New definition of MS from Mayo, Cleveland, and Yale

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New definition of MS from Mayo, Cleveland, and Yale

Postby cheerleader » Wed Dec 07, 2011 6:22 pm

It's official. MS is no longer primarily an autoimmune disease of white matter. It's now an inflammatory disease of gray matter.

Press release from Mayo-
http://www.bmedreport.com/archives/31937

Research from Yale-
http://www.biomedcentral.com/content/pd ... 11-152.pdf

so, the EAE model and diagnosis will be changing, now that new, more powerful imaging technology is allowing researchers to see beyond white matter lesions, into the cortex.
Maybe they'll look at ischemic/reperfusion injury and iron deposition in gray matter next?
always hopeful,
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby questor » Thu Dec 08, 2011 11:13 am

Here's a link to the NMSS summary of this finding:

http://www.nationalmssociety.org/resear ... x?nid=5767

It appears that cortex damage was seen in only 43% of the samples from people who eventually went on to develop MS.

--Tracy
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby questor » Thu Dec 08, 2011 1:37 pm

And here's the pubmed.gov abstract of the Yale article linked above (Walker, Huttner, and Oconnor) in cheerleader's post:

http://www.ncbi.nlm.nih.gov/pubmed/22145746
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby HarryZ » Thu Dec 08, 2011 9:01 pm

cheerleader wrote:It's official. MS is no longer primarily an autoimmune disease of white matter. It's now an inflammatory disease of gray matter.

Press release from Mayo-
http://www.bmedreport.com/archives/31937

Research from Yale-
http://www.biomedcentral.com/content/pd ... 11-152.pdf

so, the EAE model and diagnosis will be changing, now that new, more powerful imaging technology is allowing researchers to see beyond white matter lesions, into the cortex.
Maybe they'll look at ischemic/reperfusion injury and iron deposition in gray matter next?
always hopeful,
cheer


Does this mean that the measurement and number of white matter lesions used to determine the effectiveness of a drug in trials is not really a valid indicator? Hmmm.

Harry
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby Moom9335 » Sat Dec 10, 2011 9:57 am

"However, in autopsy tissues of MS patients, lesions in the cerebral cortex show demyelination without inflammation, raising a challenging issue: if cortical lesions form entirely without inflammation, then cortical demyelination would not be explainable by current theories of MS nor treatable by current MS therapies".
From the recent study of MS brains. So, where does this leave us now????? Any chance someone, anyone, might admit these CRABS are working on the wrong issue? Also, does this explain why
lesion load not not corrolate with disability? And, open the door to why PPMS shows no inflammation? Just asking. :twisted:
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby cheerleader » Sat Dec 10, 2011 12:57 pm

Harry and Moom--
exactly right. This is why my husband can have 20 white matter lesions and mountain bike, while our friend has one white matter lesion and cannot walk.
The only true correlation with MS disability and disease progression is gray matter atrophy. It's not inflammation, it's not white matter lesions. It's loss of brain tissue. I write about it on Facebook, for those interested in all the studies. This has been noted for over a decade,since the advent of higher powered MRI.
https://www.facebook.com/notes/ccsvi-in ... 6696872211

Sadly, the white matter lesions are what could be seen, and what the EAE-based therapies could affect. But that isn't really MS disease progression or disability. It's also not about the cortical "lesions" or immune activation highlighted in the MS Society report Tracy linked. It's about overall cortical DAMAGE.

Here's what the Yale paper says about this-

Despite acknowledgement in the early studies of MS and that the disease includes cognitive symptoms, cortical involvement in MS has been given less attention than the characteristic white matter lesions until recently. Given that cortical damage is now recognized as a major site of disease pathology, why has this occurred? The most plausible explanation is that cortical lesions are simply not obvious by the standard means of visualization (MRI and histopathology) and early macroscopic studies suggested that they represent a minor fraction of damage that occurs in the brain [8]. Cortical immune infiltrates associated with tissue damage are often sparse [9]. In the absence of an immune infiltrate, these lesions maintain a normal water concentration and therefore are not hyperintense on T2 weighted MRI like white matter lesions [10] highlighting why they are not easily visualized. Although identification of individual cortical lesions in MS are elusive, cortical atrophy in patients with MS is apparent, particularly in the hippocampus [11]. It has been established that the cortex atrophies more rapidly than white matter in patients with MS and that the degree of cortical atrophy is independent of that which occurs in the white matter [12]. Cortical atrophy correlates with the clinical progression of the disease better than the white matter lesion load [13-15].


