MS Abstracts 6e-2g1

CTLA-4, expressed mainly on activated T-Cells, helps maintain, through its inhibitory function, Immune System homeostasis.

Polymorphisms in the CTLA-4 Gene (CTLA4) are known to be important in several AutoImmune Diseases, including Multiple Sclerosis (MS).

Here, we have performed genotyping for CTLA4 polymorphisms, and investigated expression by peripheral blood MonoNuclear Cells of CTLA-4 mRNA and protein, in patients with MS and Myasthenia Gravis and in healthy controls.

Expression levels for mRNA and protein were similar in the patient and control groups; however, there was a clear relationship between genotype and CTLA-4 expression.

Specifically, individuals carrying Thymine at position -318 of the CTLA4 promoter (T(-318)) and homozygous for Adenine at position 49 in exon 1.

Showed significantly increased expression both of cell-surface CTLA-4 after cellular stimulation and of CTLA-4 mRNA in non-stimulated cells.

The association was seen most clearly for unsorted CD3⁺ Cells and was absent in the CD8⁺ subset.

The T(-318) allele has been shown to be negatively associated with susceptibility to MS in an earlier study by our group.

Thus, we propose that the susceptibility-influencing role of CTLA4 in MS may be related to genotypically conditioned promoter function, whereby high Gene expression may decrease the risk of disease.

Recent studies of Multiple Sclerosis (MS) and Stroke patients suggested a correlation between two patterns of abnormal performance in Lateralization Tasks and two sites of Pontine lesions.

Most patients who had lesions below or at the Superior Olivary Complex (SOC) perceived all InterAural differences in BinAural stimuli as small, while most patients who had lesions above the SOC perceived all InterAural differences as large.

The two abnormal performance patterns occurred for InterAural Time Differences (ITD) and/or for InterAural level differences (ILD).

The present model proposes a multi-level hierarchical BrainStem structure that estimates ITD and ILD.

The first level seeks dissimilarity between the left and right inputs and a second level looks for similarity between the two sides' inputs.

Each level is modeled as an ensemble of Neural arrays in which each unit performs a Logic or Arithmetic function.

The inputs are simulations of Auditory Nerve responses to broadband stimuli. Simulations yield good correspondence to the effect of both locations of Pontine lesions on BinAural performance.

Regulation of Leukocyte migration and activation by Chemokines are recognized as potentially important functions in the induction of acute and chronic inflammatory reactions.

Regulated upon activation normal T-Cell expressed and presumably secreted (RANTES), Monocyte Chemotactic Protein-1 (MCP-1).

And related molecules constitute the C-C class of the beta Chemokine supergene family with inflammatory properties.

Here we report that in experimental studies RANTES and MCP-1 provoke Mast Cell activation and increase Histidine decarboxylase mRNA expression in a dose-dependent manner.

Moreover, injections of RANTES and MCP-1 in the rat skin cause Mast Cell, Eosinophil, and Macrophage recruitment, and ProstaGlandin E2 (PGE2) generation.

In a chronic inflammatory model MCP-1 was found to mediate the recruitment of MonoNuclear Cells in calcified Granulomas.

In addition, MCP-1 mediated parasitic infections caused by Trichinella Spiralis.

In accordance with other studies, RANTES and MCP-1 were found to play an important role in the Lung Allergic Inflammation, Lung Leukocyte infiltration, Bronchial hyperresponsiveness, and the recruitment of Eosinophils in the PathoGenesis of Asthma.

Here for the first time we propose a new mechanism of pulmonary airway inflammation where RANTES and MCP-1 are deeply involved.

We also studied the apparent role played by RANTES in the PathoGenesis of Relapsing/Remitting Multiple Sclerosis enhancing the inflammatory response within the Nervous System.

Dendritic Cells (DC) are important Antigen Presenting Cells (APC) and play a major role in initiating and orchestrating Immune responses by priming T-Cells.

Little is known about involvement of DC in Multiple Sclerosis (MS), where Auto-Aggressive T-Cells against Myelin AutoAntigens are considered to contribute to inflammation and DeMyelination in the Central Nervous System.

In this study, we compared phenotype and Cytokine secretion of DC from patients with MS, Other Neurological Diseases (OND) and healthy subjects.

DC were generated from blood adherent MonoNuclear Cells (MNC) by culture for 7 days with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and InterLeukin-4 (IL-4).

The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature Myeloid lineage, comprising CD1a⁺ and CD11c⁺.

The proportion of CD1a⁺ DC, being important for presentation of Lipid Antigens to T-Cells, was higher in MS patients compared to controls.

The proportion of CD86⁺ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS.

