MS Abstracts 06b-2g5

Background
A pathological classification has been developed of early active Multiple Sclerosis (MS) lesions that reveals four patterns of tissue injury:

1. T-Cell/Macrophage associated
2. AntiBody/Complement associated
3. Distal Oligodendrogliopathy
4. Oligodendrocyte degeneration in the PeriPlaque White Matter

Mechanisms of DeMyelination in early MS may differ among the subgroups. Previous studies on biopsied MS have lacked ClinicoPathological correlation and follow up. Critics argue that observations are not generalizable to prototypic MS.

Objective
To describe the ClinicoPathological characteristics of the MS Lesion Project biopsy cohort.

Methods
Clinical characteristics and disability of patients with pathologically confirmed Inflammatory DeMyelinating Disease (excluding ADEM) classified ImmunoPathologically (n = 91) and patients from the Olmsted County MS prevalence cohort (n = 218) were determined.

Results
Most patients who underwent biopsy and had pathologically proved DeMyelinating Disease ultimately developed Definite (n = 70) or Probable (n = 12) MS (median follow up 4.4 years).

Most had a Relapsing/Remitting course and 73% were ambulatory (EDSS < or =4) at last follow up.

Nine patients remained classified as having an isolated DeMyelinating Syndrome at last follow up. Patients with different ImmunoPathological patterns had similar clinical characteristics.

Although presenting symptoms and sex ratios differed, the clinical course in biopsy patients was similar to the prevalence cohort.

Median EDSS was < 4.0 in both cohorts when matched for disease duration, sex, and age.

Conclusions
Most patients undergoing biopsy, who had pathologically confirmed DeMyelinating Disease, were likely to develop MS and remain ambulatory after a median disease duration of 4.4 years.

The ImmunoPathological patterns lacked specific clinical correlations and were not related to the timing of the biopsy.

These data suggest that pathogenic implications derived largely from MS biopsy studies may be extrapolated to the general MS population.

Background
There may be difficulties in the use of self report measurements in patients with Cognitive Impairment or serious mood disturbances which interfere with reliable self assessment, as may be the case in Multiple Sclerosis (MS).

In such cases proxies may provide valuable information. However, before using any questionnaires in a proxy sample, the questionnaire should be evaluated for proxy use.

Objective
To evaluate the psychometric properties of the 29 item Multiple Sclerosis Impact Scale (MSIS-29) when used by proxies of MS patients.

Methods
A sample of 62 partners of MS patients completed the MSIS-29.

The data were evaluated for the psychometric criteria of the MSIS-29, including data quality, scaling assumptions, acceptability, reliability, validity, and responsiveness.

Results
Psychometric evaluation was satisfactory; data quality was high, and scaling assumptions and acceptability were good.

Reliability was high (alpha>0.80). Findings were consistent with results of a psychometric evaluation in a patient sample.

Conclusions
The MSIS-29 can be used reliably in proxies of patients with MS. As a next step the relation between data obtained from patients and proxies needs to be studied, focusing on factors that may affect agreement and discrepancies.

Disease progression in Multiple Sclerosis (MS) - an Inflammatory DeMyelinating and NeuroDegenerative Disease with a presumed T-Cell driven Autoimmune origin - has long been hypothesized to be associated with Stress.

However, this notion has only recently been supported by prospective clinical studies.

Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the Immune System and the two major Stress Response Systems, the Hypothalamo-Pituitary-Adrenal (HPA) Axis and the Autonomic Nervous System.

Insensitivity to CorticoSteroid and beta-Adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA Axis has been linked to NeuroDegeneration and increased disability.

Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of Stress Response Systems in MS pathogenesis and progression.

Objective
To define the nature and the temporal evolution of Neuronal/Axonal injury in patients at the earliest clinical stage of Multiple Sclerosis (MS), using Whole Brain N-AcetylAspartate (WBNAA) proton MR Spectroscopy (1H-MRS).

Methods
Thirty-five patients at presentation with Clinically Isolated Syndromes (CIS) and MRI evidence of disease dissemination in space were studied.

The following scans of the Brain were acquired within 3 months from the onset of the disease and after 12 months:

• Dual-Echo
• WBNAA 1H-MRS
• Pre- and postcontrast T₁-weighted

The same scans were obtained in 12 age-matched healthy subjects, without contrast administration.

In patients, conventional MRI scans were also repeated 3 months after the first scanning session, to assess the presence of early disease dissemination in time (DIT).

Results
Over the study period, 24 patients showed MRI evidence of disease DIT, thus fulfilling the criteria for a diagnosis of MS.

