MS Abstracts 02b-2g7

Human ICOS is a T-Cell CoStimulatory Molecule supporting IL-10 secretion. A pilot study investigating variations of the ICOS gene 3'UTR detected 8 polymorphisms forming three haplotypes (A, B, C).

Haplotype-A and -C displayed the highest difference.

Activated T-Cells from healthy AA homozygotes expressed significantly less ICOS and secreted more IL-10 than AC heterozygotes, whereas AB heterozygotes displayed intermediate levels.

Analysis of 441 Multiple Sclerosis patients and 793 controls showed that frequency of AA homozygosity was significantly lower in MS patients with Relapsing/Remitting onset (N=416) than in controls (OR=0.70).

Moreover, AA patients with Relapsing/Remitting onset had lower relapse rate and Multiple Sclerosis severity score than non-AA patients.

Although genetic susceptibility explains the clustering of Multiple Sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance.

It cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration.

Epidemiological data provide some support for the "hygiene hypothesis," but with the additional proviso for a key role of Epstein-Barr Virus (EBV) in determining MS risk.

We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas.

This decline implies that either EBV strains in low-risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk.

The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of Vitamin D may have a protective role, particularly during adolescence.

The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention.

As discussed in Part I of this review, the geographic distribution of Multiple Sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS.

Where "environmental" is broadly defined to include differences in diet and other behaviors.

As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants.

Among these, sunlight exposure emerges as being the most likely candidate.

Because the effects of sun exposure may be mediated by Vitamin D, we also examine the evidence linking Vitamin D intake or status to MS risk.

Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence.

Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.

Ann Neurol 2007.

Objective
To investigate the impact of Interferon-beta (IFN-ß) on disease progression in Relapsing/Remitting Multiple Sclerosis patients.

Methods
A cohort of 1,504 Relapsing/Remitting Multiple Sclerosis (1,103 IFN-ß-treated and 401 untreated) patients was followed for up to 7 years.

Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: Secondary/Progressive (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6.

Times from first visit and from date of birth were used as survival time variables.

Results
The IFN-ß-treated group showed a highly significant reduction in the incidence of SP (Hazard Ratio [HR], 0.38, 95% confidence interval [CI], 0.24-0.58 for time from 1st visit;

HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth;

p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit;

HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth;

p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38-0.95 for time from first visit;

HR, 0.54, 95% CI, 0.34-0.86 for time from date of birth; p < or = 0.03) when compared with untreated patients.

SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings.

Interpretation
IFN-ß slows progression in Relapsing/Remitting Multiple Sclerosis patients.

Nitric Oxide (NO) and Peroxynitrite (ONOO(-)) are potential mediators of the injury and CytoToxicity occurring over time to Oligodendrocytes in Multiple Sclerosis (MS) lesions.

Our in vitro results indicate that human adult CNS-derived Oligodendrocytes are relatively resistant to NO-mediated damage.

In contrast, human Oligodendrocytes are highly susceptible to Peroxynitrite-mediated injury.

In situ, we found that Inducible Nitric Oxide Synthase (INOS) was expressed in Astrocytes and Macrophages in all active DeMyelinating and ReMyelinating MS lesions examined.

Yet no correlation was found between numbers of Glial Cells expressing INOS and the extent of Oligodendrocyte cell death.

Nitrotyrosine groups, indicative of the presence of Peroxynitrite in vivo, could be detected on Astrocytes, Macrophages, and Oligodendrocytes in MS lesions.

High numbers of Nitrotyrosine-positive Oligodendrocytes were found in one MS case that featured extensive Oligodendrocyte cell death.

Our results indicate that NO alone is unlikely to induce Oligodendrocyte injury, whereas its more potent byproduct Peroxynitrite is a potential mediator of injury to Oligodendrocytes in MS.

(c) 2007 Wiley-Liss, Inc.

Objective
To investigate whether Diffusion-Tensor Magnetic Resonance Imaging and Whole Brain N-AcetylAspartate (WBNAA) proton Magnetic Resonance Spectroscopy can provide complementary pieces of information.

To achieve a better understanding of the factors associated with disability in Multiple Sclerosis (MS).

Design & Setting
Cross-sectional survey. Referral hospital-based MS center.

Patients
Ten healthy control subjects, 27 patients with a Clinically Isolated Neurological Syndrome, 21 patients with Relapsing/Remitting MS, and 29 patients with Secondary/Progressive MS.

Main Outcome Measures
Conventional and Diffusion-Tensor Magnetic Resonance Imaging, as well as WBNAA proton Magnetic Resonance Spectroscopy, of the Brain was performed.

T₂-HyperIntense lesion volumes were measured. The mean values of Mean Diffusivity (MD) and Fractional Anisotropy of T₂-visible lesions were computed.

Histograms of MD and Fractional Anisotropy values were produced for Normal-Appearing White Matter and Gray Matter (GM).

