MS Abstracts 02a-2g4

Normal-Appearing White Matter (NAWM) in established Multiple Sclerosis has been shown to be abnormal using a variety of Magnetic Resonance (MR) techniques, including Proton MR Spectroscopy (₁H-MRS), although the stage at which these changes first appear is less clear.

Using a 1.5 T scanner and single-voxel ₁H-MRS [TR 3000 ms, TE 30 ms, Point-Resolved Spectroscopy (PRESS) localization], we determined NAWM metabolite concentrations in 96 patients a mean of 19 weeks (range 12-28 weeks) after onset of a Clinically Isolated Syndromes (CIS) suggestive of Multiple Sclerosis and in 44 healthy control subjects.

Absolute concentrations of N-AcetylAspartate, total Creatine and PhosphoCreatine (Cr), Choline-containing compounds, Glutamate plus Glutamine, and Myo-Inositol (Ins) were estimated automatically using the LCModel.

Compared with control subjects, the concentration of Ins was elevated in CIS NAWM (mean 3.31 mM, SD 0.86 versus mean 3.82 mM, SD 1.06; P = 0.001).

The increase in Ins was also seen in the patient subgroup with abnormal T₂-weighted MRI (mean 3.88 mM, SD 1.10; P = 0.001) and in those who satisfied the McDonald Criteria for Multiple Sclerosis (mean 4.04 mM, SD 1.31; P = 0.001).

An increase in Cr was also observed in CIS NAWM (P = 0.023), but other metabolites did not significantly differ between the whole CIS group and control subjects. There was no significant correlation between NAWM Ins and T₂ lesion load.

The early increase in Ins may reflect a process of pathogenic importance in Multiple Sclerosis NAWM. Follow-up studies will investigate whether the increase in NAWM Ins is of prognostic importance for future relapses and disability.

Purpose
To prospectively determine hemodynamic changes in the Normal-Appearing White Matter (NAWM) of patients with Relapsing/Remitting Multiple Sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced Perfusion Magnetic Resonance (MR) imaging.

Materials And Methods
Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T₁-weighted, fluid-Attenuated Inversion Recovery, and T₂-weighted images).

And, dynamic susceptibility contrast-enhanced T₂*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years).

Absolute Cerebral Blood Volume (CBV), absolute Cerebral Blood Flow (CBF), and Mean Transit Time (MTT) (referenced to an arterial input function by using an automated method).

Were determined in PeriVentricular, intermediate, and SubCortical regions of NAWM at the level of the Lateral Ventricles.

Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients.

Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of Brain regions in terms of each perfusion measure.

Results
Each region of NAWM in patients with RR-MS had significantly decreased CBF (P < .005) and prolonged MTT (P < .001) compared with the corresponding region in control patients.

No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined.

In control patients, PeriVentricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS.

Conclusion
The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls.

Copyright RSNA, 2004

The aim of the current study was to perform T₂ relaxation time measurements in Multiple Sclerosis (MS) patients and correlate them with Magnetization Transfer Ratio (MTR) measurements.

In order to investigate in more detail the various HistoPathological changes that occur in lesions and Normal-Appearing White Matter (NAWM).

A total number of 291 measurements of MTR and T₂ relaxation times were performed in 13 MS patients and 10 age-matched healthy volunteers.

Measurements concerned MS plaques (105), NAWM (80), and "Dirty" White Matter (DWM; 30), evenly divided between the MS patients, and Normal White Matter (NWM; 76) in the healthy volunteers.

BiExponential T₂ relaxation-time analysis was performed, and also possible linearity between MTR and mean T₂ relaxation times was evaluated using linear regression analysis in all subgroups.

BiExponential relaxation was more pronounced in "black-hole" lesions (16.6%) and homogeneous enhancing plaques (10%), whereas DWM, NAWM, and mildly HypoIntense lesions presented BiExponential behavior with a lower frequency(6.6, 5, and 3.1%, respectively).

Non-enhancing Isointense lesions and Normal White Matter did not reveal any BiExponential behavior.

1. Linear regression analysis between MonoExponential T₂ relaxation time and MTR measurements demonstrated excellent correlation for DWM( r=-0.78, p < 0.0001)
2. Very good correlation for black-hole lesions( r=-0.71, p=0.002)
3. Good correlation for IsoIntense lesions( r=-0.60, p=0.005)
4. Moderate correlation for mildly HypoIntense lesions( r=-0.34, p=0.007)
5. Non-significant correlation for homogeneous enhancing plaques, NAWM, and DWM

BiExponential T₂ relaxation-time behavior is seen in only very few lesions (mainly on plaques with high degree of DeMyelination and Axonal Loss).

A strong correlation between MTR and MonoExponential T₂ values was found in regions where either inflammation or DeMyelination predominates; however, when both pathological conditions coexist, this linear relationship is lost.

