MS Abstracts: 2a-2g

The Pathogenicity of Multiple Sclerosis is still poorly understood, but identification of susceptibility Genes using the animal model Experimental Allergic EncephaloMyelitis (EAE) could provide leads.

Certain Genes may be shared between different AutoImmune Diseases, and identification of such Genes is of obvious importance.

To locate Gene regions involved in the control of EAE and to compare the findings with the susceptibility loci recently identified in a model for Rheumatoid Arthritis (Pristane-induced Arthritis).

We made crosses between the EncephaloMyelitis- and Arthritis-susceptible rat strain DA and the resistant E3 strain.

Genetic analysis of animals produced in a F2 intercross identified 11 loci associated with specific EAE-associated traits.

Interestingly, five of these loci were situated at the same position as major loci controlling Pristane-induced Arthritis and showed similarities in inheritance pattern and subphenotype associations.

Our results show that different phases of EAE are controlled by different sets of Genes and that common Genes are likely to be involved in different AutoImmune Diseases.

Many NeuroSurgical procedures have been designed for or applied to the treatment of Spasticity arising from different disorders.

Including Cerebral Palsy, Traumatic, Ischemic, or Hypoxic Brain Injury, Multiple Sclerosis, and Spinal Cord Injury.

NeuroSurgical procedures are primarily aimed at reducing Spasticity by interrupting the Stretch Reflex at various sites along the Spinal Reflex Arc

Or, attempting to increase the Centrally mediated Inhibitory influence on the pool of Motor Neurons in the Anterior Horn.

Surgical interventions for Spasticity can be classified into Peripheral Ablative Procedures, such as: Rhizotomy or Peripheral Neurectomy, and Central Ablative Procedures, such as Cordectomy, Myelotomy, or Stereotactic Procedures.

NonAblative procedures include Peripheral Nerve or Motor Point Blocks, the implantation of Cerebellar or Spinal Stimulators.

And the implantation of SubDural catheters for infusion of pharmacologic agents to increase Inhibitory activity.

Several proposed mechanisms for Spasticity are reviewed so that the rationale for the various surgical interventions for Spasticity described may be better understood.

Copyright 2000 John Wiley & Sons, Inc.

Uncovering primary target Antigens in Multiple Sclerosis (MS) is of major significance for understanding the Etiology and PathoPhysiology of the disease, and for designing Immunospecific therapy.

In this study, a synthetic Peptide representing a predicted T-Cell Epitope on Myelin Oligodendrocytic Basic Protein (MOBP) was found to be EncephalitoGenic in C3H.SW mice, inducing Experimental AutoImmune EncephaloMyelitis with an abrupt onset.

Two separate preliminary studies with MOBP Peptides indicated that AutoReactivity to MOBP occurs in MS. These data strongly suggest that MOBP is a highly relevant target in MS and further point to the complexity of Antigen specificities in MS.

A patient was followed after the new onset of HemiParesis from relapse of MS with serial MR Spectroscopic and Functional MRI.

The association of clinical improvement with recovery of N-AcetylAspartate, a marker of Neuronal integrity, and progressive reduction of abnormally large functional MRI Cortical activation with movement demonstrates that dynamic reorganization of the Motor Cortex accompanies remission of MS.

Objective
To evaluate the contribution made by Cervical Cord damage, assessed using a fast Short-Tau Inversion Recovery (fast-STIR) sequence and Magnetization Transfer Ratio (MTR) Histogram analysis to the clinical manifestations of MS.

Background
Previous studies have failed to show significant correlations between the number and extent of T₂ Spinal Cord lesions and the clinical status of patients with MS.

Fast-STIR is more sensitive than T₂-weighted imaging for detecting Cervical Cord MS lesions.

MTR Histogram analysis provides estimates of the overall disease burden in the Cervical Cord with higher pathologic specificity to the more destructive aspects of MS than T₂-weighted scans.

