MS Abstracts 6c-2g


  1. Increased T-Lymphocyte InterLeukin-6 binding in Multiple Sclerosis
    Eur J Neurol 2000 May;7(3):291-7

  2. Quantitation of T2 lesion load in patients with Multiple Sclerosis: a novel semiautomated segmentation technique
    Acad Radiol 2000 Apr;7(4):237-47

  3. Conduction deficits of Callosal fibers in early Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 2000 May;68(5):633-638

  4. Detailed analysis of the Oligodendrocyte Myelin GlycoProtein Gene in NeuroFibroMatosis 1 and Primary/Progressive Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 2000 May;68(5):643-646

  5. Aberrant forms of alpha2-MacroGlobulin purified from patients with Multiple Sclerosis
    Clin Chim Acta 2000 May 1;295(1-2):27-40

  6. Adhesion Molecules in Multiple Sclerosis: relation to subtypes of disease and MethylPrednisolone therapy
    Arch Neurol 2000 Apr;57(4):546-51

  7. CerebroSpinal Fluid OligoClonal IgG bands in patients with Spinal ArterioVenous malformation and structural Central Nervous System lesions
    Arch Neurol 2000 Apr;57(4):553-7





#1

Increased T-Lymphocyte InterLeukin-6 Binding In Multiple Sclerosis

Bongioanni P, Mosti S, Romano MR, Lombardo F, Moscato G, Meucci G
Eur J Neurol 2000 May;7(3):291-7
Institute of Clinical Medicine, Dept of NeuroSciences, Section of Neurology; and Univ of Pisa, Pisa, Italy
PMID# 10886312; UI# 20345314
Abstract

Multiple Sclerosis (MS) represents a T-Cell-mediated AutoImmune DeMyelinating Disease of the Central Nervous System associated with altered ImmunoRegulation.

InterLeukin-6 (IL-6) is a Cytokine that has several effects on the NeuroImmune System. Specific IL-6 receptors have been found in human Lymphocytes and Neuroglial Cells.

The aim of the present study was to assay IL-6 binding on peripheral blood T-Lymphocytes in MS patients.

We found that T-Cells from MS patients had significantly more IL-6 receptors [Bmax: 279 +/- 7 vs. 246 +/- 8 (mean +/- SEM) receptors/cell, in patients and controls, respectively], whereas Kd values were similar to those of healthy subjects [26.8 +/- 0.7 vs. 25.4 +/- 0.6 (mean +/- SEM) pM, in patients and controls, respectively].

Significant (P < 0.05) differences in IL-6 binding values were observed between stable patients and those Relapsing (272 +/- 9 vs. 300 +/- 12 (mean +/- SEM) receptors/cell, respectively).

We found significantly (P < 0. 001) higher amounts of IL-6 receptors on CD4+ T-Cells from MS patients than on CD4+ Lymphocytes from controls (434 +/- 11 vs. 363 +/- 9 (mean +/- SEM) receptors/cell, respectively); CD8+ T-Cells showed very few IL-6 receptors in both patients and controls.

These data are discussed in terms of MS Immune PathoGenesis and PathoPhysiology, because T-Cell activation seems to be linked to increased IL-6 binding.

The upregulated IL-6 system might be involved in AntiBody-mediated DeMyelinating pathways, because IL-6 is well known to enhance Humoral Immune Response.



#2

Quantitation Of T2 Lesion Load In Patients With Multiple Sclerosis: A Novel Semiautomated Segmentation Technique

Raff U, Rojas GM, Hutchinson M, Simon JH
Acad Radiol 2000 Apr;7(4):237-47
NYU Medical Center, New York Univ, School of Medicine, Dept of Neurology, NY 10016, USA
PMID# 10789987; UI# 20248898
Abstract

Rationale And Objectives
The authors designed a segmentation technique that requires only minimal operator input at the initial and final supervision stages of segmentation.

And, has computer-driven segmentation as the Primary determinant of lesion boundaries.

The technique was applied to compute total T2-HyperIntense Lesion Volumes in patients with Multiple Sclerosis (MS).

A semi-automated segmentation technique is presented and shown to have a test-retest reliability of <5%.