The purpose of this review of the literature is to analyze the contribution of Magnetization Transfer (MT) imaging techniques in understanding the various characteristics of Multiple Sclerosis. MT imaging allows contrast augmentation by use of Magnetization Transfer contrast.

MT imaging allows lesion characterization by means of quantification of the degree of signal loss due to Magnetization Transfer contrast by a Magnetization Transfer ratio.

It is used as an indicator of tissue destruction; in particular, to DeMyelination. Both applications of MT imaging in Multiple Sclerosis are studied in this review, as well as the methodological and technical limitations.

In an attempt to clarify whether T₁ relaxation time mapping may assist in characterizing the pathological Brain tissue substrate of Multiple Sclerosis (MS).

We compared the T₁ relaxation times of lesions, areas of Normal-Appearing White Matter (NAWM) located proximal to lesions, and areas of NAWM located distant from lesions in 12 patients with the Relapsing/Remitting and 12 with the Secondary/Progressive (SP) subtype of disease.

Nine healthy volunteers served as controls. Calculated mean T₁ values were averaged across all patients within each clinical group, and comparisons were made by means of the Mann-Whitney U-test.

Significant differences were found between all investigated Brain regions within each clinical subgroup. Significant differences were also detected for each investigated Brain region among clinical subgroups.

While T₁ values of NAWM were significantly higher in patients with SP disease than in Normal White Matter (NWM) of controls, no differences were detected when corresponding Brain areas of patients with RR MS were compared with NWM of controls.

T₁ maps identify areas of the Brain that are damaged to a different extent in patients with MS, and may be of help in monitoring disease progression.

Objective
The most recent diagnostic criteria for Multiple Sclerosis (MS) ascertain that findings from Spinal Cord MRI can be used to demonstrate dissemination in space.

Because little is known about the prevalence and characteristics of Cord lesions early in the disease, the authors studied the prevalence of Spinal Cord abnormalities in patients with early-stage MS and assessed their impact on diagnostic classification.

Methods
The Brains and Spinal Cords of 104 recently diagnosed patients with MS were examined. Median interval between first symptom and diagnosis was 18.4 months.

The Brain MRI protocol included before and after Gadolinium Axial T₁-weighted conventional Spin-Echo sequences and Dual-Echo Spin-Echo images.

For Spinal Cord MRI, Sagittal cardiac-triggered Dual-Echo T₂-weighted and Sagittal T₁-weighted Spin-Echo images were included.

Clinical assessment for each patient included age, sex, clinical signs for Spinal Cord involvement, and Expanded Disability Status Scale.

Results
Abnormal Cord MRIs were found in 83% of patients, usually with only focal lesions. Diffuse Cord Abnormalities were found in 13% of patients, although in isolation they were found in only three patients.

Focal Cord lesions were often multiple (median number, 3.0), small (median, 0.8 Vertebral Segments), and primarily (56.4%) situated in the Cervical Spinal Cord. In 68 of 104 patients (65.4%), two or more focal lesions were visible on Spinal Cord images.

The criteria for dissemination in space, as defined in the McDonald Criteria for the Brain, were met in only 66.3% of the patients. This percentage increased to 84.6% when Spinal Cord MRI abnormalities were also included.

Conclusion
Spinal Cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.

We used microarrays to compare the gene expression profile in active lesions and donor-matched Normal-Appearing White Matter (NAWM) from Brain autopsy samples of patients with Secondary/Progressive Multiple Sclerosis (MS).

With that from controls who died from Non-Neurological Diseases. The 123 Genes in lesions, and 47 genes in NAWM were differentially expressed.

Lesions distinguished from NAWM by a higher expression of Genes related to ImmunoGlobulin synthesis and Neuroglial differentiation, while Cellular Immune Response elements were equally dysregulated in both tissue compartments.

Current results provide molecular evidence of a continuum of dysfunctional homeostasis and inflammatory changes between lesions and NAWM, and support the concept of MS pathogenesis being a generalized process that involves the entire CNS.

A novel method for the visual and quantitative analysis of the geometrical relationship between the Vascular architecture of the Brain and White Matter Pathology is presented.

The Cerebro Vascular System is implicated in the pathogenesis of many diseases of the Cerebral White Matter, for example, Stroke, MicroCerebroVascular Disease, and Multiple Sclerosis (MS).

In our work, White Matter lesions and Vessels are depicted using Magnetic Resonance Imaging (MRI) and extracted using image analysis techniques. We focus on measuring distance relationships between White Matter lesions and Vessels, and distribution of lesions with respect to Vessel Caliber.

Vascular distance maps are generated by computing for each voxel the Euclidean distance to the closest vessel. Analogously, radius maps assign the radius of the closest vessel to each Voxel in the image volume.

