ECTRIMS 2009

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

ECTRIMS 2009

Postby dignan » Sat Sep 12, 2009 8:35 am

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:

Charcot Award Lecture
Friday, September 11, 2009, 09:15 - 10:15

The pathogenesis of relapsing and remitting multiple sclerosis – versions one to five and counting
J. Prineas (Sydney, AU)

Charcot singled out two features in particular that seemed to him most important in understanding the nature of multiple sclerosis - the multifocal, patchy nature of tissue damage, and the fact that myelin was destroyed, leaving axons largely intact.

JW Dawson, writing some fifty years later, added to two important facts, first, that myelin loss was not the result of a slow overgrowth of glial fibres as suggested by Charcot, but that each plaques evolved through a phase of abrupt breakdown of myelin, and second, that such lesions tended to develop around blood vessels. The latter was interpreted as evidence of some noxious factor - a toxin or an enzyme with a propensity to attack myelin - diffusing into the tissue from the blood or perivascular “lymph channels”.

The next important insight into the pathogenesis of the disease was the discovery, by the 1950s, that MS was not the only primary demyelinating disease characterized by perivascular demyelination but was one of a group that included post- infectious encephalomyelitis, rabies post- vaccination encephalomyelitis, and the experimental autoimmune disease discovered in the 1930s, EAE. Subsequent morphological and immunohistochemical studies of inflammatory cells and mediators in affected tissue in MS and in EAE reinforced the idea that these were analogous disorders and that tissue destruction in MS, like that in myelin- induced EAE, was mediated by CD4- positive T cells reactive against a myelin or oligodendrocyte antigen.

The discovery in the 1960s that the adult mammalian CNS had the capacity to remyelinate following experimental demyelination provided the key to the later discovery of an unsuspected dynamic in MS, namely that the destructive phase in individual lesions lasts only a few weeks, following which the lesion exhibits signs of vigorous oligodendrocyte regeneration and the reappearance of new myelin sheaths throughout tissue still packed with macrophage and steeped in IgG. This also introduced the important concept of failed remyelination in MS.

The current view of the newly forming MS lesion is based on a number of recent immunohistochemical studies challenging the idea that myelin loss is orchestrated by antigen-specific CD4+ T cells. These include reports that show that commencing myelin breakdown is preceded by a pre-phagocytic phase characterised by an acute loss of oligodendrocyte perikarya from otherwise intact myelinated tissue and that this occurs largely in the absence of T cells.

There is a strong possibility that the next insight into the pathogenesis of MS will be rooted in what some believe may be the most important breakthrough related to the pathogenesis of MS since the discovery of EAE, namely reports that multifocal demyelination in neuromyelitis optica (NMO) is associated with the presence of a serum antibody directed against astrocytes. As MS and NMO are remarkably similar multifocal, relapsing and remitting demyelinating diseases with demyelination the result of an abrupt loss of both oligodendrocytes and astrocytes , the question that most needs addressing concerns the link that exists between these two diseases.


Pathology of MS
Friday, September 11, 2009, 15:30 - 17:00

The astrocyte lesion in neuromyelitis optica and multiple sclerosis
J. Parratt, J. Prineas (Sydney, AU)

Objective: Recent evidence suggests neuromyelitis optica (NMO), a disease historically regarded as a form of multiple sclerosis (MS), is an autoimmune disease targeting astrocyte endfeet. The present objective was to determine if an astrocyte lesion occurs in MS and whether this is similar to that in NMO.

Methods: Autopsy tissue from 13 patients with NMO and 31 MS patients was examined immunohistochemically for astrocytes, oligodendrocytes and other determinants including aquaporin-4 (AQP4), a water channel protein concentrated in astrocyte endfeet. The fine structure of astrocyte endfeet in MS was determined by electron microscopy.

