MS Abstracts 03d-2g7

Cortical pathology, Callosal Atrophy and Axonal Loss are substrates of progression in Multiple Sclerosis (MS).

Here we describe Cortical, PeriVentricular SubCortical lesions and Callosal DeMyelination in Relapsing/Remitting Experimental Autoimmune Encephalomyelitis in SJL mice that are similar to lesions found in MS.

Unlike the T-Cell infiltrates that peak during acute disease, we found that Microglia activation persists through the chronic disease phase.

Microglia activation correlated with abnormal phosphorylation of NeuroFilaments in the Cortex and stripping of Synaptic proteins in Cortical Callosal projecting Neurons.

There was significant impairment of retrograde labeling of NeuN-positive Callosal projecting Neurons and reduction in the labelling of their TransCallosal Axons.

These data demonstrate a novel paradigm of Cortical and Callosal NeuroPathology in a mouse model of MS, perpetuated by Innate Immunity.

These features closely mimic the PeriVentricular and Cortical pathology described in MS patients and establish a model that could be useful to study mechanisms of progression in MS.

Cortical involvement in Multiple Sclerosis (MS) is emerging as an important determinant of disease progression. The mechanisms responsible for MS Cortical Pathology are not fully characterized.

The objective of this study was to assess the role of ExcitoToxicity in MS Cortex.

Evaluating Excitatory Amino Acid Transporter (EAAT) expression and its relationship with DeMyelination, Inflammation, Gliosis, and Neuronal and Synaptic pathology.

EAATs are essential in maintaining low ExtraCellular Glutamate concentrations and preventing ExcitoToxicity.

Ten MS Brains (3 Relapsing/Remitting MS cases and 7 Secondary/Progressive MS cases) were evaluated by ImmunoHistoChemistry for Myelin Basic Protein, CD68, HLA-DR, EAAT1, EAAT2, Glial Fibrillary Acidic Protein, phosphorylated c-Jun N-terminal kinase (pJNK), SynaptoPhysin, and NeuroFilaments.

Cortical lesions were frequently observed in MS Brains in variable numbers and extensions.

In Cortical Lesions, activated Microglia infiltration correlated with focal loss of EAAT1, EAAT2, and SynaptoPhysin immunostaining.

And with Neuronal immunostaining for pJNK, a protein involved in response to ExcitoToxic Injury.

No reduction of EAATs or SynaptoPhysin immunostaining was observed in DeMyelinated Cortex in the absence of activated Microglia.

Alterations of the mechanisms of Glutamate reuptake are found in Cortical MS lesions in the presence of activated Microglia.

And are associated with signs of Neuronal and Synaptic damage suggestive of ExcitoToxicity.

ExcitoToxicity may be involved in the pathogenesis of DeMyelination and of Neuronal and Synaptic damage in MS Cortex.

Background
Recent pathologic investigations have shown that NeoCortical lesions are frequent in Multiple Sclerosis (MS).

Structural MRI has shown that NeoCortical Atrophy occurs early and can be substantial, but the specific substrate for this Atrophy has not been defined quantitatively.

Objective
To investigate Cortical thickness as well as Neuronal, Glial, and Synaptic densities in MS.

Methods
We studied Brain samples from 22 patients with MS and 17 control subjects. NeoCortical lesions and Cortical thickness were assessed on sections stained for Myelin Basic Protein.

Neuronal, Glial, and Synaptic densities were measured in type I LeukoCortical lesions, nonlesional NeoCortex, and non-MS control Cortex. ImmunoAutoRadiography was used to quantify Synaptic densities.

Results
NeoCortical lesions were common in patients with MS. SubPial type III (44%) and LeukoCortical type I (38%) lesions were more abundant than IntraCortical type II (18%) lesions.

An overall relative NeoCortical thinning of 10% (p = 0.016) was estimated for the patients.

Within the type I lesions, we found evidence for substantial cell (Glial, 36%, p = 0.001; Neuronal, 10%, p = 0.032) and Synaptic (47% decrease in Synaptophysin, p = 0.001) loss.

Nonlesional NeoCortex did not show significant relative changes in Neuronal, Glial, or Synaptic density.

Conclusions
NeoCortical Neuronal and Glial degeneration is significant in Multiple Sclerosis.

Synaptic loss was particularly striking in the NeoCortical lesions, which should make a major independent contribution to the expression of pathology.

New therapies should be directed toward limiting this damage.

Aim Of The Study
To analyse retrospectively course of the disease in the patients with Relapsing/Remitting Multiple Sclerosis (R-R MS), treated with Interferon-beta (IFN-ß).

