Multiple Sclerosis PathoGenesis

Diffusion Tensor Imaging (DTI) investigates Brain tissue microstructure in vivo. In Multiple Sclerosis (MS) Wallerian Degeneration of Axons traversing focal lesions is a potential mechanism of damage in Normal-Appearing White Matter.

The present study investigated the relationship between DTI-derived indices in the Normal-Appearing Corpus Callosum (CC) and the Lesion Loads (LLs) in connected Cerebral regions.

In vivo evidence for this hypothesis is limited. DTI was performed in 39 MS patients and in 21 age-matched controls.

Fractional Anisotropy (FA) and Mean Diffusivity (MD) were estimated in the Genu, Body and Splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = -0.56 and r = 0.54, p < 0.0001).

The LL of individual Cerebral Lobes correlated with both FA and MD in the corresponding Callosal regions, with the Body showing the strongest correlations with Frontal and Parietal LL (p < 0.0001).

The strong correlations between DTI indices in the CC and the extent of lesions in connected Brain regions support the hypothesis that Wallerian Degeneration of Axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS.

MRI is a very sensitive imaging modality, however with relatively low specificity.

The aim of this work was to determine the potential of image post-processing using 3D-tissue segmentation technique for identification and quantitative characterization of IntraCranial lesions primarily in the White Matter.

Forty subjects participated in this study:
1. 28 with Brain Multiple Sclerosis (MS)
2. 6 with SubCortical Ischemic Vascular Dementia (SIVD)
3. 6 with White Matter Lacunar Infarcts (LI)

In routine MRI these pathologies may be almost indistinguishable.

The 3D-tissue segmentation technique used in this study was based on three input MR images (T₁, T₂-weighted, and Proton Density).

A modified k-Nearest-Neighbor (k-NN) algorithm optimized for maximum computation speed and high quality segmentation was utilized.

In MS Lesions, two very distinct subsets were classified using this procedure. Based on the results of segmentation one subset probably represent Gliosis, and the other Edema and DeMyelination.

In SIVD, the segmented images demonstrated homogeneity, which differentiates SIVD from the heterogeneity observed in MS.

This homogeneity was in agreement with the general histological findings. The LI changes PathoPhysiologically from subacute to chronic.

The segmented images closely correlated with these changes, showing a central area of Necrosis with Cyst formation surrounded by an area that appears like reactive Gliosis.

In the chronic state, the Cyst intensity was similar to that of CSF, while in the subacute stage, the peripheral rim was more prominent.

Regional Brain lesion load were also obtained on one MS patient to demonstrate the potential use of this technique for Lesion Load measurements.

The majority of lesions were identified in the Parietal and Occipital Lobes.

The follow-up study showed qualitatively and quantitatively that the calculated MS load increase was associated with Brain Atrophy represented by an increase in CSF volume as well as decrease in "normal" Brain tissue volumes.

Importantly, these results were consistent with the patient's clinical evolution of the disease after a six-month period.

In conclusion, these results show there is a potential application for a 3D tissue segmentation technique to characterize White Matter lesions with similar intensities on T₂-weighted MR images.

The proposed methodology warrants further clinical investigation and evaluation in a large patient population.

Multiple Sclerosis (MS) is an Inflammatory DeMyelinating Disease of the Central Nervous System, and the most common Neurological Disease affecting young adults. Multiple Sclerosis is a clinically heterogeneous disorder.

It is believed to be an AutoImmune Disease, with Cell-mediated and Humoral Responses directed against Myelin proteins.

This hypothesis largely comes from pathological parallels with an animal model, Experimental AutoImmune EncephaloMyelitis (EAE).

AutoImmunity to Myelin proteins in humans may be inadvertently triggered by microbes which have structural homologies with Myelin Antigens (Molecular Mimicry).

As with other AutoImmune Diseases, susceptibility to MS is associated with certain MHC Genes/Haplotypes.

Full genomic screening of mutiplex families has underscored the role for MHC Genes as exerting moderate but the most significant effects in susceptibility.

The primary target AutoAntigen in MS has yet to be definitively identified, but as well as the major Myelin proteins.

It is now clear that minor Myelin components, such as Myelin Oligodendrocyte Glycoprotein (MOG) may play a primary role in disease initiation.

This review examines the current knowledge about the Aetiology and PathoGenesis of MS, and the important similarities with EAE.

A better understanding of the molecular mechanisms of AutoImmune pathology will provide the basis for more rational ImmunoTherapies to treat MS.

The main issues in Multiple Sclerosis research revolve around four fundamental questions.

1. What initiates the disease: AutoImmune T-Cells, a Virus, or a Toxin?
   
   
2. Is the Inflammatory Response primary to the development of DeMyelination, or is it a secondary response to injury?
   
   
3. Is the Oligodendrocyte, the Myelin-producing cell, the primary target?
   
   
4. How can Myelin repair be promoted? This review focuses on the controversies revolving around these important questions.