Results: Early NMO lesions consisted of confluent perivascular sleeves of vacuolar myelinolysis accompanied by an abrupt loss of both astrocytes and oligodendrocytes. Reparative gliosis was effected by small AQP4-negative astrocytes without reformation of astrocyte endfeet or reappearance of oligodendrocytes. Specific for NMO were linear deposits of complement on pial, vascular and root entry zone glial limiting membranes (GLMs). Early MS lesions showed a loss of astrocyte endfeet and some loss of astrocyte perikarya followed by the appearance of large AQP4-positive astrocytes that often reformed vascular endfeet.

Interpretation: Demyelination, oligodendrocyte loss and failure of remyelination in NMO result from destruction of AQP4-expressing astrocytes and endfeet. The presence of degenerative changes in astrocyte endfeet in early MS lesions raises the possibility that demyelination, oligodendrocyte loss and the eventual failure of remyelination in MS may also be a bystander effect of an astrocyte or GLM lesion, and that like NMO, MS is not a disease primarily of oligodendrocytes and myelin.


Pathology of MS
Friday, September 11, 2009, 15:30 - 17:00

Multiple sclerosis: distribution of inflammatory cells in newly forming lesions
A. Henderson, M. Barnett, J. Parratt, J. Prineas (Sydney, AU)

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. 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.

Twenty-six active lesions from eleven 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 pre-phagocytic, phagocytic and immediately postphagocytic areas.

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 IgG positive plasma cells. Lesions in two exceptionally early cases contained relatively few T and B cells, and no IgG positive plasma cells.
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.
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Postby dignan » Sat Sep 12, 2009 8:41 am

Here are the abstracts on genetics and environment:

Genetics – an update
Thursday, September 10, 2009, 11:10 - 11:30

Environment versus or together with genetics
G. Ebers (Oxford, UK)

Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of multiple sclerosis (MS). However, the available data accommodate more than one type of environmental effect. Migration studies show that changes to early environment can greatly affect risk, and there are recent indications that risk can be altered in situ. The rising incidence rates of MS in Canada implied by longitudinal increases in sex ratio place this effect in temporal context and narrow the candidates for mediating the effect of environment. Similarly, geographical patterns in Australia imply that modifiable environmental factors hold the key to preventing some 80% of cases. Genetic epidemiology provides overwhelming evidence that genetic background has an important complementary role. If genetic factors are held constant, the environment sets the disease threshold. Although these could be independent additive risk factors, it seems more likely that susceptibility is mediated by direct interactions between the environment and genes.


Epidemiology - 2
Friday, September 11, 2009, 15:30 - 17:00

Prenatal, perinatal and early life factors in MS susceptibility
S Ramagopalan, C. Guimond, M. Criscuoli, I. Yee, D. Dyment, G. Ebers, D. Sadovnick (Oxford, UK; Vancouver, CA)

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations.

The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) has collected prenatal, perinatal and early life information on a cohort of more than 30,000 families in which at least one member has MS, as well as on spouse (same-sex, different sex, married, common-law) controls.

Using this longitudinal, population-based cohort we investigated whether or not birth weight, preterm birth, parental age at birth, maternal gestational diabetes and childhood allergies were associated with MS.
The only association found with MS risk was with maternal gestational diabetes, which was found at a higher frequency in MS cases as compared to controls (p=0.02, OR=3.87, 95% CI 1.18 to 12.7).

Intriguingly maternal gestational diabetes is associated with low levels of vitamin D and has also been shown to increase the risk of schizophrenia, a disorder which also displays a season of birth effect similar to MS.
It is thus plausible that maternal gestational diabetes impacts on the intrauterine environment and foetal neurodevelopment ultimately increasing the risk of developing MS.


Epidemiology - 2
Friday, September 11, 2009, 15:30 - 17:00

Environmental risks for multiple sclerosis: quantitative analyses and biological mechanisms
S. Sloka, C. Silva, W. Pryse-Phillips, J. Wang, L. Metz, S. Patten, V.W. Yong (Calgary, St John's, CA)

Background: Multiple sclerosis (MS) is a disease with purported environmental causes. Consistent correlations have been found in various settings for latitude, smoking exposure, sunlight, and vitamin D deficiency. We analysed the contribution of various environmental factors to the risk of developing MS from a population perspective. We then looked at the molecular biology of the largest contributor to risk (available ultraviolet radiation) through its biological correlate (vitamin D).

