MS Abstracts 01a-2g8

Background
The reason for increased Peripheral Blood Leukocyte (PBL) Nitric Oxide (NO) production in patients with Multiple Sclerosis (MS) is unknown.

Objective
To investigate whether PBL NO production is related to measures of Oxidative Stress.

Methods
PBL Nitrite, Diene Conjugates (DC, a measure of undergone Oxidative Stress), AntiRadical Activity (ARA) and AntiOxidant Acitvity (AOA) were measured in 35 healthy control persons and 80 patients with MS.

We investigated the correlation of these measures with a partial correlation analysis, with age as the control variable.

Results
There was a significant correlation in both MS patients and healthy control persons between PBL Nitrite levels and PBL DC, ARA and AOA.

The correlations were stronger in healthy control persons.

An analysis by disease subtype showed that the correlations were present in patients with Relapsing/Remitting MS and Secondary/Progressive MS, but absent in Primary/Progressive MS.

Conclusions
PBL Nitrite levels and measures of Oxidative Stress are closely related in MS-patients as well as in healthy control persons.

Increased Serum NO levels in MS may be the result of a physiologic reaction to overall Oxidative Stress.

The differences in the strength of correlation between different disease subtypes may reflect differences in Leukocyte biology.

Multiple Sclerosis 2007; 00: 00-00.

OligoClonal IgM Bands (OCMB) against Myelin Lipids predict an aggressive Multiple Sclerosis (MS) course.

However, the clinical significance of OCMB without lipid specificity, present in other MS patients, remains unknown.

We describe here a characterization of these AntiBodies and study their role in MS progression.

Fifty-four MS patients showing CSF-restricted OCMB were included in this study at disease onset and followed-up during 61.1+/-2.7 months.

The specificity of OCMB and the CSF B-Cell profile were investigated. A second CSF IgM study was performed in a group of eight patients.

Thirty-eight patients showed OCMB against Myelin Lipids (M+L+) and other sixteen had OCMB lacking this specificity (M+L-).

The CD5+ B-Cell subpopulation, responsible for most persistent IgM responses, was considerably higher in M+L+ than in M+L- patients (3.3+/-0.6% versus 0.8+/-0.2, P=0.009).

In addition, M+L+ bands persisted during disease course, while M+L- disappeared during follow-up.

M+L+ patients suffered more relapses (4.2+/-0.6 versus 1.6+/-0.3, P=0.002) and reached higher disability (EDSS score of 2.2+/-0.2 versus 1.2+/-0.2, P=0.02) than M+L- group.

These data corroborate that Anti-Lipid OCMB associate with an aggressive MS course and show that OCMB that do not recognize Myelin Lipids represent a transient Immune Response related to a more Benign disease course.

Multiple Sclerosis 2007; 00: 00-00.

Multiple Sclerosis (MS) is an inflammatory disease where Phagocytic Cells infiltrate the nerve tissue and act as terminal agents in destruction of the Myelin sheath.

However, the mechanism that triggers the ability of these cells to recognize Myelin remains obscure.

We show that Myelin Basic Protein (MBP), a major AutoAntigen in MS, is a potent and specific Ligand for the Integrin (M)ß² (Mac-1, CD11b/CD18) expressed mainly on Phagocytic Cells.

MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the Myelin sheath.

The MS drug Glatiramer Acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with (M)ß², and inhibits the MBP binding to (M)ß².

Our study reveals a link between MBP, Glatiramer Acetate, and the (M)ß² Integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the (M)ß² Integrin.

An important contribution of B-Cells and AutoAntiBodies has been demonstrated in the pathogenesis of Multiple Sclerosis (MS), leading to interest in the use of such AutoAntiBodies as diagnostic or prognostic biomarkers.

The objective of this study was to identify novel Ab biomarkers for MS using "serological Ag selection".

Using a phage display library derived from MS Brain plaques, we applied serological Ag selection to identify antigenic targets specifically interacting with Abs present in the CerebroSpinal Fluid (CSF) of 10 Relapsing/Remitting MS patients.

These antigenic targets were further evaluated on a large panel of CSF from 63 other MS patients, 30 patients with Other Inflammatory Disorders, and 64 patients with NonInflammatory Neurological Disorders.

A panel of eight antigenic targets was identified that showed a 86% specificity and 45% sensitivity in discriminating MS patients and controls.

Four of the antigenic targets showed exclusive reactivity (100% specificity; 23% sensitivity) in the MS group as compared with the control group.

Detailed bio-informatic analyses revealed a novel Ag, SPAG16. Among the novel phage Peptides identified, novel epitopes were generated from untranslated sequences and out-of-frame sequences.

