MS Abstracts 05a-2g5

Although functional changes are often interpreted as Adaptive and as a contributing factor in limiting the clinical deficit, no longitudinal studies have yet been performed for Multiple Sclerosis.

Sixteen patients with Multiple Sclerosis, two patients with Possible Multiple Sclerosis and nine age-matched controls underwent two fMRI studies with a time interval of 15-26 months.

The Motor Task consisted of a self-paced sequential finger opposition movement with the right hand. Patients with Multiple Sclerosis exhibited greater BiLateral activation than controls in both fMRI studies.

At follow-up, patients showed a reduction in functional activity in the IpsiLateral SensoriMotor Cortex and in the ContraLateral Cerebellum. No significant differences between the two fMRI studies were observed in controls.

Activation changes in IpsiLateral Motor Areas correlated inversely with age, extent and progression of T₁ lesion load, and occurrence of a new relapse.

This study may help the understanding of the evolution of Brain plastic changes in Multiple Sclerosis.

Indicating that, in younger patients with a less structural Brain damage and Benign clinical course, the Brain reorganizes its functional activity towards a more lateralized pattern of Brain activation.

The tendency towards a normalization of Brain functional activity is hampered in older patients and in those developing relapses or new irreversible Brain damage.

The findings in literature show high evidence that people with Multiple Sclerosis experience high levels of Sexual Dysfunction.

Most of them with hypoactive sexual behaviour often associated with dissatisfaction in relationship, and also the partners seem to show lower sexual and partnership satisfaction.

The most common problems in women are lack of sexual interest and decreased libido, often with problems in orgasmic capacity, while men report Erectile Dysfunction and also lack of sexual interest. The impact of the level of disability and duration of the illness remains unclear.

Positive familial support can often help the patient in coping with the illness, nonetheless problems with changing roles and Multiple-Sclerosis-minimizing can improve the need of contacts to outstanding persons.

Background
Epidemiological and Ecological studies suggest links between Vitamin D deficiency and increased Multiple Sclerosis (MS) prevalence.

Objective
To evaluate the safety and tolerability of oral Calcitriol therapy in an open label pilot study.

Methods
15 ambulatory patients with Relapsing/Remitting MS and at least one clinical relapse within the previous 12 months received oral Calcitriol (target dose: 2.5 microg/d) for 48 weeks.

Dietary Calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the Expanded Disability Status Scale (EDSS), and Brain Magnetic Resonance imaging (MRI).

Results
Two patients withdrew because of symptomatic Hypercalcaemia (Serum Calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion.

Two diet compliant patients required temporary dose adjustments for mild asymptomatic Hypercalcaemia.

Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point.

Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks.

Conclusions
Oral Calcitriol is safe and well tolerated for up to one year by diet compliant Relapsing/Remitting MS patients. Further study of Vitamin D related mechanisms is warranted in MS.

Oxidative Stress has been implicated in the pathophysiology of Multiple Sclerosis (MS). Increased levels of Reactive Oxygen Species (ROS) derived from infiltrating Macrophages and Microglial Cells have been shown to reduce the levels of endogenous antioxidants and to cause the Oxidation of various substrates within the MS plaque.

To determine whether Oxidative damage takes place beyond visible MS plaques, the occurrence of Total Carbonyls (TCOs) and Protein Carbonyls (PCOs) in the Normal-Appearing White Matter (NAWM) and Gray Matter (NAGM) of eight MS brains was assessed and compared with those of four control Brains.

The data show that most (7/8) of the MS-WM samples contain increased amounts of PCOs as determined by reaction with 2,4-DinitroPhenylhydrazine and Western Blot analysis.

These samples also have high levels of Glial Fibrilary Acidic Protein (GFAP), suggesting that Oxidative damage is related to the presence of small lesions. In contrast, we detected no evidence of protein Thiolation (Glutathionylation and Cysteinylation) in the diseased tissue.

To our surprise, MS-NAGM specimens with high GFAP content also showed three times the concentration of TCOs and PCOs as the controls.

The increase in PCOs is likely to be a consequence of reduced levels of Antioxidants, in that the concentration of nonprotein Thiols in both MS-WM and -GM decreased by 30%.

Overall, our data support the current view that both NAWM and -GM from MS Brains contain considerable biochemical alterations.

The involvement of GM in MS was also supported by the decrease in the levels of NeuroFilament light protein in all the specimens analyzed.

To the best of our knowledge, this is the first study demonstrating the presence of increased protein Carbonylation in post-mortem WM and GM tissue of MS patients.

(c) 2005 Wiley-Liss, Inc.