Methods: We collated global data of MS prevalence from 54 studies over the previous 10 years and calculated the degree of risk contributed by latitude, longitude, ultraviolet radiation (from NASA satellite data and formulae for available sunlight hours), population smoking rates (from WHO data), gender, study date, study demographics, and several socioeconomic factors. We report a very significant negative correlation between MS prevalence and available ultraviolet (UV) radiation. Furthermore, we explored the molecular biology of vitamin D, focusing on the polarization of T cell subsets (Th1/Th17 vs Th2) using ELISA and real time quantitative PCR (rt-qPCR) for cytokines and transcription factors. We also investigated potential neuroprotective roles of Vitamin D.

Results: The lack of available UV radiation outweighs other factors by at least 20 fold (p<10^-8 ) from single variate regression analysis. Multiple regression analysis revealed that latitude and longitude are also significant factors; smoking provides a minimal role. The 8 studies from Scandinavia produced prevalences that were lower than expected, given their global geospatial positioning. Cytokine secretion, measured by ELISA, consistently demonstrated a significant production shift from IFNg and IL-17 to IL-5 when several concentrations of vitamin D were added to T cells at two different levels of activation. This shift to Th2 cytokines from Th1/Th17 cytokines was confirmed using rt-qPCR and in the transcription factors (TBX21/RORC to GATA-3) using rt-qPCR. Finally, using imaging techniques, we show that the T cell killing of neurons was abrogated by several concentrations of vitamin D (p<0.0001), suggesting a neuroprotective role for vitamin D.

Conclusions: The available ultraviolet radiation is a significant environmental factor, more so than all the other factors examined. Vitamin D, a biological correlate of ultraviolet radiation, is a strong immunomodulator and has additional neuroprotective effects.
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Postby dignan » Sat Sep 12, 2009 8:50 am

Here are the clinical trial abstracts:

Neuroprotection
Thursday, September 10, 2009, 15:30 - 17:00

The effect of oral temsirolimus on brain atrophy
F. Barkhof, E. Fisher, I. van den Elskamp, M. Miller, B. Jasperse, R. Allen, R. Rudick, L. Kappos (Amsterdam, NL; Cleveland, US; Philadelphia, US; Basel, CH)

Introduction: In MS most active immunomodulatory agents have only modest effects on brain volume. CCI-779 (temsirolimus) is an immunosuppressive compound which suppresses cytokine-driven cell proliferation specifically blocking the interleukin 2-driven T-cell proliferation. In addition, as a neuroimmunophilin ligand (binding to FKBP-12) temsirolimus potentially exerts a neuroprotective effect; thereby targeting two key pathological mechanisms in MS. Previously, CCI-779 demonstrated its immunosuppressive efficacy in a phase II MS clinical trial, with a significant decrease in relapse rate and a reduction in the number of enhancing lesions on MRI in the 8mg group. Here we report the effect of CCI-779 on brain volume change on MRI.

Methods: In a phase II trial, 297 MS patients were randomized to receive either placebo or different doses (2, 4, 8 mg orally per day) of temsirolimus for 9 months. The MRI protocol included conventional T1-weighted and dual-echo T2-weighted 2D spin-echo images with 3mm slices. Brain volume changes were assessed on the former using a registration based method (SIENA) and on the latter using a segmentation based method (BPF). Brain volume changes were compared between treatment groups using ANCOVA with adjustment for baseline brain volume and log-transformed number of enhancing lesions.

Results: Technically successful analyses were possible in 262 patients for SIENA and 274 for BPF. At baseline, all groups were well-matched in terms of normalized brain volume and BPF (p > 0.4 for BPF, p>0.3 for SIENAX). In the placebo-group, a significant change in brain volume occurred: -0.37% (SE=0.13%) for SIENA and -0.32% (SE=0.08%) for BPF. Treatment with temsirolimus significantly reduced the rate of brain atrophy measured by both methods in the 8mg group, with complete stabilization or even minor increase in brain volume in the 8mg group: +0.14% (SE= 0.13%) for SIENA and +0.02% (SE=0.07%) for BPF (p=0.0063 and p= 0.0015 vs. placebo respectively). A dose-dependent effect on the rate of brain volume decline was observed using both methods - for BPF, comparison of the lower doses reached significance versus placebo (p=0.042 for 2mg and p=0.0097 for 4mg).