The average WBNAA amount was lower in CIS patients than in controls both at baseline (13.7 vs 16.9 mM, p < 0.001) and at 1-year follow-up (12.6 vs 16.2 mM, p < 0.001).

But the average yearly percentage change of WBNAA did not differ between the two groups. No MRI or 1H-MRS quantities were significantly associated with the disease DIT over the study period.

Conclusion
Irreversible Brain damage associated with Axonal dysfunction occurs at a very early stage in patients with Clinically Isolated Syndromes, but it does not seem to be related with the disease evolution in the subsequent short-term period.

Diffusion imaging is a quantitative, MR-based technique potentially useful for the study of Multiple Sclerosis (MS), due to its increased pathologic specificity over conventional MRI.

And its ability to assess in vivo the presence of tissue damage occurring outside T₂-visible lesions, i.e., in the so-called Normal-Appearing White and Gray Matter.

The present review aims at critically summarizing the state-of-the-art and providing a background for the planning of future Diffusion studies of MS.

Several pieces of evidence suggest that Diffusion-weighted and Diffusion Tensor MRI are sensitive to MS damage and able to detect its evolution over relatively short periods of time.

Although a significant relationship between Diffusion-weighted MRI findings and MS clinical disability was not found in the earliest studies, with improved Diffusion imaging technology correlations between Diffusion abnormalities and MS clinical aspects are now emerging.

However, the best acquisition and postprocessing strategies for MS studies remain a matter of debate and the contribution of newer and more sophisticated techniques to Diffusion Tensor MRI investigations in MS needs to be further evaluated.

Although changes in Diffusion MRI indices reflect a net loss of structural organization, at present we can only speculate on their possible pathologic substrates in the MS Brain.

Postmortem studies correlating Diffusion findings with histopathology of patients with MS are, therefore, also warranted.

Objective
To compare the effects of IntraVenous MethylPrednisolone (IVMP) in patients with Relapsing/Remitting (RR-MS), Secondary/Progressive (SP-MS) and Primary/Progressive Multiple Sclerosis (PP-MS).

Methods
Clinical and NeuroPhysiological follow-up was performed in 24 RR-MS, 8 SP-MS and 9 PP-MS patients receiving 500 mg Solu-Medrol/d during 5 days for exacerbations involving the motor system.

We used Motor Evoked Potentials (MEPs) to measure Central Motor Conduction Time (CMCT) and applied the Triple Stimulation Technique (TST) to assess conduction deficits.

The TST allows an accurate quantification of the number of conducting Central Motor Neurons, expressed by the TST amplitude ratio.

Results
There was a significant increase in TST amplitude ratio in RR-MS (p < 0.001) and SP-MS patients (p < 0.02) at day 5, paralleling an increase in muscle force.

TST amplitude ratio and muscle force remained stable at 2 months. In PP-MS, TST amplitude ratio and muscle force did not change. CMCT did not change significantly in any MS group.

Conclusions
In RR-MS and SP-MS patients, IVMP is followed by a prompt increase in conducting Central MotoNeurons paralleled by improvement in muscle force, which most likely reflects partial resolution of Central Conduction Block.

The lack of similar clinical and NeuroPhysiological changes in PP-MS patients corroborates previous clinical reports on limited IVMP efficacy in this patient group and points to PathoPhysiological differences underlying exacerbations in PP-MS.

OligoClonal IgM bands restricted to CerebroSpinal Fluid are an unfavorable prognostic marker in MS, the most common DeMyelinating Disease of the CNS.

We have attempted to identify the B-Cell subpopulation responsible for OligoClonal IgM secretion and the specificity of these bands. In addition, we explored the relationship between specificity and disease evolution.

Intrathecal B-Cell subpopulations present in 29 MS patients with OligoClonal IgM bands and 52 without them were analyzed.

A considerable increase in CD5⁺ B-Lymphocytes was found in patients with OligoClonal IgM bands.

These cells mostly secrete IgM AntiBodies recognizing nonproteic molecules. We also studied whether OligoClonal IgM bands present in CerebroSpinal Fluid of 53 MS patients were directed against Myelin Lipids.

This was the case in most patients, with PhosphatidylCholine being the most frequently recognized lipid. Disease course of 15 patients with OligoClonal IgM against Myelin lipids and 33 patients lacking them was followed.

Patients with Anti-Lipid IgM suffered a second relapse earlier, had more relapses, and showed increased disability compared with those without Anti-Lipid IgM.

