This Is MS Multiple Sclerosis Community: Knowledge & Support

The 2009 ECTRIMS conference is wrapping up today. I went through the abstracts and will post those I found most interesting. There seem to be 3 categories of abstracts that were drawing my attention this time around, the topics are roughly:

1. early disease process
2. environment and genetics
3. clinical trial results.

Here are the early disease process abstracts with what I think are the interesting bits in bold:

Here are the abstracts on genetics and environment:

Here are the clinical trial abstracts:

do you know where we can see all the other abstracts... you know I am looking for the ones on stem cells
Carole

This statement saddens me for various reasons:

in what some believe may be the most important breakthrough related to the pathogenesis of MS since the discovery of EAE,

other statements make me think that the fast and furious back-peddle on, "In MS, the body's own immune system attacks and damages the myelin." has begun.

MS is being re-defined. Its going to be interesting to see how neurologists and pharm spin their being wrong for so long.

.

Thank You Dignan, this conference every year is a good place to keep tabs on what is happening in the MS research think tank. I appreciate your effort to bring us this research!!

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carolew, click the "scientific programme" link on the left side of this page: http://www.congrex.ch/ectrims2009/

I didn't include links because I figure they will probably take the abstracts down sooner or later, but they are all at the above link.

mose, I know what you mean about that quote, although I also look at it as the glass is half full, this discovery about the astrocytes could be HUGE. I wish they hadn't compared it to EAE, it could be far more significant than EAE. I think this avenue of research is up there with venous obstruction in how significant it could be for a full understanding of this disease. This is coming from extremely reputable MS researchers who are saying autoimmunity is wrong and a focus on the T cell activity that has been the main focus for at least the last 10 years is misguided. It's huge. I say that also because these are researchers coming right from the middle of things in the MS research world -- they are not outsiders trying to convince a group of sceptics like what Zamboni et al are facing in their battle to gain acceptance. So I think both groups are pursuing really important avenues, and Prineas et al might have an easier time getting people to change their minds.

I wish we could know how many people read the poster by Zamboni and took interest in it.

Dignan, thanks for your roundup !

--Frank

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Treatment: CCSVI both IJV ballooned 09/2010, No DMDs, Tysabri on hold after 24 Infusions, after LDN, ABX Wheldon Regime for 1 year.

thanks Dignan, I found it...

Below are a couple of Pubmed abstract that address the Prineas et al research about the earliest damage in MS being related to astrocytes. The relevance of this research doesn't depend on a belief in autoimmunity.


Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis.

Acta Neuropathol. 2009 Aug;118(2):219-33.
Wolburg-Buchholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, Wolburg H.
Institute of Pathology, University of Tübingen, Liebermeisterstrasse 8, 72076 Tübingen, Germany.

In multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), dysfunction of the blood-brain barrier (BBB) leads to edema formation within the central nervous system. The molecular mechanisms of edema formation in EAE/MS are poorly understood. We hypothesized that edema formation is due to imbalanced water transport across the BBB caused by a disturbed crosstalk between BBB endothelium and astrocytes.

Here, we demonstrate at the light microscopic and ultrastructural level, the loss of polarized localization of the water channel protein aquaporin-4 (AQP4) in astrocytic endfeet surrounding microvessels during EAE. AQP4 was found to be redistributed over the entire astrocytic cell surface and lost its arrangement in orthogonal arrays of intramembranous particles as seen in the freeze-fracture replica. In addition, immunostaining for the astrocytic extracellular matrix receptor beta-dystroglycan disappeared from astroglial membranes in the vicinity of inflammatory cuffs, whereas immunostaining for the dystroglycan ligands agrin and laminin in the perivascular basement membrane remained unchanged.

Our data suggest that during EAE, loss of beta-dystroglycan-mediated astrocyte foot process anchoring to the basement membrane leads to loss of polarized AQP4 localization in astrocytic endfeet, and thus to edema formation in EAE.

http://www.ncbi.nlm.nih.gov/pubmed/19533155



Reactive Astrocytes Form Scar-Like Perivascular Barriers to Leukocytes during Adaptive Immune Inflammation of the CNS.

J Neurosci. 2009 Sep 16;29(37):11511-22.
Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, Sofroniew MV.
Departments of Neurology and Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1763.

Factors that regulate leukocyte entry and spread through CNS parenchyma during different types of CNS insults are incompletely understood. Reactive astrocytes have been implicated in restricting the spread of leukocytes from damaged into healthy parenchyma during the acute and local innate inflammatory events that follow CNS trauma, but the roles of reactive astrocytes during the chronic and widespread CNS inflammation associated with adaptive or acquired immune responses are uncertain.