Materials And Methods
The method used a single segmented section with MS lesions.

A probabilistic neural net performed segmentation into four tissue classes after supervised training.

This reference section was deconstructed into the entire set of possible 4 x 4-pixel subregions, which was used to segment all-Brain sections in steps of 4 x 4-pixel, adjacent image blocks.

Intra- and interimage variabilities were tested by using 3-mm-thick, T2-weighted, dual-echo, Spin-Echo MR images from five patients, each of whom was imaged twice on the same day.

Five different reference sections and three temporally separated training sessions involving the same reference section were used to test the segmentation technique.

Results
The coefficient of variation ranged from 0.013 to 0.068 (mean +/- standard deviation, 0.037 +/- 0.039) for results from five different reference sections for each Brain.

And, from 0.007 to 0.037 (mean, 0.027 +/- 0.021) for Brains segmented with the same reference section on three temporally separated occasions.

Test-retest (intra-imaging) reliability did not exceed 5% (except for a small lesion load of 1 cm3 in one patient). Interimaging differences were approximately 10%.

Conclusion
The segmentation technique yielded intra-imaging variabilities (2%-3%, except for very small MS lesion loads) that compare favorably with previously published results.

New repositioning techniques that minimize imaging-repeat imaging variability could make this approach attractive for resolving MS lesion detection problems.



#3

Conduction Deficits Of Callosal Fibers In Early Multiple Sclerosis

Schmierer K, Niehaus L, Roricht S, Meyer BU
J Neurol NeuroSurg Psychiatry 2000 May;68(5):633-638
Humboldt-University, Dept of Neurology, Unit for Motor Disturbances and Cortex Function, Charite Campus Virchow-Klinikum, Augustenburger Platz 1, D-13344 Berlin, Germany
PMID# 10789987; UI# 20248898
Abstract

Objective
To study the diagnostic usefulness of TransCallosal Inhibition (TI) elicited by TransCranial Magnetic Stimulation (TMS) in detecting Central Conduction Deficits in early Multiple Sclerosis.

CorticoSpinally mediated excitatory responses Evoked by TMS are accepted as a sensitive diagnostic tool in Multiple Sclerosis.

Recently, TI Evoked by TMS has been introduced as a new paradigm to test the function of Callosal fibers interconnecting both hand associated Motor Cortices.

Methods
Focal TMS of the Motor Cortex was performed in 50 patients with early Relapsing/Remitting Multiple Sclerosis.

CorticoSpinally mediated (Central Motor Latencies, Amplitudes) and TransCallosally mediated (onset latency and duration of TI) stimulation effects were investigated.

Results
TMS disclosed abnormalities of CorticoSpinally mediated responses in 62% and of TI in 80% of the patients.

Conclusion
The assessment of TI allows the discovery of lesions within the PeriVentricular White Matter that were not accessible by NeuroPhysiological techniques before.

This new paradigm increases the sensitivity of TMS with which to detect Central Conduction Deficits in early Multiple Sclerosis.



#4

Detailed Analysis Of The Oligodendrocyte Myelin GlycoProtein Gene In NeuroFibroMatosis 1 And Primary/Progressive Multiple Sclerosis

Johnson MR, Ferner RE, Bobrow M, Hughes RA
J Neurol NeuroSurg Psychiatry 2000 May;68(5):643-646
Guy's Kings and St Thomas' School of Medicine, Dept of Clinical NeuroSciences, Guy's Hospital, Hodgkin Building, London SE1 9RT, UK
PMID# 10789987; UI# 20248898
Abstract

NeuroFibroMatosis 1 (NF1) is a common AutoSomal Disorder with a wide range of Neurological manifestations.

The case histories of five patients, including two siblings, are reported who have both NeuroFibroMatosis 1 and Primary/Progressive Multiple Sclerosis (PPMS). A further patient with both NF1 and PPMS has since been identified.

More recently, a systematic clinical review of 138 unselected adult patients with NF1 identified one patient with a slowly Progressive Spastic Paraparesis and multiple high signal HyperIntensities on T2 weighted MRI.

Molecular Genetic studies suggest a mechanism by which the clinical association of Progressive White Matter Disease and NF1 might arise.