Methods
We obtained fast-STIR and Magnetization Transfer (MT) scans from 96 patients with MS (52 with Relapsing/Remitting [RRMS], 33 with Secondary/Progressive [SPMS], and 11 with Primary/Progressive [PPMS] MS and 21 control subjects.

Dual-echo scans of the Brain were also obtained and lesion load measured.

Results
Eighty-one of the patients with MS had an abnormal Cervical Cord scan.

Patients with SPMS had more Cervical Cord lesions and more images with visible Cervical Cord damage than did patients with RRMS or PPMS (p = 0.04).

The entire cohort of patients with MS had lower average MTR of the Cervical Cord (p = 0.006) than control subjects.

Compared to control subjects, patients with RRMS had similar Cervical Cord MTR Histogram-derived measures.

Whereas, those with PPMS had lower average MTR (p = 0.01) and peak height (p = 0.02).

Patients with SPMS had lower Histogram peak height than did those with RRMS (p = 0.03).

The peak position and height of the Cervical Cord MTR Histogram were independent predictors of the probability of having locomotor disability.

We found no correlation between Brain T₂ lesion load and any of the Cervical Cord MTR Histogram metrics.

Conclusions
This study shows that the amount and severity of MS pathology in the Cervical Cord are greater in the Progressive forms of the disease.

An accurate assessment of Cervical Cord damage in MS gives information that can be used in part to explain the clinical manifestations of the disease.

Objective
To correlate Mx protein (Mx) levels in lysed blood Leukocytes with the clinical response to Interferon-beta-1b (IFN-ß-1b) in Relapsing/Remitting MS (RR-MS) patients for monitoring treatment.

Background
Intracellular Mx expression is exclusively induced by the Type I IFNs (IFN-, -ß, and -omega) or by Viruses and is strongly increased under IFN treatment.

Quantitative determination of Mx allows objective assessment of biological effects of IFN.

Methods
Mx protein levels were measured in blood Leukocyte lysates from IFN-ß-1b-treated RR-MS patients by ELISA and correlated to clinical parameters, including relapse rate and clinical deterioration.

Results
In stable IFN-ß-1b-treated MS patients, Mx levels were significantly increased compared to patients with or without ImmunoSuppressive treatment. In IFN-ß-1b-treated MS patients during relapse, Mx levels were significantly lower than during stable phases of the disease.

Mean values of Mx (MVMx) over time of treatment in patients with a reduction of relapse rate were significantly higher than in patients without response.

Conclusion
Mx levels in lysed blood cells may represent a useful surrogate marker for IFN-ß-1b activity corresponding to the clinical response during treatment of MS.

Objective

To evaluate:
1. The ability of Magnetization Transfer Ratio (MTR) Histogram analysis to detect the extent of changes occurring outside MS lesions seen on conventional scans,
   
   
2. Whether such changes vary in the different MS clinical phenotypes,
   
   
3. Whether the changes are associated with the extent and severity of the macroscopic lesion load,
   
   
4. The contribution to Brain Atrophy.

Methods
Dual-echo, T₁-weighted, and MT scans of the Brain were obtained from 77 patients with varying MS courses and 20 age- and sex-matched control subjects.

To create MT Histograms of the Normal-Appearing Cerebral Tissue, MS lesions were segmented from dual-Echo Scans, superimposed automatically, and nulled out from the coregistered and scalp-stripped MTR maps.

Average MTR, peak height, and peak position were considered. T₂ and T₁ lesion loads, average lesion MTR, and Brain Volume were also measured.

Results
Average Histogram MTR (p<0.0001) and peak position (p<0.0001) from patients with Relapsing/Remitting MS (RRMS) were lower than those from control subjects.

Patients with Primary/Progressive MS (PPMS) had lower average Histogram MTR (p = 0.002) and Histogram peak height (p = 0.01) than control subjects.

Patients with Secondary/Progressive MS (SPMS) had a lower peak height (p = 0.05) than those with RRMS.