Multiple Sclerosis (MS) is a chronic Inflammatory Disease of the Central Nervous System (CNS). Oligodendrocyte damage and subsequent Axonal DeMyelination is a hallmark of this disease.

Different pathomechanisms, for example, Immune-mediated inflammation, Oxidative Stress and ExcitoToxicity, are involved in the ImmunoPathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids.

Polyunsaturated Fatty Acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defense mechanisms have been observed in MS patients.

Furthermore, antioxidant and PUFA treatment in Experimental Allergic Encephalomyelitis, an animal model of MS, decreased the clinical signs of disease.

Low-molecular-weight antioxidants may support cellular antioxidant defenses in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation.

PUFAs may not only exert ImmunoSuppressive actions through their incorporation in Immune Cells but also may affect cell function within the CNS.

Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

Agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in Experimental Autoimmune Encephalomyelitis (EAE), a model for Multiple Sclerosis.

In contrast, the effect of PPAR-delta (PPAR-delta) agonists in EAE is not yet known.

We show that oral administration of the selective PPAR-delta agonist GW0742 reduced clinical symptoms in C57BL/6 mice that had been immunized with Encephalitogenic Myelin Oligodendrocyte Glycoprotein (MOG) peptide.

In contrast to previous results with PPAR-gamma agonists, GW0742 only modestly attenuated clinical symptoms when the drug was provided simultaneously with immunization, but a greater reduction was observed if administered during disease progression.

Reduced clinical symptoms were accompanied by a reduction in the appearance of new Cortical lesions, however Cerebellar lesion load was not reduced.

Treatment of T-Cells with GW0742 either in vivo or in vitro did not reduce IFN-γ production; however GW0742 reduced Astroglial and Microglial inflammatory activation and IL-1-beta levels in EAE Brain.

RTPCR analysis showed that GW0742 increased expression of some Myelin genes. These data demonstrate that PPAR-delta agonists, like other PPAR ligands, can exert protective actions in an AutoImmune model of DeMyelinating Disease.

Objectives
The aim of this study was to identify clinical, Magnetic Resonance Imaging (MRI) and biological markers predictive of long-term clinical response to Interferon-beta (IFN-ß) therapy in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
Sixty-eight patients treated with IFN-ß were followed over a 6-year period. Relapse rate and disability progression were evaluated throughout the study.

We considered suboptimal clinical response to be either the presence of sustained disability progression, or more than two relapses.

Baseline and 12-month demographic, clinical and MRI findings, as well as the development of Neutralizing AntiBodies (NABs) against IFN-ß during the first year of therapy were analyzed as predictors of long-term clinical outcome.

Results
"Black holes" on MRI were the best baseline predictor of disability progression (odds ratio [OR] 6.8; p < 0.001).At 1 year, both male gender (OR 4.9; p = 0.009) and NABs (OR 7.3; p = 0.003) were independently associated with a high risk of developing subsequent disability.

The presence of Gadolinium enhancement, both at baseline (OR 4.7; p = 0.005) and on the 1-year MRI scan (OR 7.9; p = 0.002), was the unique variable associated with the number of relapses over the study period.

Conclusions
Variables assessable within the first year of treatment significantly influence relapse rate and disability progression in patients with RRMS treated with IFN-ß.

These findings may help clinicians to make decisions regarding therapy regimen over time, and highlight the need for a prognostic algorithm.

The use of ImmunoHistoChemical methods has led to a new understanding of the prevalence and significance of Cortical lesions in Multiple Sclerosis but these lesions have not yet been formally described in an animal model.

In this study we have set out to use ImmunoHistoChemical techniques to identify and describe Cortical lesions in marmosets with Experimental Autoimmune Encephalomyelitis (EAE).

Using AntiBodies to ProteoLipid Protein (PLP), we found a total of 70 Cortical lesions in 11 tissue blocks from 6 animals. These lesions were subdivided into LeucoCortical (40), IntraCortical (12) and SubPial lesions (18).

We quantified the density of inflammatory cells within lesions using a double labelling protocol which employed Anti-PLP in addition to AntiBodies against markers of B-Lymphocytes (CD20), T-Lymphocytes (CD3), Macrophages (MAC387) and MHC-II expressing cells (CR3/43).

This analysis revealed that the large SubPial lesions accounted for the majority of DeMyelinated Cortex (88%) despite possessing the lowest density of inflammatory cells.

This study has shown that lesions in this model share many of the major features of Cortical lesions in Multiple Sclerosis both in terms of morphology and inflammatory cell content.