Conclusion: In addition to an anti-inflammatory effect of CCI-779 on MRI lesion development and relapses, this drug demonstrated a beneficial effect on brain volume change using two independent analysis methods. These results suggest a possible neuroprotective effect of temsirolimus.


Immunomodulation - 1
Thursday, September 10, 2009, 15:30 - 17:30

A phase II open-label multicentre safety and efficacy study of oral recombinant ovine interferon tau administered daily in patients with relapsing-remitting multiple sclerosis
G. Buckle, D. Bourdette, E. Waubant, N. Kachuck, B. Healy, R. Bakshi, C. Guttmann, D. Gilman, C. Liu, H. Weiner (Brookline, Portland, San Francisco, Los Angeles, Reno, Alameda, US)

Objective: To determine the safety and obtain preliminary evidence of efficacy of a novel oral interferon (Tauferon) 3.0 mg TID for nine months, in patients with RRMS.

Methods: This was a Phase II, open-label, multi-center study to evaluate the safety and preliminary efficacy of oral IFN tau (Tauferon) administered daily to patients with RRMS. All patients had at least one Gadolinium (Gd)-enhanced lesion on at least one of three run-in MRIs taken during the three months prior to treatment. Patients received 3.0 mg of oral IFN tau three times per day (TID) for nine months. Patients were followed for an additional three months off treatment and MRI was repeated. The primary analysis compared the mean number of new lesions observed at the scans for months 7-9 after treatment to the mean number of new lesions observed at the second and third pre-treatment scans using a Wilcoxon signed rank test. Secondary analyses compared the pre-treatment mean to the mean at months 1-3 and months 4-6 after treatment using a Wilcoxon signed rank test.

Results: Twenty-five (25) subjects, 5 male and 20 female, at least 18 years of age, with a clinical diagnosis of RRMS according to McDonald (2001) criteria were enrolled and 22 completed the study protocol. The primary analysis showed no significant treatment effect at months 7-9 (p=0.15), but secondary analyses showed a significant decrease in the number of new lesions at months 1-3 (p=0.0001) and at months 4-6 (p=0.0006). Post treatment scans showed no evidence of a rebound effect. Five patients experienced an MS exacerbation on treatment. Laboratory values were typically within the normal range throughout the study. Adverse events were generally mild and did not result in discontinuation of the study drug.

Conclusion: Although Tauferon 3mg TID was not effective at reducing the number of new enhancing lesions at the original time point of interest, the treatment appeared effective during the first six months of treatment. Based on the clinical and laboratory data, daily doses of Tauferon 3mg TID for up to 9 months was safe and well tolerated. Given the safety and potential for efficacy of the treatment, future investigation of this treatment is warranted.


Late breaking news
Saturday, September 12, 2009, 09:30 - 09:45

Atorvastatin therapy in patients with clinically isolated syndrome and high-risk for conversion to multiple sclerosis: the STAyCIS study
E. Waubant, D. Pelletier, M. Mass, J. Cohen, M. Kita, A. Cross, A. Bar-Or, T. Vollmer, M. Racke, O. Stüve, S. Schwid, A.D. Goodman, N. Kachuck, J. Preiningerova, B. Weinstock-Guttman, P. Calabresi, A. Miller, M. Mokhtarani, L. Ding, E. Rosenberg, . ITN020AI Study Management Team, D. Iklé, C. Spencer, S.S. Zamvil (San Francisco, Portland, Cleveland, Seattle, St. Louis, US; Montreal, CA; Phoenix, Dallas, Rochester, Los Angeles, New Haven, Buffalo, Baltimore, New York, Bethesda, Chapel Hill, US)

Background: Oral atorvastatin reverses EAE and promotes immune modulation. Open-label studies suggest statins may be beneficial in RRMS.
Objective: A phase II, double-blind, placebo-controlled, multicenter trial tested efficacy and safety of atorvastatin (80 mg/day) in CIS patients.