Jeff has had a reversal of gray matter atrophy since venoplasty for CCSVI almost 3 years ago. His gray matter is plump and normal again, as shown on MRI. He continues to feel even better than he did a year ago. More alert, energized, working from 6am-midnight, traveling around the globe, alive again. I'm wondering how many more years will pass before the McDonald criteria is updated, before the EAE model is done with. It does seem that the MS specialists will try to find a way to connect the gray matter demyelination with the immune system. We'll see. But once again, it's not about lesions (even in the gray matter) it's about atrophy.
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby Moom9335 » Sat Dec 10, 2011 3:03 pm

Cheer,
I think I am very sad that truth does not influence dynastic thinking and ego.
In simple words, stop giving mice MS likedisease. Face the
truth of the research that is meaningful and DO SOMETHING ABOUT IT THAT
HAS RESULTS. It is the tree falling in the forest, but nobody hears. Heartbreaking.
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby cheerleader » Sat Dec 10, 2011 5:20 pm

Don't be sad, Moom. Trees (like inexact mouse models) are falling, people are hearing them--and sharing with each other.
Here's Dr. Terry Wahls talking about how she reversed her gray matter atrophy through nutrition, exercise and electrical stim:
http://www.youtube.com/watch?v=KLjgBLwH3Wc

Here's how my husband reversed his (note, he also changed his diet and lifestyle after venoplasty at Stanford)
www.ccsvi.org

And this organization is dedicated to getting to the TRUTH of MS- complete with a new animal model.
http://www.isnvd.org/

people all over the world are doing something about it.
cheer
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby THEGREEKFROMTHED » Sat Dec 10, 2011 6:21 pm

Inside out or outside in this disease sucks all the way around. Lesions or not atrophy or not. It just plain sucks. I feel for the anxious ms population that finds comfort in CRABS. Could it be said they offer a placebo effect?!
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby marcstck » Sun Dec 11, 2011 3:40 am

Moom9335 wrote:"However, in autopsy tissues of MS patients, lesions in the cerebral cortex show demyelination without inflammation, raising a challenging issue: if cortical lesions form entirely without inflammation, then cortical demyelination would not be explainable by current theories of MS nor treatable by current MS therapies".
From the recent study of MS brains. So, where does this leave us now????? Any chance someone, anyone, might admit these CRABS are working on the wrong issue? Also, does this explain why
lesion load not not corrolate with disability? And, open the door to why PPMS shows no inflammation? Just asking. :twisted:


Actually, the researchers found that there is inflammation in the cortex and in the meninges that surrounds it. You can hear it right from the horse's mouth (from the researcher leading the project) in a video found here:

http://newsblog.mayoclinic.org/2011/12/05/ms-study/

The most extensive article I have found so far on this research can be found here (you may have to register for the site to access the article. It's well worth it, this is one of the most valuable sites for MS research):

http://www.medscape.com/viewarticle/755146

from the above article:

Using cortical tissue obtained during brain biopsy for other reasons, researchers found that cortical lesions were "frequent, inflammatory, and strongly associated with meningeal inflammation."

"Our study shows the cortex is involved early in MS," Claudia F. Lucchinetti, MD, co-lead author of the study and a neurologist at the Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News. "The cortex in some cases may even be the initial target."


The question of from whence the observed inflammation arises still has not been answered, but inflammation is an indicator of immune activity, so immunomodulating drugs would still have some effect, as has been seen over the last 15 years or so. Let's not lose sight of the fact that extreme immunosuppression (à la HSCT, or Campath therapy) shows a dramatic degree of decrease in disease activity. Not saying the autoimmune model of the disease is correct, but this particular research doesn't put a stake in its heart…
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby HarryZ » Sun Dec 11, 2011 6:43 am

The question of from whence the observed inflammation arises still has not been answered, but inflammation is an indicator of immune activity, so immunomodulating drugs would still have some effect, as has been seen over the last 15 years or so. Let's not lose sight of the fact that extreme immunosuppression (à la HSCT, or Campath therapy) shows a dramatic degree of decrease in disease activity. Not saying the autoimmune model of the disease is correct, but this particular research doesn't put a stake in its heart…


And that situation warrents the big question....does another process cause the inflammation in the first place which leads the immune system to come to the resuce and cause even further damage. We know there have been autopsies on MS patients which have shown severely damaging lesions but no indication of immune system activity at the site. While the immunosuppressive drugs temper this action, they certainly aren't the long term answer....unless of course, you have a big investment in pharmaceutical stock!
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby CVfactor » Sun Dec 11, 2011 1:56 pm

marcstck wrote: Let's not lose sight of the fact that
extreme immunosuppression (à la HSCT, or
Campath therapy) shows a dramatic degree of
decrease in disease activity.