Results
Patients with a Clinically Isolated Neurological Syndrome had a significantly (P=.002) lower WBNAA concentration than control subjects.

Patients with Relapsing/Remitting MS had significantly higher T₂ lesion volume (P=.007), mean lesion MD (P=.003), Normal-Appearing White Matter Fractional Anisotropy peak height (P=.03), and a lower WBNAA concentration (P < .001) than patients with a Clinically Isolated Neurological Syndrome.

Patients with Secondary/Progressive MS had significantly higher T₂ lesion volume (P=.01), lower mean Normal-Appearing White Matter Fractional Anisotropy (P=.003), higher mean GM MD (P=.004), and lower GM MD peak height (P=.01) than patients with Relapsing/Remitting MS.

Disease duration, GM MD peak height, and WBNAA concentration entered a multivariate model, explaining nearly 70% of the disability variance.

Conclusions
The accumulation of macroscopic lesions and Normal-Appearing White Matter damage seems to occur mainly during the earliest clinical phases of MS.

Whereas, pathological features of GM may be a hallmark of the late Progressive stage of the disease. This supports the notion of MS as a "2-stage" disease.

Cervical Cord damage is likely to contribute to the accumulation of disability in Multiple Sclerosis (MS) and can be quantified in vivo using MRI.

We used conventional and Diffusion Tensor (DT) MRI to:
1. Define the temporal evolution of intrinsic tissue injury and Atrophy in the Cervical Cord from MS patients
2. Investigate how these two aspects of Cord damage are interrelated
3. Assess the correlation of Cord MRI metrics with concomitant Brain damage and disability

Conventional and DT MRI of the Brain and Cervical Cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years.

At each time-point, we measured: Cervical Cord lesion number, Cross-Sectional Area, Mean Diffusivity (MD) and Fractional Anisotropy (FA).

Brain T₂ lesion volume, Gray Matter MD, Normal-Appearing White Matter (NAWM) MD and FA, as well as longitudinal Normalized percentage Brain Volume changes were also measured.

In MS patients, Cervical Cord Cross-Sectional Area (P < 0.001) and FA (P = 0.01) decreased, and Cervical Cord MD increased (P < 0.001) during follow-up.

Cord FA decrease, but not Cord Cross-Sectional Area and MD, was significantly higher (P = 0.05) in Primary/Progressive MS patients than in those with either Relapsing/Remitting or Secondary/Progressive MS.

At baseline and follow-up, moderate correlations were found between intrinsic Cord Diffusivity abnormalities and Cord Cross-Sectional Area (r values ranging from 0.34 to 0.58), but not between their changes over time.

No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of Cord T₂-visible lesions. Brain NAWM MD (P = 0.03) and Brain Volume (P < 0.001) also changed in patients.

There was no significant correlation between Cord and Brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up.

Baseline Cord Cross-Sectional Area (r = -0.40, P = 0.01) and FA (r = -0.40, P = 0.03) correlated with increase in disability at follow-up.

This study shows that both progressive tissue loss and injury to the remaining tissue occur in the Cervical Cord of MS patients.

And, that these two components of Cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage.

MS Cord pathology also seems to be independent of concomitant Brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.

Multiple Sclerosis (MS) is a major inflammatory and DeMyelinating Disease of the Central Nervous System and has an increasing prevalence in populations residing at higher latitudes.

This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of Vitamin-D in the MS population.

The Vitamin-D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as Apoptosis and Immune regulation in Immune Cells such as T Helper Cells and Dendritic Cells.

Evidence from Experimental Autoimmune Encephalomyelitis and prospective studies on MS suggests an important role of Vitamin-D as a modifiable environmental factor in MS.

These provide guidance for future studies with regard to the potential role of Vitamin-D in the prevention and/or treatment of MS. Here, we first review the metabolism and Immune functions of Vitamin-D.

Then, we describe the current thinking on the etiology of Vitamin-D in MS and the accumulating evidence pointing to a link between Vitamin-D and MS.

Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the Vitamin-D receptor.

This review also discusses the therapeutic potential of Vitamin-D for treating MS.

Diffusion-Weighted Imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in Gray Matter and White Matter Brain compartments in patients with Multiple Sclerosis (MS).

However, DWI has been applied to the study of MS clinical subtypes in only a few studies.

The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures.

We also wanted to assess the correlation between Whole Brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients.

For this purpose we studied 432 consecutive MS patients (mean age 44.4+/-10.2 years), 16 patients with Clinically Isolated Syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI.

Clinical disease subtypes were as follows: 294 Relapsing/Remitting (RR), 123 Secondary/Progressive (S/P) and 15 Primary/Progressive (PP). Mean disease duration was 12+/-10 years.

Mean Expanded Disability Status Scale (EDSS) was 3.3+/-2.1. Brain Parenchymal Fraction (BPF), Gray Matter Fraction (GMF) and White Matter Fraction (WMF) were calculated using a fully automated method.