To compare clinical data within the periods before, during and after IFN-ß treatment and to refer these parameters to clinical state of patients at the beginning of treatment.

Material And Method
The study comprised 40 patients (18 men, 22 women, aged 22-55 years) with R-R MS, treated with IFN-ß for at least 12 months, with documented follow-up before the treatment and for at least 12 months after it was discontinued.

Annual exacerbation rate (AER) and annual rate of disability progression measured by means of Expanded Standard Disability Status Scale (ap-EDSS).

Within the periods before, during and after the IFN-alpha treatment were compared for all the patients and referred to duration of the disease and EDSS score at the beginning of treatment.

AER and ap-EDSS were also analyzed for subgroups of patients who were relapse-free or whose EDSS score improved during the treatment.

Results
Mean values of AER and ap-EDSS were significantly lower during the IFN-ß treatment than before and after the treatment.

AER during and after the treatment correlated positively with EDSS score at the beginning of the treatment.

ap-EDSS during the treatment was significantly lower for the patients with EDSS < 3 at the beginning of the treatment than for those with EDSS > or = 3.

The patients who were relapse-free during the treatment had significantly lower EDSS score at the beginning of treatment and lower AER after the treatment in comparison with those who had relapses.

The patients whose EDSS score improved during the treatment had significantly lower EDSS score at the beginning of treatment and lower AER after the treatment in comparison with those whose EDSS score worsened or remained unchanged.

AER and ap-EDSS did not depend upon duration of IFN-ß treatment.

Conclusions
In patients with R-R MS IFN-ß has significant influence upon course of the disease: it causes decrease in exacerbation rate and slower progression of disability.

However, improvement of these parameters persists only during the treatment.

Clinical effect of treatment depends on initial stage of disability but does not depend on dynamics of the disease before the treatment.

For optimal results of IFN-ß treatment, it should be introduced possibly early in the course of MS.

There are few long-term clinical and Magnetic Resonance Imaging (MRI) data on patients treated with Interferon-beta (IFN-ß) for Relapsing/Remitting Multiple Sclerosis (RRMS).

The aim of this study was to provide clinical and MRI data on 68 patients with RRMS treated over a 6-year period and to investigate whether a baseline MRI predicts their long-term clinical and MRI outcome.

Six MRI scans were performed monthly before treatment and a further 13 scans were performed during treatment with IFN-ß, the last of which 6 years after commencement of treatment.

The relapse rate, disability as measured by the Expanded Disability Status Scale (EDSS), and MRI parameters.

Including Gd-enhancing lesion load (Gd-LL), T₂ hyperintense lesion load (T₂-LL) T₁ HypoIntense lesion load (T₁-LL) and SupraTentorial Brain Volume (SBV) were measured throughout the study.

The mean annual relapse rate over the 6 years was 0.52 (SD 0.67), which is significantly lower (68.6%) than the mean annual relapse rate of 1.6 observed during the 2-year period before the commencement of treatment (P < 0.01).

The median EDSS score increased from 2 to 2.5, remaining stable in 60% of the patients.

From the baseline scan to the final scan, there was a median increase of 7% in the T₂-LL and 23.9% in the T₁-LL, whilst SBV decreased by 2.7%.

The increase in the EDSS over the course of the study was significantly correlated with a reduction in Brain Volume (r = 0.46, P = 0.001).

Greater Brain Damage at baseline, as measured by both T₂-LL and T₁-LL, was significantly associated with an increase in disability over the 6 years (r = 0.44, P = 0.0009; r = 0.50, P = 0.0007, respectively).

This study shows a sustained effect of IFN-ß on the relapse rate, which is lower than during the 2 years before treatment commencement. More than half the patients showed an improvement or stabilization in the EDSS score.

The increment in disability was correlated with the development of Brain Atrophy but not with increases in lesion burden.

Finally, the finding that the extent of lesion burden at the baseline was a strong predictor of increasing disability.

Suggests that IFN-ß treatment might have a moderate effect in modifying the Multiple Sclerosis (MS) disease course over 6 years unless preventive treatment is started early.

Brain Atrophy in Multiple Sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit.

Little is known about the rate of Atrophy in specific Brain Regions in relation to specific clinical deficits.

We determined the displacement of the Brain surface between two T₁-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly disabled MS patients.

Voxel- and cluster-wise permutation-based statistics were used to identify Brain Regions in which Atrophy development was significantly related to:

Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT). Clusters were considered significant at a corrected cluster-wise p-value of 0.05.