Low proportions of CD86⁺ DC were only observed in untreated MS patients but not in patients treated with IFN-ß.

Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls.

These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.

Multiple Sclerosis (MS) has been associated with the Human Leukocyte Antigen DR15 allele in Caucasians of North and Central European origin.

However, the relative effect of the DR15 homozygous and the DR15 heterozygous genotypes on the disease susceptibility is unclear.

Based upon results from three North European studies we have examined this by meta-analysis.

Our results suggested that the effect of the DRB1*1501, DQA1*0102, DQB1*0602 haplotype on the susceptibility to MS is additive.

Perhaps reflecting that development of the disease is facilitated by a high density surface expression of the Antigen Presenting Molecules encoded by this haplotype.

Possible implications of our finding to future studies of the Genetic background of MS is discussed.

The mechanisms by which IFN-ß-1b acts in the treatment of patients with Multiple Sclerosis (MS) are not completely known.

ImmunoModulatory effects of IFN-ß-1b were investigated in patients with Relapsing/Remitting (RR) MS in vivo and in vitro.

Compared to baseline and controls, defined as patients with RR-MS without ImmunoModulatory therapy.

The expression of TGF ß-1-mRNA by Peripheral Blood MonoNuclear Cells (PBMC

The expression of TNF--mRNA decreased from day 1 to month 3 compared to day 0 and the controls (p < 0.01).

The expression of TNF-alpha--R-I-mRNA increased dose-dependently after stimulation with IFN-ß-1b for 24 h in vitro.

Serum levels of soluble Vascular Cell Adhesion Molecule (sVCAM-1

The CD8CD38 Lymphocyte subpopulation was continuously elevated from day 5 up to month 6 (p < 0.01) in the MS patients treated with IFN-ß-1b in vivo.

The present data suggest that IFN-ß-1b induces the mRNA expression of TGF ß-1 and TGF ß-R-II by PBMC, decreases that of TNF-alpha- and increases levels of sVCAM-1 and of circulating activated CD8 cells (CD8CD38) in blood.

These might be other mechanisms by which IFN-ß-1b mediates its positive effects in the treatment of MS patients.

Gadolinium enhanced Magnetic Resonance Imaging detects focal Blood-Brain Barrier breakdown in new inflammatory Multiple Sclerosis lesions, but such lesions do not correlate with disease progression.

To explore whether the latter might relate to subtle but widespread Blood-Brain Barrier (BBB) breakdown with low grade inflammation mediating tissue damage.

Quantitative techniques were used to detect subtle Gadolinium enhancement within otherwise Normal-Appearing White Matter and within lesions not showing visible enhancement.

T₁-weighted imaging was performed prior to and at 5, 20 and 40 min following injection of 0.3 mmol/kg Gadopentate Dimeglumine in 33 patients with Multiple Sclerosis and five healthy control subjects.

In healthy controls, a significant increase in White Matter signal, 5 min following contrast injection was observed (1.8%, P < 0.0005); the signal returned to baseline values by 20 min.

In Multiple Sclerosis patients, a non-significant trend was noted for signal to remain elevated in Normal-Appearing White Matter.

At the 20 and 40 min post-contrast time points; this was most apparent in Primary/Progressive Multiple Sclerosis.

Significant increases in signal intensity were noted at all time points post contrast in apparent non-enhancing lesions

The transient post contrast signal increase in controls is likely due to IntraVascular Gadopentate Dimeglumine.

The persistent increases in signal intensity in non-enhancing lesions suggest more widespread abnormalities in BBB than is visually apparent.

But substantiation of BBB leakage in Normal-Appearing White Matter will require further study using more sensitive methods.

To observe the pattern of recovery after treatment with IntraVenous MethylPrednisolone (I.V. MP) for a relapse of Multiple Sclerosis (MS).

And to determine the best time to plan further interventions such as rehabilitation, we assessed consecutive outpatients (n = 24) treated with I.V. MP for a relapse over a period of 12 weeks.

Outcomes measures used were the Expanded Disability Status Scale (EDSS), the Incapacity Status Scale (ISS), the MOS Short Form-36 (SF-36), the Mental Health Inventory (MHI), and the MS-Related Symptom Checklist (MSSCL).

There was statistically significant early improvement of EDSS and ISS scores, which was sustained until week 12, and significant improvement of MHI and MSSCL scores between 4 and 12 weeks.

Although trends for improvement of scores reflecting the same pattern of recovery were observed with the SF-36 physical and mental composites, these changes did not reach statistical significance.

Our results suggest that improvement of impairments and disability after treatment with I.V. MP for a relapse of MS occurs early, while improvement of subjective health status is delayed

Even after maximum improvement is reached, patients are left with multiple symptoms and functional limitations, and may benefit from additional rehabilitative interventions.