The Gene for NF1 is located on Chromosome 17q, spans 350 kb of genomic DNA, and contains 60 exons. The Gene for Oligodendrocyte Myelin GlycoProtein (OMgp) is embedded within intron 27b of the NF1 Gene.

OMgp is a membrane GlycoProtein that appears in the human CNS at the time of Myelination. It can be detected ImmunoHistoChemically on CNS Myelin and on the surface of cultured Oligodendrocytes.

Structurally, OMgp has the potential to function as an Adhesion Molecule and could contribute to the interactions between the Plasma membranes of Oligodendrocytes and Axons required for Myelination and/or Axon survival.

This study considers the specific hypothesis that PPMS in patients with NF1 results from concurrent mutation of the OMgp Gene.

The OMgp Genes of four unrelated patients with NF1 and PPMS were examined using a combination of Southern blot, dosage polymerase chain reaction, and chemical cleavage of mismatch.

The entire OMgp coding sequence, all intronic sequence, the intron-exon boundaries, and 1 kb of flanking sequence were screened.

The DNA from two patients was found to contain an alteration in the OMgp Gene resulting in an Amino Acid change of Glycine to Aspartic Acid at codon 21.

It is concluded that PPMS in patients with NF1 can occur without concurrent mutation of the OMgp Gene.

The Glycine to Aspartic Acid PolyMorphic alteration at codon 21 is neither sufficient nor necessary for the development of PPMS.



#5

Aberrant Forms Of alpha2-MacroGlobulin Purified From Patients With Multiple Sclerosis

Gunnarsson M, Stigbrand T, Jensen PE
Clin Chim Acta 2000 May 1;295(1-2):27-40
Umea University, Dept of Immunology, S-901 85, Umea, Sweden
PMID# 10789987; UI# 20248898
Abstract

The biochemical properties of alpha2-MacroGlobulin were investigated in four patients with Multiple Sclerosis and compared to alpha2-MacroGlobulin from healthy controls.

An impaired stability of alpha2-MacroGlobulin from the Multiple Sclerosis patients was demonstrated as a spontaneous conversion to an electrophoretic"fast" form of alpha2-MacroGlobulin upon purification and storage, with a concomitant decrease in functional capacity to inhibit proteinases.

The ability to form complexes with proteinases was significantly reduced in alpha2-MacroGlobulin purified from the Multiple Sclerosis patients.

The aberrant molecular arrangements of the protein were not due to proteinase cleavages in the bait regions of alpha2-MacroGlobulin, as demonstrated by gel electrophoresis and protein sequencing.

The number of functional Thiol Esters, however, was reduced in alpha2-MacroGlobulin purified from the Multiple Sclerosis patients, an observation compatible with the impaired Proteinase binding property.

Furthermore, differences in isoelectric points were observed between alpha2-MacroGlobulin from the Multiple Sclerosis patients and alpha2-MacroGlobulin from healthy controls.

The results suggest that aberrant forms of alpha2-MacroGlobulin may be present in patients with Multiple Sclerosis.



#6

Adhesion Molecules In Multiple Sclerosis: Relation To Subtypes Of Disease And MethylPrednisolone Therapy

Elovaara I, Ukkonen M, Leppakynnas M, Lehtimaki T, Luomala M, Peltola J, Dastidar P
Arch Neurol 2000 Apr;57(4):546-51
Tampere Univ Hospital, Dept of Neurology, Finland
PMID# 10789987; UI# 20248898
Abstract

Objectives
To determine levels of Adhesion Molecules in blood and CerebroSpinal Fluid (CSF) samples from patients with different subtypes and activities of Multiple Sclerosis (MS).

And to assess the effect of IntraVenous MethylPrednisolone Sodium succinate treatment on the levels of Soluble Adhesion Molecules.

Design
The expressions of very Late Activation Antigen 4 (VLA-4), Lymphocyte function associated Antigen 1 (LFA-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and InterCellular Adhesion Molecule 1 (ICAM-1) were determined ImmunoCytoChemically.