Of 10 Relapsing/Remitting patients used for serological Ag selection, Ab reactivity toward one of the eight antigenic targets was also demonstrated in serum of 38% CSF-positive patients.

AutoAntiBody profiles against Epitopes derived from MS Brain tissue could serve as diagnostic markers or form the basis for the identification of a subgroup of MS patients.

Diffusion Tensor Imaging (DTI) parameters such as Mean Diffusivity (MD) and Fractional Anisotropy (FA) assess aspects of structural integrity within tissue.

In Relapsing/Remitting (RR) Multiple Sclerosis (MS), abnormalities in Normal-Appearing Brain Tissue (NABT) have been shown cross-sectionally.

The evolution of these abnormalities over time is unclear. We present a longitudinal study investigating early RRMS subjects.

The aims were to determine DTI changes over two years and assess the potential of DTI as a longitudinal quantitative marker at this stage of MS.

Fifteen controls and 28 patients with RR MS (median disease duration 1.9 years; median EDSS 1.5) had DTI yearly for two years. NABT and Whole Brain Tissue (NABT plus lesions) FA and MD Histograms analyzed.

At baseline, differences in FA were noted between patients and controls (mean [p = 0.042] and peak height [p = 0.008]), while at two years differences in MD were observed (mean [p = 0.008] and peak location [p = 0.024]).

However there were no significant DTI differences in longitudinal rates of change between patients and cohorts.

In conclusion, although subtle NABT abnormalities were detected in early RR MS, the absence of longitudinal change suggests a limited role for global DTI assessment of NABT in following the early disease course.

Multiple Sclerosis (MS) is an Inflammatory and Degenerative Disease of the Central Nervous System (CNS) that causes White Matter and Cortical lesions over many years.

The CNS is selectively affected by the disease with a great variety of symptoms between patients.

In this study, we describe the impact on various aspects of Cognition over an 8-year follow-up period in 31 consecutive MS patients subgrouped as Relapsing/Remitting (RRMS) , Secondary/Progressive (SPMS) , and Primary/Progressive (PPMS) .

Results showed a differential pattern of Cognitive decline already at baseline in Speed Of Information Processing.

During the follow-up, a pronounced decline occurred in Speed Of Information Processing, Finger-Motor Speed, Copying Geometrical Designs, Episodic Memory, and VisuoSpatial Short-Term Memory.

A striking difference was observed between a marked decline in Visual Reaction Time, whereas no significant change was seen in Auditory Reaction Time.

In contrast, there was no time-related decline in Verbal abilities.

However, an initial marked Cognitive Impairment predicted further Cognitive decline over the 8-year follow-up. Information-processing tests were found to be an especially strong predictor of long-term Cognitive decline.

In addition, high EDSS score at follow-up was associated with decline in information processes.

Results also showed that SP-MS patients deteriorated significantly more than the other two groups, particularly in Visual compared to Auditory information processing.

To conclude, Cognitive Decline appeared particularly in SP-MS patients and in Visual Information Processing.

2007 S. Karger AG, Basel

Multiple Sclerosis (MS) is the most common inflammatory DeMyelinating disorder of the Central Nervous System (CNS).

An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process.

Statins are effective in the treatment of MS animal models and are promising candidates for future treatment.

Minocycline ameliorates clinical severity of Experimental Autoimmune Encephalomyelitis (EAE) and exhibits several anti-inflammatory and NeuroProtective activities.

In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with Myelin Oligodendrocyte Protein (MOG).

Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, DeMyelination and Axonal Loss.

Stereological analysis revealed that the combined treatment significantly guarded against NeuroInflammation and NeuroDegeneration. Moreover, a significant suppression of Anti-MOG AntiBody production in animals treated with the two medications was found.

In conclusion, our findings prove that this combination of drugs is NeuroProtective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.

Objective
Visual Evoked Potentials (VEPs) may be suitable surrogate outcome measures in Multiple Sclerosis (MS) ReMyelination trials.

The extent of spontaneous changes of SubClinically delayed VEP is unknown, whereas VEP improve after acute Optic Neuritis (ON).

Methods
In all, 124 patients with three VEP recordings at least 3 months apart: 71 patients with MS who had never suffered clinical ON; 53 patients with ON (isolated ON or ON as an attack of MS at first recording).

Latencies of P100 were analyzed by multivariate analysis of variance.

Results
Eyes of patients with MS had a mean P100 latency of 110.2 ms, worsening mildly over time (n = 104 eyes, P = 0.022).

MS patients' eyes with SubClinical DeMyelination (delayed P100 latency at first recording > 116 ms) showed no significant evidence of ReMyelination (n = 24 eyes, P = 0.27).