Objective
To evaluate the relations between perceived Cognitive function and objective Cognitive deficit and to assess variables affecting perceived Cognitive function among Multiple Sclerosis (MS) patients.

Methods
A cross sectional study of patients with MS. All patients were interviewed and the Expanded Disability Status Scale (EDSS) score was determined.

The dependent variables were four items assessing perceived concentration and Thinking, Attention, Memory, and whether others have noticed Memory or Concentration problems.

The explanatory variables were age, sex, duration of disease, number of relapses in the last 2 years, EDSS score, Depressive Symptoms Score (CES-D).

And the domains of the NeuroBehavioral Cognitive Status Examination (NCSE) assessing Cognitive performance. Bivariate and then multivariate analysis were performed.

Results
One hundred and sixty-one MS patients were included. Mean age was 44.2 years (s.d. 11.3 years), mean EDSS score was 4.86 (s.d. 1.93).

Seventy-two per cent of the patients had objective Cognitive Impairment and 51% reported decreased perceived Cognitive function.

In all models assessing perceived Cognitive function we could explain only a small part of the variance (R2 ranged between 18-26%).

In all these models Depressive symptoms explained the highest portion of the variance (partial R2 ranging between 13-26%).

The only domain of the NCSE that entered some of the models was Calculation (partial R2 ranging between 3-7%).

Conclusions
These findings emphasize the gap between objective and subjective assessment of Cognitive function and the high correlation between perceived Cognitive deficit and Depressive symptoms.

Quality of Life (QoL) is discussed as an additional outcome measure in Multiple Sclerosis (MS). However, few questionnaires assessing disease specific QoL in MS have been published.

On the basis of the literature and interviews with clinicians and MS patients, we have developed a disease specific QoL instrument and validated it in a broad range of patients with MS.

In this study, a heterogeneous sample of n = 237 MS patients completed the newly developed Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS, in German language) and a battery of already validated questionnaires.

They further underwent Neurological scoring and objective tests. By these means, we investigated its validity, appropriateness, internal consistency, and retest reliability.

Internal consistency and retest coefficients were high and satisfied psychometric standards.

Convergent and discriminant validity was supported by direction, magnitude and pattern of correlations with other health measures.

HAQUAMS subscales and its total score distinguished between patient groups of varied disease severity, Cognitive Impairment, and affective symptomatology.

No floor or ceiling effects were found in either of the HAQUAMS subscales.

The HAQUAMS is a reliable, valid and appropriate instrument for QoL assessment in Multiple Sclerosis. Data of responsiveness are currently being obtained.

Objectives
To establish the spectrum of disability and handicap in a population based sample of Multiple Sclerosis (MS) patients.

Background
Much knowledge exists about the epidemiology of MS but, despite its importance for health and social service planning

There remains relatively little data on the extent and nature of disability and handicap in this population.

Methods
In a prevalence study in the north-east of N. Ireland, 288 patients (Poser criteria) were identified.

Disability and handicap were assessed using the Incapacity Status Scale and Environmental Status Scale of the Minimal Record of Disability for MS.

Results
Both scales were completed for 248 (86%) of patients. Just 71 (29%) are fully independent in all basic ADL's of bathing, dressing, grooming and feeding.

Fifty-seven (23%) are unable to climb a flight of stairs and 102 (42%) acknowledge problems with sexual function.

Sixty-one (25%) were working essentially full-time and 53 (21%) had no external financial support.

Forty-five (18%) had changed residence due to MS, 12 (5%) were institutionalised and 86 (35%) required assistance for at least 1 h/day with ADL's.

Eighty-one (33%) were unable to drive a car or use public transport. Forty-two (17%) access community services for at least 1 h/day on average.

Conclusions
This data gives a clear indication of the considerable range of basic health and social issues in a typical MS community.

Further work is required to establish patient perceptions of the adequacy of care provision and whether standards of care for MS patients are being met.

In this preliminary study we measured maximum walking distance and walking time on four consecutive days in 29 patients with clinically stable Multiple Sclerosis (MS).

Patients were included in the study if they could achieve a maximum unaided walking distance of 100 up to 500 m.

Our results showed a certain day-to-day variability of maximum walking distance.

In some cases meaning changes up to 1.5 points in the Expanded Disability Status Scale (EDSS), which could be misinterpreted as a progression of the disease.

Simultaneous measurements of maximum walking time showed a similar variability, unlike the mean walking speed which turned out to be more stable.

Our results therefore suggest that scoring of MS patients should not be based on one single measurement of the maximum walking distance.

The more reliable parameter appears to be the mean walking speed.