And levels of soluble VCAM-1, ICAM-1, and E-Selectin, by means of enzyme Immunoassay technique. The volumes of T2- and T1-weighted MS plaques and Brain Atrophy were determined by means of the semiautomatic Magnetic Resonance Imaging (MRI) segmentation technique.

Setting & Patients
A university hospital in Finland. One hundred subjects (71 patients with MS and 29 healthy control subjects).

    The subtypes of MS were:
  1. Relapsing/Remitting (R/R-MS [n = 26])
  2. Secondary/Progressive (SPMS [n = 20])
  3. Primary/Progressive (PPMS [n = 25])

Results
In patients with R/R-MS and SPMS, the expressions of VLA-4 and LFA-1 on Immune Cells from blood were at least 1.5- to 3-fold higher than in controls (R/R-MS, P = .002 and P<.001, respectively; SPMS, P = .03 and P =.001, respectively).

In R/R-MS, LFA-1 and ICAM-1 expression in blood was more up-regulated than in SPMS (P = .03 and P = .01, respectively).

The expressions of Adhesion Molecules on CSF Lymphocytes in R/R-MS and SPMS were of similar magnitude, but the proportions of CSF VLA-4- and LFA-1-expressing Lymphocytes were 3- to 4-fold higher than in controls (P = .04 and P = .008, respectively).

The levels of Serum soluble VCAM-1 were higher in SPMS than in R/R-MS (P = .005) or PPMS (P = .04).

IntraVenous MethylPrednisolone treatment of patients with R/R-MS in exacerbation caused a significant reduction in the Serum levels of soluble VCAM-1 and E-Selectin (P<.001).

In SPMS, the volumes of T2-weighted plaques correlated with the Serum level of soluble ICAM-1 (r = 0.64; P = .03).

Conclusions
Up-regulated Adhesion Molecules in blood and CSF indicate sustained potential for Inflammation in the CNS throughout the clinical spectrum of MS. Therapies interfering with cell adhesion may be of key importance in suppressing MS.



#7

CerebroSpinal Fluid OligoClonal IgG Bands In Patients With Spinal ArterioVenous Malformation And Structural Central Nervous System Lesions

Cohen O, Biran I, Steiner I
Arch Neurol 2000 Apr;57(4):553-7
Hadassah Univ Hospital, Dept of Neurology, Jerusalem, Israel
PMID# 10768631; UI# 20229118
Abstract

Objective
To investigate the incidence and characteristics of patients with structural Central Nervous System (CNS) lesions and CerebroSpinal Fluid OligoClonal IgG Bands.

Design & Method
A retrospective study. The medical records of patients with CerebroSpinal Fluid OligoClonal IgG Bands were evaluated for the presence of structural CNS lesions, their location and cause, and for clinical characteristics.

Setting
CerebroSpinal Fluid OligoClonal IgG bands were examined in the NeuroImmunology Laboratory, Hadassah Univ Hospital, Jerusalem, Israel.

Patients
Two hundred seventy of 570 patients with positive CerebroSpinal Fluid OligoClonal IgG Bands were available for analysis. Twenty patients had structural CNS lesions.

Results
Twenty (7.5%) of the 270 patients had structural CNS lesions: 3 patients had Spinal ArterioVenous Malformation; 5 patients had Tumors; 9 patients had Compressive Cervical Myelopathy.

Traumatic Leukomalacia, Arnold-Chiari Malformation type 1, and CNS Hemosiderosis were present in 1 patient each.

In 2 patients (1 patient with recurrent Meningioma and 1 patient with Post Traumatic Encephalomalacia) the presence of a structural CNS lesion was followed by the development of Multiple Sclerosis.

In all 3 patients with Spinal ArterioVenous Malformation, OligoClonal IgG identification prolonged the time to diagnosis and therapy, which varied from a few weeks to 3 years.

Conclusions
Structural CNS lesions, responsible for the Neurological Disorder, were present in 20 patients (7.5%) with CerebroSpinal Fluid OligoClonal IgG Bands.

The mechanism underlying OligoClonal IgG presence in Spinal ArterioVenous Malformation and the coexistence of Multiple Sclerosis and structural CNS lesions is unknown, but may be related to recurrent tissue damage with repeated presentation of CNS Antigens to the Immune System.



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