Average Lesion MTR (p<0.0001) correlated highly with the Histogram MTR. Average Histogram MTR (p<0.0001) and T₂ Lesion Load (p = 0.001) correlated highly with Brain Volume.

Conclusions
The amount of microscopic changes account for an important fraction of the Lesion Load in MS.

They may contribute to the development of Brain Atrophy and tend to be more evident in patients with Secondary/Progressive MS.

Objective
To quantitate the extent of Neuronal Cell loss in MS via the Whole Brain's N-AcetylAspartate (NAA) concentration (WBNAA).

Methods
Because NAA is assumed to be present only in Neuronal Cell Bodies and their Axons, we measured WBNAA.

A marker for viable Neurons in 12 patients (9 women and 3 men, 26 to 53 years of age) suffering from Relapsing/Remitting (RR) MS for at least 5 years and compared them with 13 age- and sex-matched normal controls.

Total Brain NAA was determined with Proton MR Spectroscopy, and WBNAA was obtained by dividing it by the total Brain Volume, calculated from high resolution MRI.

Results
The WBNAA of the RR MS patients was lower than their matched controls (p<0.005). This difference was greater among older than younger subjects.

The linear prediction equations of WBNAA with age indicate a faster, x10, decline in the patients, approximately 0.8% per year of age (p = 0.022).

Conclusion
The age-dependent decrease of Whole Brain's N-AcetylAspartate (WBNAA) in the patients suggests that Progressive Neuronal Cell Loss is a cardinal feature of this disease.

WBNAA offers a quick, highly reproducible measure of disease progression and may be an important marker of treatment efficacy in MS as well as other NeuroDegenerative Diseases.

Theiler's Murine EncephaloMyelitis Virus (TMEV) is a PiCornaVirus of the CardioVirus genus.

Certain strains of TMEV may cause a Chronic DeMyelinating Disease, which is very similar to Multiple Sclerosis in humans, associated with a persistent Viral infection in the mouse Central Nervous System (CNS).

Other strains of TMEV only cause an acute infection without persistence in the CNS. It has been shown that Sialic Acid is a receptor moiety only for the persistent TMEV strains and not for the nonpersistent strains.

We report the effect of Sialylation on cell surface on entry and the complex structure of DA Virus, a persistent TMEV, and the receptor moiety mimic, SialylLactose, refined to a resolution of 3.0 A.

The Ligand binds to a pocket on the Viral surface, composed mainly of the Amino Acid residues from Capsid protein VP2 puff B, in the vicinity of the VP1 loop and VP3 C terminus.

The interaction of the receptor moiety with the persistent DA strain provides new understanding for the DeMyelinating persistent infection in the mouse CNS by TMEV.

Infection of C57BL/6 mice with Mouse Hepatitis Virus (MHV) results in a DeMyelinating EncephaloMyelitis.

Characterized by MonoNuclear Cell infiltration and White Matter destruction similar to the pathology of the human DeMyelinating Disease Multiple Sclerosis.

The contributions of CD4⁺ and CD8⁺ T-Cells in the PathoGenesis of the disease were investigated.

Significantly less severe Inflammation and DeMyelination were observed in CD4(-/-) mice than in CD8(-/-) and C57BL/6 mice (P </= 0.002 and P </= 0.001, respectively).

ImmunoPhenotyping of Central Nervous System (CNS) infiltrates revealed that CD4(-/-) mice had a significant reduction in numbers of activated Macrophages/Microglial Cells in the Brain.

Compared to the numbers in CD8(-/-) and C57BL/6 mice, indicating a role for these cells in Myelin destruction.

Furthermore, CD4(-/-) mice displayed lower levels of RANTES (a C-C Chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the PathoGenesis of MHV-induced Neurologic Disease.

Administration of RANTES AntiSera to MHV-infected C57BL/6 mice resulted in a significant reduction in Macrophage infiltration and DeMyelination (P </= 0.001) compared to those in control mice.

These data indicate that CD4⁺ T-Cells have a pivotal role in accelerating CNS inflammation and DeMyelination within infected mice.