Worse EDSS change-score and worse follow-up EDSS were related to Atrophy development of PeriVentricular and BrainStem regions and right-sided Parietal, Occipital and Temporal regions.

Worse PASAT at follow-up was significantly related to Atrophy of the Ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to Atrophy around the Ventricles and of the BrainStem.

Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the Atrophy of widely distributed peripheral regions, as well as Atrophy of PeriVentricular and BrainStem regions.

Our findings suggest that decline in ambulatory function is related to Atrophy of Central Brain Regions exclusively.

Whereas decline in Neurologically more complex tasks for coordinated hand function is related to Atrophy of both Central and Peripheral Brain Regions.

Multiple Sclerosis (MS) is no longer considered to be simply an Autoimmune Disease.

In addition to inflammation and DeMyelination, Axonal Injury and Neuronal loss underlie the accumulation of disability and the disease progression.

Specific treatment strategies should thus aim to act within the Central Nervous System (CNS) by interfering with both NeuroInflammation and NeuroDegeneration.

Specific treatment strategies to Autoimmune Neurological Disorders should aim to act within the CNS by interfering with both NeuroInflammation and NeuroDegeneration.

The cumulative effect of Glatiramer Acetate (GA; Copaxone(R), Copolymer 1), an approved drug for the treatment of MS:

Reviewed herewith, draws a direct linkage between anti-inflammatory ImmunoModulation, NeuroProtection, NeuroGenesis, and therapeutic activity in the CNS.

GA treatment augmented the three processes characteristic of NeuroGenesis, namely, Neuronal Progenitor Cell proliferation, migration, and differentiation.

The newborn Neurons manifested massive migration through exciting and dormant migratory pathways, into injury sites in Brain regions.

Which do not normally undergo NeuroGenesis, and differentiated to mature Neuronal phenotype, thus, counteracting the NeuroDegenerative course of disease.

The plausible mechanism underlying this multifactorial effect is the induction of GA-reactive T-Cells in the periphery.

And their infiltration into the CNS, where they release ImmunoModulatory Cytokines and Neurotrophic Factors in the injury site.

The French West Indies (FWI), i.e., the islands of Martinique and Guadeloupe, have recently experienced the emergence of Multiple Sclerosis (MS).

This epidemiological upheaval followed a return migration of the FWI population that had previously migrated to continental France.

The MS prevalence was 14.8/10(5) (95% CI: 11.9-17.7) on Dec. 31, 1999 and its mean annual incidence was 1.4/10(5) (95% CI: 1.0-1.8) for the period July 1997 to June 2002.

The prevalence of MS in Martinique, that received more return migration, is higher than that of Guadeloupe (21.0/10(5) vs. 8.5/10(5)).

This emergence of MS has been accompanied also by an inversion of its clinical spectrum, with recurrent NeuroMyelitis Optica accounting for only 17.8% of cases.

The standardized ratio of the incidence of MS among migrants is 1.71 (95% CI: 1.19-2.38; P < 0.01) and if migration to continental France occurred before the age of 15 it is 4.05 (95% CI: 2.17-6.83; P < 0.0001).

According to recent data, a drastic reduction in exposure to sunlight and to intestinal parasites during childhood, found preferentially among migrants, are possible environmental factors responsible for this emergence.

The Cannabis plant (Cannabis sativa) has been known by many names but the question remains 'Can we call it medicine?'

There has been renewed interest in the value of cannabis for the control of NeuroInflammatory conditions such as Multiple Sclerosis, where it has been shown to have some effect on Spasticity and Pain both experimentally and in clinical trials in humans.

However, in addition to symptom control potential, the question remains whether Cannabinoids can modify the NeuroInflammatory element which drives Relapsing Neurological attacks and the accumulation of progressive disability.

In experimental studies it has been recently shown that synthetic Cannabinoids can affect the Immune Response both:

1. Indirectly via CB(1) Receptor-Mediated Signalling Nerve Centres controlling the systemic release of ImmunoSuppressive molecules
2. Directly by CB(2) Receptor-Mediated Inhibition of Lymphocyte and Macrophage/Microglial Cell function

However, these ImmunoSuppressive possibilities that would limit the frequency of Relapsing attacks will probably not be realized clinically, following use of medical Cannabis, due to dose constraints.

However, Cannabinoids may still affect the Glial response within the damaged Central Nervous System, which facilitate the slow, Degenerative processes that account for Progressive NeuroDegeneration.

And, therefore may have utility in addition to value of Cannabis-related drugs for symptom control.