The presence of Intrathecal Anti-Myelin Lipid IgM AntiBodies is therefore a very accurate predictor of aggressive evolution in MS.

Postmortem MRI-guided tissue sampling significantly enhances the yield of MS lesions in autopsy material, but so far it is unknown whether abnormalities concur with Blood-Brain Barrier

Here we sampled MS lesions with focal and diffuse abnormalities (Diffusely Abnormal White Matter; DAWM) on MRI; both were coupled to the presence of MS lesions upon NeuroPathological examination.

ExtraVascular distribution of fibrinogen, indicating BBB disturbance, was observed in so-called (p)reactive lesions that reflect discrete areas of Microglial activation without DeMyelination within an otherwise Normal-Appearing White Matter.

Leakage became more extensive in active DeMyelinating MS lesions to chronic inactive lesions. An enlargement of the PeriVascular (Virchow-Robin Space) containing infiltrated Leukocytes was associated with both DAWM and focal abnormalities on postmortem MRI.

This study shows for the first time that in MS Brain changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI.

The mechanism(s) responsible for generating the different forms of Multiple Sclerosis, Primary/Progressive (PP) and Secondary/Progressive (SP) versus Relapsing/Remitting (RR), is not well understood.

Using Myelin Oligodendrocyte Glycoprotein (MOG <=>)(92-106), we have established animal models that mimic the different types of Multiple Sclerosis.

A.SW mice develop PP or SP-Experimental Allergic Encephalomyelitis (EAE) with large areas of DeMyelination and high titers of MOG AntiBody whereas SJL/J mice develop RR-EAE with PeriVascular T-Cells and mild DeMyelination.

In A.SW Progressive EAE, we found atrophy of the Thymus, Spleen, and Lymph Nodes with depletion of T and B-Cells and massive Apoptosis, as demonstrated by ImmunoHistoChemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis.

To test whether Lymphoid Apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic Thymocytes. Injection of Apoptotic Cells resulted in greater than 20% of mice developing SP-EAE with Ataxia.

SJL/J mice with SP-EAE had large areas of DeMyelination, high MOG AntiBody Titers and Atrophic Lymphoid organs. Spleen cells from mice with progressive EAE produced less Interferon-γ than those from RR-EAE when stimulated with mitogen.

We suggest that induction of Lymphoid Apoptosis alters the balance of Th1 versus Th2 Immune Responses and increases MOG <=> AntiBody production, leading to exacerbation of DeMyelination and subsequent disease progression.

In established Multiple Sclerosis, Magnetization Transfer Ratio (MTR) Histograms reveal abnormalities of Normal-Appearing White Matter (NAWM) and Gray Matter (NAGM).

The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with Clinically Isolated Syndromes suggestive of Multiple Sclerosis.

Magnetization Transfer Imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a Clinically Isolated Syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years).

SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T₂ lesions, White Matter and Gray Matter were calculated.

Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed Multiple Sclerosis if this occurred sooner (n = 20).

Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects.

The MTR Histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the Histogram.

Mean NAWM and NAGM MTR were also reduced in the patients who developed Clinically Definite Multiple Sclerosis and Multiple Sclerosis according to the McDonald Criteria but not in the 24 patients with normal T₂-weighted Brain Magnetic Resonance Imaging (MRI).

MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of Multiple Sclerosis.

There are few longitudinal studies of Cognition in patients with Multiple Sclerosis, and the results of these studies remain inconclusive.

No serial NeuroPsychological data of an exclusively Primary/Progressive series are available.

Cross-sectional analyses have revealed significant correlations between Cognition and Magnetic Resonance Imaging (MRI) parameters in Primary/Progressive Multiple Sclerosis (PPMS).

This study investigated Cognitive and MRI change in 99 PPMS patients from five European centres for 2 years.

They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression.

The MRI parameters of T₁ HypoIntensity load, T₂ lesion load, and partial Brain volume were also calculated at each time point.

There were no significant differences between the mean Cognitive scores of the patients at year 0 and year 2.

However, one-third of the patients demonstrated absolute Cognitive decline on individual test scores.

Results indicated that initial Cognitive status on entry into the study was a good predictor of Cognitive ability at 2 years.

There was only a small number of significant correlations between changes in Cognition and changes on MRI, notably T₁ hypointensity load with the two Attentional Tasks (r = -0.266, P = 0.017; r = -0.303, P = 0.012).

It is probable that multiple factors underlie this weak relation between the Cognitive and MRI measures.

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 defence 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 defences 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.