Will the real multiple sclerosis please stand up?

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Will the real multiple sclerosis please stand up?

Postby MSUK » Wed Jul 04, 2012 4:25 am

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Summary: MS has typically been viewed as a disease with an autoimmune basis, which is thought to account for its association with other autoimmune diseases. The authors of this article challenge this conventional view of MS and propose that it is in fact a neurodegenerative disorder with relapses occurring as a consequence of immune reaction to the breakdown products from the degenerative process.

The authors term the conventional model of MS as an ‘outside-in’ model and they hypothesise that in fact we should examine this disease as an ‘inside-out’ model. Firstly the inconsistencies in current clinical observations are outlined, including a review of pathology and therapeutics in MS. Secondly the different phenotypes of MS are compared and it is argued that primary progressive MS represents the true disease, while the relapsing-remitting form is a secondary immune response to the underlying process. Comparisons are drawn with other neurological disorders and lastly a proposed mechanism is explored for this novel approach to this incurable disease.

This review article makes a compelling case for re-evaluating current thinking on the proposed mechanisms involved in the pathogenesis of MS.... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... pageid/722
MS-UK - http://www.ms-uk.org/
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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Wed Jul 04, 2012 11:47 am

Brilliant! Thanks to Dr. Peter Stys, a stroke researcher, for looking at PPMS as the "real" MS, and noting how

....questions have been raised as to whether inflammation and/or autoimmunity are really at the root of the disease, and it has been proposed that MS might in fact be a degenerative disorder. We argue that MS may be an 'immunological convolution' between an underlying primary degenerative disorder and the host's aberrant immune response. To better understand this disease, we might need to consider non-inflammatory primary progressive MS as the 'real' MS, with inflammatory forms reflecting secondary, albeit very important, reactions.


Here's the paper:
http://www.nature.com/nrn/journal/v13/n ... n3275.html

Those interested in understanding MS as a disease of neurodegeneration might learn a lot from Finn's wonderful thread on this topic:
general-discussion-f1/topic3707.html
Gray matter atrophy is the only feature of MS which begins the disease process and lasts throughout, into the progressive phase. We need to measure gray matter and look at hypoperfusion and neurodegeneration.
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Re: Will the real multiple sclerosis please stand up?

Postby HarryZ » Wed Jul 04, 2012 3:05 pm

Cheer,

This paper will certainly bring a lot of not so pleasant response from the "auto-immune" theory research crowd. Many scientists over the years have hung their careers on this theory and to be told that they are wrong won't sit well. For years pretty much all the medications for MS (suppressing, altering, etc the immune system) look like they have been treating the symptoms and not the root cause.

It's nice to see that MS research has been branching out in other directions the past few years. While this new theory certainly needs to be proven, let's hope it leads to the long awaited cure.

Harry
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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Thu Jul 05, 2012 11:28 am

I have the whole paper, Harry. Without violating copyright, I'd like to include one quote which affirms what Marie and Finn and I (and many others) on this board have been saying for awhile. The inflammatory response seen in MS is not unique. It is seen in other neurodegenerative disease and in stroke. We have focused on the inflammation to the exclusion of neurodegeneration for 60 years....and have come no closer to understanding the disease. It will take stroke researchers and others like Dr. Stys to take away the hold EAE and immunology has on MS.

What does Dr. Stys think is the difference between Alzheimers. Parkinsons and MS? Age of onset.

One might reasonably ask why other common neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, do not also result in relapsing–remitting neuroinflammation. In fact, both diseases do exhibit inflammation in pathologically vulnerable regions 83,84. Indeed, in these research fields there is also an ongoing debate about whether inflammation is a reaction to, or cause of, ongoing degeneration. For example, post-mortem examination of human and primate brains after exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that induces parkinsonian features by killing dopaminergic neurons, reveals a sustained inflammatory response that continues for years after exposure to the toxin 85,86. Clearly, in this example the initiating insult was a monophasic degenerative one (toxin-induced death of a specific neuronal population), which secondarily entrained a protracted inflammatory reaction and, interestingly, continued neurodegeneration that long outlasts the toxic insult. The reasonable question that was raised was whether such secondary inflammation could now feed back and promote further degeneration, completing an analogous ‘inside-out’ cycle as we propose for multiple sclerosis (MS) (FIG. 1). Because diseases such as Alzheimer’s and Parkinson’s have a much more prominent degenerative rather than inflammatory phenotype, the initial assumption was that a degenerative mechanism (or mechanisms) was primarily responsible, with inflammation perhaps a secondary, but possibly important, consequence of the degeneration. In MS, the situation is reversed: inflammation occurs early and is very prominent in many patients, so it was naturally assumed that autoimmunity might be causal; but, as we argue throughout this Perspective, such an assumption may be incorrect. If MS is primarily a degenerative disorder in line with an inside-out mechanism, why would this disease be unique in engendering such prominent and cyclic inflammation? The differences may be related to age: Alzheimer’s disease and Parkinson’s disease present decades later than MS, and immune responsiveness wanes with age through a process of ‘immune senescence’ (REFS 21,87). Indeed, the responsiveness of T cells, which are known to be centrally involved in the immunopathogenesis of MS 88, appears to be particularly altered with age 87. Moreover, it is conceivable that the putative cytodegeneration involving the myelinating unit (oligodendroglia, their processes and myelin) in MS releases debris that is more antigenic 35,36,66 than the debris that is shed from the mainly synaptic and neuronal degeneration in Alzheimer’s disease and other traditional neurodegenerative disorders.


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Re: Will the real multiple sclerosis please stand up?