Etreme immunosupression is absolutely not what HSCT does. HSCT restores self tolerance by eliminating the memory mechanisms of the immune system that are responsible for tissue destruction. Blanket immune system suppression is not the answer in stopping MS.
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby marcstck » Sun Dec 11, 2011 6:03 pm

CVfactor wrote:
marcstck wrote: Let's not lose sight of the fact that
extreme immunosuppression (à la HSCT, or
Campath therapy) shows a dramatic degree of
decrease in disease activity.


Etreme immunosupression is absolutely not what HSCT does. HSCT restores self tolerance by eliminating the memory mechanisms of the immune system that are responsible for tissue destruction. Blanket immune system suppression is not the answer in stopping MS.



True enough, I stand corrected. I misstated the precise mechanism of action for the immunoablative therapies. They do indeed wipe out the immune system, so it may be replaced by cells that are not autoreactive. Still, this does demonstrate that the immune system plays a large role in MS disease etiology. Immunosuppressants such as Rituxan and Tysabri, despite their well-known (and, in the case of Rituxan, wildly overblown) drawbacks, also significantly suppress MS disease activity, sometimes to a dramatic degree.

Again, not saying that the genesis of MS necessarily lies within the immune system , a fact that I've railed about in my blog. But it's also a mistake to minimize its role in the disease process. MS is without question the multifactorial disease, the pathogenesis of which likely varies from patient to patient. There is no one-size-fits-all answer, unfortunately…
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby marcstck » Sun Dec 11, 2011 6:10 pm

HarryZ wrote:
The question of from whence the observed inflammation arises still has not been answered, but inflammation is an indicator of immune activity, so immunomodulating drugs would still have some effect, as has been seen over the last 15 years or so. Let's not lose sight of the fact that extreme immunosuppression (à la HSCT, or Campath therapy) shows a dramatic degree of decrease in disease activity. Not saying the autoimmune model of the disease is correct, but this particular research doesn't put a stake in its heart…


And that situation warrents the big question....does another process cause the inflammation in the first place which leads the immune system to come to the resuce and cause even further damage. We know there have been autopsies on MS patients which have shown severely damaging lesions but no indication of immune system activity at the site. While the immunosuppressive drugs temper this action, they certainly aren't the long term answer....unless of course, you have a big investment in pharmaceutical stock!


I think it's unquestionable that some unknown process must at the very least set the immune system into its misdirected action. Might that mechanism be abnormal blood flow due to anomalous venous anatomy? Certainly a possibility, especially in concert with genetic and environmental factors that serve to brew up a perfect storm…
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Re: New definition of MS from Mayo, Cleveland, and Yale

Postby cheerleader » Sun Dec 11, 2011 7:58 pm

Inflammation (or the activation of the immune system in the gray matter) can be created by-
1.
Refluxing oscillatory blood flow, which favours expression of adhesion molecules on endothelial cells, becoming a previously overelooked inflammatory mechanism in MS.

http://phleb.rsmjournals.com/content/25/6/269.full

2. Ischemic injury and reperfusion --known to create inflammation in the cortex.
http://www.nature.com/jcbfm/journal/v24 ... 1642a.html


3.iron deposition in MS and TBI
http://www.ajnr.org/content/early/2011/ ... 3.abstract
http://www.ajnr.org/content/32/10/1851.full

These disease models, which we already know create cortical inflammation and atrophy in vivo, need to be given the same millions of research dollars as the immunological focus. Why the NIH continues to fund immunological studies into MS, but refuses to fund mechanistic blood flow studies (such as the ones proposed by Dr. Cooke at Stanford and Dr. Haacke--who were both denied NIH money for the first times in their careers) astounds me.
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