The distance and radius maps are used to analyze the distribution of lesions with respect to the vessels' locations and their calibers. The method was applied to three MS patients to demonstrate its functionality and feasibility.

Preliminary findings indicate that larger MS lesions tend to be farther from detected vessels and that the caliber of the vessels nearest to larger lesions tends to be smaller, suggesting a possible role of relative HypoPerfusion or Hypoxia in lesion formation.

Objective
We used Diffusion Tensor MRI to redefine the size of Multiple Sclerosis (MS) plaques on Fractional Anisotropy (FA) maps.

Materials And Methods
Thirty-six White Matter (WM) plaques were identified in 20 patients with MS. Plaque FA was measured by placing Regions Of Interest (ROIs) on plaques on Diffusion Tensor images.

We compared FA values in identical mirror-image ROIs placed on Normal-Appearing WM in the ContraLateral Hemisphere.

This comparison showed a mean decrease in FA of 41% in plaques, serving as the threshold for outlining abnormal regions in Normal-Appearing WM surrounding plaques. ROIs were placed around each plaque and FA values were compared with those in the mirror-image ROIs.

Combined areas of PeriLesional Normal-Appearing WM with 40% or more FA reduction plus plaque were compared with the areas of abnormality on T₂-weighted images using a paired Student's t test. A p value of 0.05 or less was considered significant.

Results
Mean plaque area was 60 mm(2) (range, 15-103 mm(2)), mean plaque FA was 0.251 (range, 0.133-0.436), and mean FA of ContraLateral Normal-Appearing WM was 0.429 (range, 0.204-0.712).

Applying a threshold of 40% FA reduction, mean combined area of abnormal WM (including plaque seen on T₂-weighted sequences) was 87 mm(2) (range, 30-251 mm(2)) or 145% of the mean Plaque area that was seen on T₂-weighted images (p < 0.001).

Conclusion
Using an operator-defined threshold of abnormal FA values based on plaque Anisotropy characteristics, we saw a statistically significant increase in plaque size.

Primary/Progressive Multiple Sclerosis (MS) differs from the more common form of MS which has an initial Relapsing/Remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment.

The lesions in Primary/Progressive MS tend to be more diffuse, less inflammatory and less likely to ReMyelinate than those occurring in Relapsing/Remitting MS and Secondary/Progressive MS; there are also fewer focal lesions in the Brain in Primary/Progressive MS.

Recent evidence suggests that AntiBodies to Central Nervous System (CNS) Antigens have an important role in disease progression. Such AntiBodies could cause DeMyelination, inhibit ReMyelination and cause Axonal destruction.

Ongoing Immune attack by AutoAntiBody and lack of CNS repair could be responsible for the gradually increasing disability in Primary/Progressive MS.

Further research on the B-Cell and AutoAntiBody response in Primary/Progressive MS might lead to advances in diagnosis and treatment. Inhibition of AutoAntiBody production by inducing B-Cell Apoptotic with Rituximab is a potential new therapy for Primary/Progressive MS.

Chronic disabilities in Multiple Sclerosis are believed to be due to Neuron damage and degeneration, which follow ReMyelination failure.

Due to the presence of numerous Oligodendrocyte Precursors inside DeMyelination plaques, one reason for DeMyelination failure could be the inability of Oligodendrocyte Precursor Cells to turn into Myelinating Oligodendrocytes.

In this study, we show that Thyroid Hormone enhances and accelerates ReMyelination in an experimental model of chronic DeMyelination, i.e., Experimental Allergic Encephalomyelitis in congenic female Dark Agouti rats immunized with complete guinea pig Spinal Cord.

Thyroid Hormone, when administered during the acute phase of the disease, increases expression of platelet-derived Growth Factor alpha Receptor, restores normal levels of Myelin Basic Protein mRNA and protein

And, allows an early and Morphologically competent reassembly of Myelin Sheaths. Moreover, Thyroid Hormone exerts a NeuroProtective effect with respect to Axonal pathology.

Glatiramer Acetate (GA) therapy of patients with Multiple Sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T-Cells is consistently observed and associated with clinical benefit in a human AutoImmune Disease.

We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 Cytokine Network of Monocytes in vivo.

We further show that Th1- or Th2-polarized GA-reactive T-Cells isolated from untreated or treated MS patients mediate Type 1 and 2 APC differentiation of human Monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T-Cells, respectively.

These observations are extended to human Microglia, providing the first demonstration of Type 2 differentiation of CNS-derived APCs.

Finally, we confirm that the fundamental capacity of polarized T-Cells to reciprocally modulate APC function is not restricted to GA-reactive T-Cells, thereby defining a novel and dynamic positive feedback loop between human T-Cell and APC responses.

In the context of MS, we propose that GA therapy results in the generation of Type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients.

In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic Immune modulation.