Methods/design: Based on the CHAMPS study and the London, UK, CIS cohort, we assumed that 69% of placebo-treated subjects with CIS and at least two silent T2 areas on an initial brain MRI scan would develop 3 or more new T2 lesions, or 1 clinical exacerbation by 12 months. The protocol called for a sample size of 152 subjects, enabling us to detect a 39% therapeutic effect (power 0.80, 2-tailed, 0.05). Participants were randomized to atorvastatin or placebo (3:2) within 90 days of CIS onset. Visits occurred at baseline, months 1, 2 and 3, and then every 3 months (physical, EDSS, MSFC, brain MRI scans). Study drug was discontinued at month 12, with subsequent follow-up through month 18. Patients meeting the primary endpoint (PEP) continued study drug, but were offered additional weekly IM IFN beta-1a (Avonex).

Results: Due to slow recruitment, enrollment was stopped after 81 patients were randomized (76.5% female, 92.6% white, mean age 33.8 ± 9 years, mean duration of CIS at randomization 66 ± 25 days). Initial events included optic neuritis (40.7%), spinal cord syndrome (34.6%), brainstem/cerebellar (17.3%), and others (6.2%). Mean number of T2 and gadolinium-enhancing (Gd+) lesions at baseline were 20.8 ± 17 and 0.5 ± 2.1, respectively. Overall, atorvastatin was well tolerated. 49% of atorvastatin recipients (n=24/49) met PEP compared to 56.3% placebo recipients (n=18/32) (p=0.65). Median time to meet PEP was 386 and 285 days in the atorvastatin and placebo groups, respectively (HR=0.87, p=0.66, Cox proportional hazard ratio adjusted for type of symptoms at onset, and number of T2 lesions at baseline). The median cumulative numbers of new T2 lesions up to month 12 or to starting Avonex were 0 (range 0-17) and 2 (range 0-10) in atorvastatin and placebo groups, respectively. The proportion of patients who did not develop new T2 lesions up to month 12 or to starting Avonex was 55.3% and 27.6% in atorvastatin and placebo groups, respectively (p=0.032).

Conclusion: The study was underpowered to detect the planned effect size due to discontinuation of enrollment and did not meet its PEP. Nevertheless, atorvastatin decreased new brain MRI T2 lesion activity in patients with CIS.
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Postby carolew » Sat Sep 12, 2009 9:49 am

do you know where we can see all the other abstracts... you know I am looking for the ones on stem cells :roll:
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Postby mose » Sat Sep 12, 2009 10:12 am

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.
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Postby Lyon » Sat Sep 12, 2009 10:57 am

.
Last edited by Lyon on Sat Nov 26, 2011 9:23 am, edited 1 time in total.
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Postby mrhodes40 » Sat Sep 12, 2009 11:21 am

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!!
I'm not offering medical advice, I am just a patient too! Talk to your doctor about what is best for you...
http://www.thisisms.com/ftopic-7318-0.html This is my regimen thread
http://www.ccsvibook.com Read my book published by McFarland Health topics
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Postby dignan » Sat Sep 12, 2009 6:37 pm

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.
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Postby whyRwehere » Sun Sep 13, 2009 2:18 am

I wish we could know how many people read the poster by Zamboni and took interest in it.
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Postby Frank » Sun Sep 13, 2009 4:11 pm

Dignan, thanks for your roundup :D!

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby carolew » Tue Sep 15, 2009 4:07 am

thanks Dignan, I found it...
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Postby dignan » Sat Sep 19, 2009 8:04 am

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
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Postby dignan » Sat Sep 19, 2009 12:09 pm

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.
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Hollie's Notes from Ectrims 2009

Postby Shayk » Mon Sep 21, 2009 6:01 pm

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
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Postby dignan » Sun Jan 10, 2010 3:39 pm

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
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dignan
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