Myelin-derived self-Peptide and suggest that Microglia/Macrophages rather than Astrocytes are the predominant APCs in these lesions.


Evaluation Of The Clinical Utility Of CerebroSpinal Fluid (CSF) Indices Of Inflammatory Markers In Multiple Sclerosis

McMillan SA, McDonnell GV, Douglas JP, Hawkins SA
Acta Neurol Scand 2000 Apr;101(4):239-43
Royal Group of Hospitals, Regional Immunology Laboratory, Belfast, Northern Ireland
PMID# 10770519; UI# 20231288

Accumulating evidence indicates significant Heterogeneity in MS and soluble (s) Adhesion Molecules are postulated as markers of disease activity.

We sought to evaluate Intrathecal production of these and other molecules across the clinical spectrum of MS.

CSF indices of IgG, sICAM-1, sVCAM-1, sE-selectin and sCD30 were calculated in 17 Primary/Progressive (PPMS) patients, 15 Secondary/Progressive patients (SPMS), 28 Relapsing/Remitting patients in relapse (RRMSR) and 14 RRMS patients in remission (RRMSNR) using commercially available ELISA kits.

Patients had not received any ImmunoModulating Therapy within the previous 6 months. MS patients were compared with 44 patients with Non-Inflammatory Neurological Diseases (NINDs).

The most sensitive CSF index at a 90% level of specificity was for IgG which had 93% sensitivity in RRMSR and 92% sensitivity in RRMSNR.

Corresponding sensitivity in PPMS and SPMS was 71% and 73% respectively. None of the other indices had sensitivity >50% apart from sVCAM-1 (64% in RRMSR and 52% RRMSNR) and sCD30 (53% in PPMS).

Unsurprisingly the strongest association in MS was with the Intrathecal production of IgG.

Similar results in PPMS and SPMS may reflect comparable rates of progression in these 2 groups. Of the other molecules only Intrathecal sVCAM-1 production is significantly associated with MS and only in Relapsing/Remitting disease.


Staging Of Multiple Sclerosis (MS) Lesions: Pathology Of The Time Frame Of MS

van der Valk P, De Groot CJ
Neuropathol Appl NeuroBiol 2000 Feb;26(1):2-10
Free UnivAcademic Hospital, Dept of Pathology, Amsterdam, Research Institute NeuroSciences Vrije Universiteit, Graduate School of NeuroSciences, Amsterdam, The Netherlands
PMID# 10736062; UI# 20200588

Several processes take place during an attack of DeMyelination in Multiple Sclerosis (MS). The timing of these various processes, and thus of the attack in its entirety, is important if therapeutic stratagies are to be planned.

Attempts have been made to introduce and investigate variables relevant to timing the disease processes, leading to staging systems for MS.

Here, the terminology and the various parameters used are reviewed, including Inflammatory Cells, Glial Cells, Axonal loss and Myelin staining; then the different systems are compared, including the system put forward by Bo and Trapp, our own modification of that, the Bruck and Lassmann system and the recent consensus reached at a Vienna meeting.

It is concluded that an ideal staging system does not yet exist, and that, more than anything else, the material dictates the choice for a staging system. The terminology of the Vienna consensus could be used as a reference to facilitate international comparison.


Serial Magnetic Resonance Imaging In Multiple Sclerosis: Correlation With Attacks, Disability, And Disease Stage

Weiner HL, Guttmann CR, Khoury SJ, Orav EJ, Hohol MJ, Kikinis R, Jolesz FA
J NeuroImmunol 2000 May 1;104(2):164-73
Brigham and Women's and Massachusetts General Hospitals, Center for Neurologic Diseases, Partners Multiple Sclerosis Center, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115-5817, USA
PMID# 10713356; UI# 20183743

Serial MRI and clinical testing was performed on 45 well-defined untreated Multiple Sclerosis patients in different categories of disease (Relapsing/Remitting, Progressive, stable).

Up to 24 MRIs were scheduled over a 1-year period for each patient. Clinical evaluation was performed monthly and at times of attacks using the Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI).

MRI scans were performed both with and without Gadolinium enhancement. MRI lesion volume was determined by computerized analysis and Gadolinium-enhancing lesions were counted by Radiologists.

We observed an increase in lesion volume over 1 year in all patient groups except those classified clinically as stable.

In Relapsing/Remitting patients there were correlations between increases in the number of gadolinium enhancing lesions and increases in EDSS and the occurrence of attacks.