Mean Parenchymal Diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and Entropy (ENT) were obtained.

T₂- and T₁-lesion volumes (LV), EDSS, Ambulation Index (AI) and Nine-Hole Peg Test (9-HPT) were also assessed.

MS patients had significantly lower BPF (d=1.26; p < 0.001) and GMF (d=0.61; p=0.003), and higher ENT (d=1.2; p < 0.0001), MPD (d=1.04; p < 0.0001) and PH (d=0.47; p=0.045) than NC subjects.

A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T₂-LV and T₁-LV (p < 0.0001), WMF (p=0.001) and MPD (p=0.023).

In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r=0.54 to 0.67, p < 0.0001) and clinical (r=0.31 to 0.36, p < 0.0001) variables than MPD (r=0.23 to 0.41, p < 0.001 for MRI and r=0.13 to 0.18; p=0.006 to p < 0.001 for clinical variables).

The GMF and BPF showed a slightly stronger relationship with all clinical variables (r=0.33 to 0.48; p < 0.0001), when compared to both lesion and DWI measures.

ENT (R(2)=0.28; p < 0.0001) and GMF (R(2)=0.26; p < 0.001) were best related with SP disease course.

This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes.

ENT is a sensitive marker of overall Brain Damage that is strongly related to clinical impairment in patients with SP MS.

In Multiple Sclerosis (MS), Atrophy occurs in various Cortical and SubCortical regions. However, it is unclear whether this is mostly due to Gray (GM) or White Matter (WM) loss.

Recently, a new Semi-Automatic Brain Region Extraction (SABRE) technique was developed to quantify Parenchyma Volume in 13 Hemispheric regions.

This study utilized SABRE and tissue segmentation to examine whether Regional Brain Atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course.

We studied 68 MS patients and 39 normal controls with 1.5 T Brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) Regional Brain Parenchymal Fractions (RBPFs).

While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant.

The largest mean RBPF percent differences between groups (MS < NC) were in the Posterior Basal Ganglia/Thalamus region (-19.3%), Superior Frontal (-15.7%), and Superior Parietal (-14.3%) regions.

Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region.

Significant trends emerged for differences in GM, but not WM between Secondary/Progressive (SP) and Relapsing/Remitting MS patients.

Percent differences in GM between the two groups were largest in Superior Frontal (-9.9%), Medial Superior Frontal (-6.5%), and Superior Parietal (-6.1%) regions, with SP patients having lower volumes.

Overall, Atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and Superior Frontal-Parietal regions.

Multiple Sclerosis (MS) is a chronic inflammatory DeMyelinating disease of the CNS. Approximately 2 million people worldwide have MS, with females outnumbering males 2:1.

Because of its high prevalence, MS is the leading cause of nontraumatic Neurologic Disability in young adults in the United States and Europe.

Axon loss is the major cause of irreversible disability in patients with MS. Axon damage, including transection of the Axon, begins early in MS and correlates with inflammatory activity.

Several mechanisms lead to Axon loss, including inflammatory secretions, loss of Myelin-derived support, disruption of Axonal Ion concentrations, Energy Failure, and Ca2⁺ accumulation.

Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing Axon survival and, ultimately, their ability to delay progression of Neurologic Disability in patients with MS.

Interferon-gamma (IFN-γ) is one of the most important Microglia stimulators in vivo participating in inflammation and Th1 activation/differentiation.

IFN-γ-mediated signaling involves the activation of the Jak/STAT1 pathway. The NeuroPeptides Vasoactive Intestinal Peptide (VIP).

And, the Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) are two potent Microglia-deactivating factors that inhibit the production of proinflammatory mediators in vitro and in vivo.

The present study investigated the molecular mechanisms involved in the VIP/PACAP regulation of several IFN-γ-induced Microglia-derived factors.

Including IFN-γ-Inducible Protein-10 (IP-10), Inducible Nitric-Oxide Synthase (INOS), and CD40.

The results indicate that VIP/PACAP inhibit Jak1-2 and STAT1 phosphorylation, and the binding of activated STAT1 to the IFN-γ activated site motif.

In the IFN regulatory factor-1 and CD40 promoter and to the IFN-stimulated response element motif of the IP-10 promoter.

Through its effect in the IFN-γ-induced Jak/STAT1 pathway, VIP and PACAP are able to control the gene expression of IP-10, CD40.

And INOS, three Microglia-derived mediators that play an essential role in several pathologies, i.e. Inflammation and Autoimmune Disorders.

The effects of VIP/PACAP are mediated through the specific Receptor VPAC1 and the cAMP/protein kinase A transduction pathway.

Because IFN-γ is a major stimulator of Innate and Adaptive Immune Responses in vivo, the down-regulation of IFN-γ-induced gene expression by VIP.

And, PACAP could represent a significant element in the regulation of the inflammatory response in the Central Nervous System by endogenous NeuroPeptides.