British Journal of Pharmacology (2007) 152, 649-654; doi:10.1038/sj.bjp.0707458; published online 24 September 2007.

Introduction
In this study, we investigated the influence of in vivo disease pathology (measured as Magnetic Resonance Imaging (MRI) lesion load and Brain Volume reduction) on Cognitive functioning.

Especially the Speed Of Processing, in Multiple Sclerosis (MS) patients.

Since MS is characterized by Cognitive Slowing rather than impaired accuracy, we used the Amsterdam NeuroPsychological Tasks (ANT) program, a computerized test proven to be very sensitive to Cognitive slowing in MS patients.

Methods
Thirty-two patients performed the ANT and underwent MRI scanning.

Using the ANT computerized tests, we investigated Focused, Divided, Sustained Attention, Executive function and Psychomotor function.

And, examined associations of speed, speed fluctuation and accuracy of performance of these tests with MRI lesion load and Brain Volume Parameters.

Results
A decrease in the speed of processing and response speed stability, and a decrease in psychomotor accuracy and stability were clearly associated with less Brain Volume.

And, with higher lesion loads, in particular at Frontal and Occipital areas.

Correlations with Brain Volume reduction were found for all domains, except for Visuo-Spatial processing.

In particular, speed and speed fluctuation scores correlated with Brain Volume reduction, while accuracy of performance, in general, did not correlate.

Only some test speed scores and speed fluctuation scores correlated with lesion load measurements.

Conclusion
This study shows that, in MS patients, accuracy of processing is not compromised unless high Working Memory demands are involved.

Problems in NeuroCognitive functioning in MS are mainly modulated by speed and stability of speed processing, in particular when Attention-demanding controlled information processing is required.

Abnormalities in these domains are most strongly associated with Brain Volume Loss, confirming that pathology beyond focal lesions is important in MS.

We sought to identify clinical characteristics and socio-demographic variables associated with longitudinal patterns of Fatigue in Multiple Sclerosis (MS) patients.

A questionnaire including the Fatigue Severity Scale (FSS) was mailed to a community sample of 502 MS patients three times 1 year apart.

Three patterns of Fatigue were defined: persistent Fatigue (PF) (mean FSS score >/=5 at all time-points), Sporadic Fatigue (SF) (mean FSS score >/=5 at one or two time-points) and No Fatigue (mean FSS score < 5 at all time-points).

Among the 267 (53%) patients who responded at all time-points, 101 [38%, 95% confidence intervals (CI) 32-44] had persistent, 98 (37%, 95% CI 31-43) sporadic and 68 (25%, 95% CI 20-31) no fatigue.

Persistent and sporadic Fatigue were more common in patients with, increased Neurological Impairment (P < 0.001):

Primary /Progressive MS (P = 0.01), Insomnia (P < 0.001), Heat Sensitivity (P < 0.001), sudden-onset Fatigue (P < 0.001) or mood disturbance (P < 0.001) compared with patients Without Fatigue.

Multivariable analysis showed that Depression (PF P = 0.02, SF P < 0.001), Heat Sensitivity (PF P = 0.04, SF P = 0.02) and Physical Impairment (PF P = 0.004, SF P = 0.01) were associated with both sporadic and persistent Fatigue.

About 75% of the patients had persistent or sporadic Fatigue over a 2 years observation period.

Multivariable analyses confirmed a significant association between levels of Depression, Physical Impairment and persistent Fatigue.

Background
Fatigue is one of the most common disabling symptoms in patients with Multiple Sclerosis (MS), but the putative role of ProInflammatory Cytokines remains to be elucidated.

Methods
Thirty-seven patients (27 women, 10 men) with Relapsing/Remitting (n = 29) and Secondary/Progressive (n = 8) MS, aged 41.0 +/- 10.2 years, were studied.

Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for Interferon-gamma (IFN-γ) Tumor Necrosis Factor-alpha (TNF-) and InterLeukin-10 (IL-10) were measured by real time RT PCR.

Autonomic function was evaluated by standard tests for ParaSympathetic and Sympathetic function, as well as by Serum levels of NorEpinephrine and Epinephrine.

Results
Median levels of TNF- mRNA expression were significantly higher in MS patients with (FSS > or = 4.0 and > or = 5.0, n = 26 and n = 14, respectively).

Than in those Without Fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression.

Cytokine levels were not correlated to autonomic tests or to Serum Catecholamine levels.

Conclusions
These results suggest that TNF-, as a principal ProInflammatory mediator, is associated with MS-related Fatigue.

This is in support of a pathogenic role of the MS-related inflammatory process in the development of Fatigue.