Although many investigators believe that T-Cell receptors on CD4⁺ Cells interact with Myelin Antigens to initiate an Inflammatory cascade that leads to Myelin destruction.

Others maintain that a Viral agent may have a direct or indirect role in the PathoGenesis of Multiple Sclerosis.

The concept that the Immune System contributes to the tissue destruction in Multiple Sclerosis is generally accepted.

However, the debate about cause versus consequence of the pathologic process remains unresolved, as does the identification of the initial event or focus of the damage.

Electron microscopic studies have disclosed evidence of ReMyelination (albeit often incomplete) in lesions of Multiple Sclerosis.

Enhanced understanding of the factors limiting ReMyelination could help formulate strategies to promote repair.

By innovative experimental design and application of available molecular techniques, the answers to these questions may provide insights on how to prevent or treat Multiple Sclerosis.

Multiple Sclerosis (MS) is a DeMyelinating Disease during which an AutoImmune reaction is directed against Oligodendrocytes.

Alterations of normal Myelin structure or Oligodendrocyte metabolism may be primary events that influence the susceptibility to MS.

Once triggered, the Immune System attacks and destroys Myelin and the Myelin forming cell.

Evidence is presented that the Oligodendrocyte responds to the attack by Immune Cells and their secreted products through modulation of its metabolism and Gene expression.

Cytokines, ImmunoGlobulins, and Complement Complexes may elicit a survival response in the Oligodendrocytes, involving the induction of Heat Shock Proteins and other protective molecules.

The possibility of manipulating these complex Glial Cell functions and controlling their pathologic interactions with Immune Cells will illuminate how Myelin damage can be contained and how the injured tissue can be repaired.

One of the characteristic features of Microglia is their rapid activation in response to Injury, Inflammation, NeuroDegeneration, Infection, and Brain Tumors.

This review focuses on the role of the Microglia in Multiple Sclerosis (MS), a Chronic Inflammatory DeMyelinating Disease of the Central Nervous System (CNS), and in the animal model of MS, Experimental Allergic EncephaloMyelitis (EAE).

Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of ProInflammatory Cytokines, Matrix MetalloProteinases, and Free Radicals.

In addition, activated Microglia serve as the major Antigen Presenting Cell in the CNS, likely contributing to aberrant Immune reactivity at this site.

A mechanistic understanding of the way in which Microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS AutoImmune Disease.

Comment in: J Mol Med 1997 Mar;75(3):164

It is postulated that the PathoGenesis of DeMyelination in Multiple Sclerosis (MS) might lie in the cooperative effect of a T-Cell response against one Myelin Antigen (e.g. Myelin Basic Protein - MBP).

And, a B-Cell response against a second Myelin component which may act as a Hapten or a carrier for the primary Antigen.

The hypothesis is based upon recent experiments in guinea pigs in which the EncephalitoGenicity of MBP was enhanced by the Myelin GlycoLipid, (MOG).

This PathoGenetic mechanism might be analogous to AntiBody-dependent, Cell-mediated DeMyelination.

Based upon this assumption, therapeutic trials in MS should take into consideration the possibility that instead of MBP alone, MBP might be more effective in combination with a Lipid Hapten.

DeMyelination and Axonal Loss have been described as the histological hallmarks of inflammatory lesions of Multiple Sclerosis (MS) and are the pathological correlates of persistent Disability.

However, the Immune mechanisms underlying Axonal Damage in MS remain unknown.

Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded CerebroSpinal Fluid (CSF) B-Cells to show the role of an Anti-Axon Immune response in the Central Nervous System (CNS) in MS.

The cellular and subcellular distribution of the Antigen(s) recognized by these CSF-derived clonal scFv AntiBodies (CSFC-scFv Abs) was studied by ImmunoChemical staining of Brain Tissues obtained at autopsy from patients with MS.

Immunochemistry showed specific binding of CSFC-scFv Abs to Axons in acute MS lesions. The stained Axons showed three major types of Axonal pathological changes:

There is increasing evidence that Multiple Sclerosis (MS) is not only characterized by Immune mediated inflammatory reactions but also by NeuroDegenerative processes.

In NeuroDegenerative Diseases, Neuronal and Axonal loss is mediated by Oxidative Stress and ExcitoToxicity which constitute a final common toxic pathway.

Importantly, Peroxynitrite is the key mediator of those two intertwined pathomechanisms.

In MS, Peroxynitrite is consistently associated with active lesions and produces highly toxic nitrating and oxidizing radical species that alter lipid, protein, DNA and Mitochondrial structures and functions.

During the Remitting phase, Peroxynitrite participates to Neuron and Oligodendrocyte damage in association with inflammatory processes.

During the Chronic phase, Peroxynitrite contributes to self-perpetuating mechanisms responsible for disease progression.