We believe that this tool can be exploited in future studies to investigate the Etiology, development and clinical significance of Cortical lesions in DeMyelinating Disease.

The prevalence of Multiple Sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of Vitamin D(3).

Consistent with this theory, previous research has shown a strong protective effect 1,25-DihydroxyVitamin D3 in Experimental Autoimmune Encephalomyelitis (EAE), an MS model.

However, it is not known whether the hormone precursor, Vitamin D3, has protective effects in EAE.

To address this question, B10.PL mice were fed a diet with or without Vitamin D3, immunized with Myelin Basic Protein, and studied for signs of EAE and for metabolites and transcripts of the Vitamin D3 Endocrine System.

The intact, Vitamin D3-fed female mice had significantly less clinical, HistoPathological, and Immunological signs of EAE than ovariectomized females or intact or castrated males.

Correlating with reduced EAE, the intact, Vitamin D3-fed female mice had significantly more 1,25-DihydroxyVitamin D3 and fewer CYP24A1 transcripts, encoding the 1,25-DihydroxyVitamin D3-inactivating enzyme, in the Spinal Cord than the other groups of mice.

Thus, there was an unexpected synergy between Vitamin D3 and Ovarian tissue with regard to EAE inhibition.

We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the Spinal Cord, so the locally-produced 1,25-DihydroxyVitamin D3 accumulated and resolved the inflammation before severe EAE developed.

If humans have a similar gender difference in Vitamin D3 metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.

ReMyelination of DeMyelinated Central Nervous System (CNS) Axons is considered as a potential treatment for Multiple Sclerosis, and it has been achieved in experimental models of DeMyelination by transplantation of Pro-Myelinating Cells.

However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated ReMyelination since they were performed in conditions in which the chance for graft rejection was minimized.

This article focuses on the factors determining survival of allogeneic Oligodendrocyte lineage cells and their contribution to the ReMyelination of DeMyelinating CNS lesions.

The Immune status of the CNS as well as the suitability of different models of DeMyelination for graft rejection studies are discussed, and ways of enhancing allogeneic Oligodendrocyte-mediated ReMyelination are presented.

Finally, the effects of Glial graft rejection on host ReMyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for Myelin repair.

Objective
Our objective was to study the impact of pregnancy and delivery on VesicoUrethral Disorders in patients with Multiple Sclerosis (MS).

Design And Setting
We performed a retrospective chart review of records of women diagnosed with MS who were referred to the clinic.

Participants
A total of 102 women with MS (mean age of 44.7+/-11.4 years at the time of the study and mean age of 30.0+/-9.6 years at the onset of MS) participated in the study.

The mean duration of disease was 15+/-10 years. The mean Expanded Disability Status Scale score was 5.4+/-1.8.

Main Outcome Measures
For each patient, demographic data, disease characteristics, Urological and Obstetrical history and Urodynamic data were collected.

Urinary Disorders were classified as irritative (Urinary urgency and frequency) or as obstructive (hesitancy of micturition, reduced or interrupted urinary stream and sensation of incomplete Bladder emptying).

Urodynamic study consisted of Cystometry with continuous recording of Urethral Sphincter Electromyography in 77 (76%) cases.

IntraVesical and IntraUrethral pressures were recorded. Bladder dysfunctions were classified into Neurogenic Detrusor overactivity or Detrusor underactivity.

Results
Pregnancies and deliveries did not influence symptoms. Moreover, the only statistical difference from a Urodynamic point of view was a decrease in maximal Urethral closure pressure.

Conclusion
No interaction between pregnancy, delivery and urinary symptoms was found in this study.

The effects of pregnancy and delivery seemed to be the same in women with MS and in healthy women, with a tendency towards a decrease in Urethral pressure in women with MS.

Statin treatment is proposed to be a new potential therapy for Multiple Sclerosis (MS), an Inflammatory DeMyelinating Disease of the Central Nervous System. The effects of Statin treatment on Brain cells, however, are hardly understood.

We therefore evaluated the effects of SimvaStatin treatment on the migratory capacity of Brain Microglial Cells, key elements in the pathogenesis of MS.

It is shown that exposure of human and murine Microglial Cells to SimvaStatin reduced cell surface expression of the Chemokine Receptors CCR5 and CXCR3.

In addition, SimvaStatin treatment specifically abolished Chemokine-induced Microglial Cell motility, altered Actin CytoSkeleton distribution, and led to changes in IntraCellular Vesicles.

These data clearly show that SimvaStatin inhibits several Immunological properties of Microglia, which may provide a rationale for Statin treatment in MS.

(c) 2005 Wiley-Liss, Inc.