In Chronic/Progressive patients, increases in lesion volume were correlated with both increases in EDSS and AI.

These results demonstrate a linkage between MRI and clinical disease that depends both on the stage of MS and the MRI measures used and support the use of MRI as a surrogate marker of clinical disability in the study of Multiple Sclerosis.


Linomide In The Treatment Of Multiple Sclerosis: MRI Results From Prematurely Terminated Phase-III Trials

Tan IL, Lycklama A Nijeholt GJ, Polman CH, Ader HJ, Barkhof F
Mult Scler 2000 Apr;6(2):99-104
Univ Hospital Vrije Universteit, Dept of Radiology, Amsterdam, The Netherlands
PMID# 10789987; UI# 20248898

Due to an unexpected increase in serious CardioVascular events in MS patients treated with Linomide, a synthetic ImmunoModulator, two Phase-III multinational Relapsing/Remitting (RR) and Secondary/Progressive (SP) MS trials had to be discontinued.

MRI results of 413 patients who participated for at least 3 months were analyzed. Patients received placebo, 2.5 or 5 mg Linomide. Scans were performed at pre-enrolment, month 3 and termination. The number and volume of enhancing lesions (ELV), and the number of active scans were evaluated.

At month 3, the decrease in the number of enhancing lesions in the placebo group was 11%, compared with 15% in the 2.5 mg group (P=0.027) and 23% in the 5 mg group (P=0.057).

Using the percentage of active scans as outcome parameter, the odds ratio for improvement between placebo and 2.5 mg group was 1.62 (P=0.14); between placebo and 5 mg Linomide group 3.58 (P=0.003). At termination, a rebound effect was noted in the 2.5 mg group (P=0.01).

Analysis of the ELV showed no significant difference between placebo and treatment groups. Although Linomide has unacceptable side effects, it seems to have a modest effect on MS disease activity, as measured by MRI.

Multiple Sclerosis (2000) 6, 99 - 104


Kurtzke Scales Revisited: The Application Of Psychometric Methods To Clinical Intuition

Hobart J, Freeman J, Thompson A
Brain 2000 May;123(Pt 5):1027-1040
Institute of Neurology, Neurological Outcome Measures Unit, London, UK
PMID# 10789987; UI# 20248898

When developing his disability scales for Multiple Sclerosis, Kurtzke demonstrated perception and insight. However, 45 years later, the evaluation of his clinically derived scales remains limited, particularly for more disabled patients.

Indeed, many of Kurtzke's assumptions underpinning the development of the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) are untested.

This study aims to build on previous work and provide a more detailed examination using psychometric methods of the EDSS and FS.

    There are three study objectives:

  1. To examine comprehensively the psychometric properties of the EDSS in more disabled people with Multiple Sclerosis undergoing in-patient rehabilitation;

  2. To examine the reliability of the FS and test Kurtzke's assumptions that they measure different aspects of the Neurological Examination and measure different constructs from that measured by the EDSS; and

  3. To examine whether the FS can be summed to generate a summary score.

The EDSS was examined for its acceptability (score distributions), reliability (inter- and intra-rater reproducibility, standard error of measurement), validity (convergent and discriminant validity, measurement precision, discrimination between individuals) and responsiveness (effect size).

The FS were examined for their reliability (inter- and intra-rater reproducibility), intercorrelations, correlations with the EDSS and the extent to which they satisfy Likert's criteria as a summed rating scale.

In this more disabled sample of people with Multiple Sclerosis, the EDSS is an acceptable measure but demonstrates limited variability.

Inter-rater reproducibility (intraclass correlation coefficient; ICC = 0.78) is adequate for group comparison studies, but intra-rater reproducibility is variable (ICC = 0.62-0.94).

Convergent and discriminant validity for the EDSS is supported, but its measurement precision relative to the Functional Independence Measure is limited (56%).

Also, the EDSS has a limited ability to distinguish between individuals in terms of their disability and its responsiveness is poor (effect size = 0.10).

Results indicate that the FS measure constructs distinct from each other (intercorrelations = -0.23 to +0.52) and from the EDSS (correlations = -0.10 to +0.59).

Intra-rater, but not inter-rater reproducibility is adequate for group comparison studies. The FS do not satisfy criteria as an eight-, seven- or six-item summed rating scale.

Despite being based on sound clinical intuition, the lack of psychometric input into the development of the EDSS and FS has limited their usefulness as evaluative outcome measures in Multiple Sclerosis.

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