By contrast, in ON patients' affected eyes, mean P100 latency decreased (P = 0.001), whereas unaffected eyes remained stable (P = 0.26).

Clinically non-affected eyes from both diagnostic groups with SubClinically prolonged latencies remained stable (n = 32: mean P100 at 124.8 +/- 10.7, 123.5 +/- 13.6, and 122.8 +/- 13.1 ms; P = 0.57).

Whereas non-affected eyes with normal latency at baseline deteriorated slightly (P = 0.001).

A subgroup with more homogeneously defined follow-up periods confirmed this observation.

Non-affected eyes selected for stability (difference < 5 ms) between first and second recording deteriorated (normal baseline, n = 66 eyes, P = 0.013) or remained stable (prolonged baseline, n = 18 eyes, 95% confidence interval of change -5.42 to +6.89 ms, P = 0.805).

Conclusion
Prolonged P100 latencies in eyes never affected by clinical ON remain stable and thus can be used as surrogate outcome measure for ReMyelination trials.

Objective
To evaluate whether Constraint-Induced Movement therapy (CI therapy) may benefit chronic upper extremity HemiParesis in Progressive Multiple Sclerosis (MS).

Methods
Five patients with Progressive MS, who had chronic upper extremity HemiParesis.

And evidence for learned non-use of the paretic limb in the life situation, underwent 30 hours of repetitive task training and shaping for the paretic limb over 2-10 consecutive weeks.

Along with physical restraint of the less-affected arm and a "transfer package" of behavioral techniques to reinforce treatment adherence.

Results
The patients showed significantly improved spontaneous, real-world limb use at post-treatment and 4 weeks post-treatment, along with improved Fatigue ratings and maximal movement ability displayed in a laboratory motor test.

Conclusions
The findings suggest for the first time that slowly Progressive MS may benefit from CI therapy. Further studies are needed to determine the retention of treatment responses.

Macrophage-Derived Chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS).

MDC/CCL22 gene is part of a Chemokine cluster, which includes also Thymus and Activation-Regulated Chemokine (TARC/CCL17).

The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22.

As well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls.

A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls.

The frequency of the AT haplotype was significantly decreased in MS patients (P=0.017, OR: 0.49, CI: 0.28-0.87).

Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18, 95% CI: 0.06-0.50), whereas no significant differences were observed in females.

Therefore, the presence of the AT haplotype in Chromosome 16 Chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.

Background
Findings from a small clinical study suggested that Statins may counteract the therapeutic effects of Interferon-beta (IFN-ß) in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFN-ß-1a in Patients With Relapsing/Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of Statins on efficacy of IFN-ß.

SENTINEL was a prospective trial of patients with RRMS treated with Natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFN-ß-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFN-ß-1a 30 microg.

Clinical and MRI outcomes in patients treated with IM IFN-ß-1a only (No-Statins group, n = 542) were compared with those of patients taking IM IFN-ß-1a and Statins at doses used to treat HyperLipidemia (Statins group, n = 40).

Results
No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of Gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T₂-HyperIntense lesions (p = 0.802) at 2 years.

More patients in the Statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the No-Statins group.

Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes.

Conclusions
Statin therapy does not appear to affect clinical effects of IM Interferon-ß-1a in patients with Relapsing/Remitting Multiple Sclerosis or the primary molecular response to Interferon-beta treatment.

Axonal degeneration is an important determinant of progressive Neurological disability in Multiple Sclerosis (MS). Thus, therapeutic approaches promoting NeuroProtection could aid the treatment of Progressive MS.

Here, we used what we believe is a novel water-soluble Fullerene derivative (ABS-75) attached to an NMDA receptor antagonist.

Which combines AntiOxidant and Anti-ExcitoToxic properties, to block Axonal Damage and reduce disease progression in a Chronic Progressive EAE model.

Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with Myelin-Oligodendrocyte Glycoprotein (MOG).

Reduced disease progression in ABS-75-treated mice was associated with reduced Axonal Loss and DeMyelination in the Spinal Cord.

Fullerene ABS-75 halted Oxidative Injury, CD11b⁺ infiltration, and CCL2 expression in the Spinal Cord of mice without interfering with Antigen-specific T-Cell responses.

In vitro, Fullerene ABS-75 protected Neurons from Oxidative and Glutamate-induced injury and restored Glutamine synthetase and Glutamate transporter expression in Astrocytes under inflammatory insult.

Glutamine synthetase expression was also increased in the White Matter of Fullerene ABS-75-treated animals.

Our data demonstrate the NeuroProtective effect of treatment with a Fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of Progressive MS and other NeuroDegenerative Diseases.