Here, we investigated the effects of transgenically targeted ablation of proliferating, scar-forming reactive astrocytes on the acquired immune inflammation associated with experimental autoimmune encephalitis (EAE). In wild-type mice with EAE, we found that reactive astrocytes densely surrounded perivascular clusters of leukocytes in a manner reminiscent of astrocyte scar formation after CNS trauma. Transgenically targeted ablation of proliferating astrocytes disrupted formation of these perivascular scars and was associated with a pronounced and significant increase in leukocyte entry into CNS parenchyma, including immunohistochemically identified macrophages, T lymphocytes and neutrophils. This exacerbated inflammation was associated with a substantially more severe and rapidly fulminant clinical course.

These findings provide experimental evidence that reactive astrocytes form scar-like perivascular barriers that restrict the influx of leukocytes into CNS parenchyma and protect CNS function during peripherally initiated, acquired immune inflammatory responses in the CNS. The findings suggest that loss or disruption of astrocyte functions may underlie or exacerbate the inflammation and pathologies associated with autoimmune diseases of the CNS, including multiple sclerosis.

http://www.ncbi.nlm.nih.gov/pubmed/19759299

Another astrocyte-related Pubmed abstract:


Acute astrocyte activation in brain detected by MRI: new insights into T(1) hypointensity.

J Cereb Blood Flow Metab. 2008 Mar;28(3):621-32.
Sibson NR, Lowe JP, Blamire AM, Martin MJ, Obrenovitch TP, Anthony DC.
Experimental Neuroimaging Group, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK. nicola.sibson@dpag.ox.ac.uk

Increases in the T(1) of brain tissue, which give rise to dark or hypointense areas on T(1)-weighted images using magnetic resonance imaging (MRI), are common to a number of neuropathologies including multiple sclerosis (MS) and ischaemia. However, the biologic significance of T(1) increases remains unclear.

Using a multiparametric MRI approach and well-defined experimental models, we have experimentally induced increases in tissue T(1) to determine the underlying cellular basis of such changes. We have shown that a rapid acute increase in T(1) relaxation in the brain occurs in experimental models of both low-flow ischaemia induced by intrastriatal injection of endothelin-1 (ET-1), and excitotoxicity induced by intrastriatal injection of N-methyl-D-aspartate (NMDA). However, there appears to be no consistent correlation between increases in T(1) relaxation and changes in other MRI parameters (apparent diffusion coefficient, T(2) relaxation, or magnetisation transfer ratio of tissue water).

Immunohistochemically, one common morphologic feature shared by the ET-1 and NMDA models is acute astrocyte activation, which was detectable within 2 h of intracerebral ET-1 injection. Pretreatment with an inhibitor of astrocyte activation, arundic acid, significantly reduced the spatial extent of the T(1) signal change induced by intrastriatal ET-1 injection.

These findings suggest that an increase in T(1) relaxation may identify the acute development of reactive astrocytes within a central nervous system lesion. Early changes in T(1) may, therefore, provide insight into acute and reversible injury processes in neurologic patients, such as those observed before contrast enhancement in MS.

Dignan

Let me echo my thanks...

And, I see that Hollie from the Accelerated Cure Project has posted her notes from Ectrims 2009 here.

Thanks Hollie--always look forward to your reports too.

Sharon

More interesting stuff from Prineas et al on the early stages of lesion formation. I think the last sentence is key, "The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte."


Multiple sclerosis: distribution of inflammatory cells in newly forming lesions

Ann Neurol. 2009 Dec;66(6):739-53.
Henderson AP, Barnett MH, Parratt JD, Prineas JW.
Institute of Clinical Neuroscience, Department of Medicine, University of Sydney, Sydney, Australia.

OBJECTIVE: CD4 T-cell-dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis (MS). However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions.

METHODS: Twenty-six active lesions from 11 patients with early MS were serially sectioned and immunostained for T and B cells, plasma cells, ramified microglia, macrophages, monocytes, and CD209-positive dendritic cells. Cell counts were compared in prephagocytic, phagocytic, and immediately postphagocytic areas.

RESULTS: Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells, and immunoglobulin G (IgG)-positive plasma cells. Lesions in 2 exceptionally early cases contained relatively few T and B cells, and no IgG-positive plasma cells.

INTERPRETATION: Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.

http://www.ncbi.nlm.nih.gov/pubmed/20035511