Postby HarryZ » Thu Jul 05, 2012 1:08 pm

Extremely interesting, Cheer. The MS research world, or should I say big pharma MS research world, has been fixated with the EAE MS model for decades. Despite bits and pieces of research over the years that doubted and questioned the autoimmune theory, it has survived mostly because of the immense revenue that has been generated with the MS drugs that have been developed.

I often wonder if the kind of money that has been given to autoimmune theory research had been channeled into other possibilities, we would be much closer to a cause and cure for MS. Wishful thinking at best!

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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Thu Jul 05, 2012 1:48 pm

Stys received 3.8 million from the MS Society of Canada to look at the degenerative process which precedes and follows inflammation---certainly a drop in the bucket, compared to drug studies....but at least it's another model aside from EAE.

"This study hypothesizes that the inflammatory response in MS is the result of an underlying degenerative process rather than the primary cause of injury," says Dr. Peter Stys, lead researcher, Department of Clinical Neurosciences, University of Calgary. "In other words, an underlying mechanism causes degeneration that prompts the inflammatory process, which in turn causes more degeneration."

http://www.dailyfinance.com/rtn/pr/ms-s ... 508736304/
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Re: Will the real multiple sclerosis please stand up?

Postby ScaredofMS » Thu Jul 05, 2012 6:50 pm

HarryZ wrote:Cheer,


It's nice to see that MS research has been branching out in other directions the past few years. While this new theory certainly needs to be proven, let's hope it leads to the long awaited cure.

Harry


How does one cure a degenerative disease? Have any other neurodegenerative diseases ever been cured?
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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Thu Jul 05, 2012 7:15 pm

ScaredofMS wrote:How does one cure a degenerative disease? Have any other neurodegenerative diseases ever been cured?


no, scared--none have cures. We still have Alzheimers, Parkinsons, and vascular dementia--all neurodegenerative diseases. More and more, researchers are looking at what these diseases have in common---and stating that lifestyle modifications and prevention might the best bet. These diseases share oxidative stress and slowed perfusion (or blood flow thru the brain). We may never find a "cure" for these diseases--outside of stem cell reparation. But maybe we can prevent the worsening of damage.

"While the search for a pharmaceutical cure plays front and center, quietly in the background countless neuroscientists worldwide have concluded that Alzheimer's, as well as memory decline and other age-related dementias are actually slow-developing chronic diseases, like heart disease and cancer, partly dependent on lifestyle and other treatable diseases.

I have discovered a large contingent of Alzheimer's researchers who are extremely positive about prevention and not counting on an elusive drug to stymie the growing Alzheimer's epidemic of aging baby boomers. Investigators Gregory Cole and Sally Frautschy at UCLA's Center for Alzheimer's Research and Gary W.Arendash, PhD, at the Florida Alzheimer's Research Center, for example, are all focusing on prevention. There is a plethora of upbeat dialogue in the scientific community that does not grab headlines because it's not about big money and a magic cure. It's primarily about what people can do to change their own trajectory toward Alzheimer's.

De la Torre, for example, is convinced that Alzheimer's and dementia are particularly tied to cardiovascular factors, notably, constricted blood flow to brain cells, and that midlife screening to detect and correct such heart-related deficits would help prevent much brain degeneration during aging. The special journal issue produced by de la Torre, called "Basics of Alzheimer's Disease Prevention," also included new research on the relationship between Alzheimer's and diabetes, high blood pressure, triglycerides, cholesterol, and the effects of a Mediterranean diet, exercise, fish oil, B vitamins and antioxidants.

http://www.huffingtonpost.com/jean-carp ... 95706.html

The good news is that there are researchers looking at how to improve cerebral bloodflow in MS-- through venoplasty, nutrition, exercise, smoking cessation, stress relief and lifestyle changes. For more info, see http://www.ccsvi.org
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Re: Will the real multiple sclerosis please stand up?

Postby HarryZ » Thu Jul 05, 2012 7:29 pm

How does one cure a degenerative disease? Have any other neurodegenerative diseases ever been cured?


Just as I was about to post a message to your question, I see that Cheer has posted a reply. My answer was going to be the similar to hers but with far less detail...and that is you want to prevent the neurodegeneration from happening in the first place and/or stopping it from progressing once it has begun. MS, like the other diseases, take a long time to reach the severe stage. In the case of my deceased wife who had MS, it took 36 years for the disease to get to this point.

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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Mon Jul 09, 2012 5:18 pm

I think it's important to note that Peter Stys is looking at HUMAN brains in studying MS and neurodegenerative disease. He argues in his new review that EAE is not an appropriate model for MS, because of the natural bias to address inflammation, rather than the neurodegenerative process of MS, which continues, unabated in MS. By looking at PPMS as the "real MS"---Dr. Stys and his fellow researchers are addressing the degeneration of MS, which includes atrophy.

Indeed, the failure of potent immunosuppression to affect later, progressive MS suggests that a primary cytodegenerative mechanism could be a more plausible initiating event, and progressive non-inflammatory MS (that is, primary progressive MS) may thus be most reflective of the real underlying disease.

Finally, these arguments have fundamentally important implications for therapeutic design. Using EAE to test and develop drugs to treat MS will naturally bias the outcome towards effective anti-inflammatory agents,without necessarily engineering in effectiveness against degenerative processes; this has been our experience to date with MS therapeutics.



I suggest that those interested in learning more about Stys' work, and the movement to define neurodegeneration and gray matter atrophy as the initiating event in MS purchase the full paper to learn more. The link is here---

http://www.nature.com/nrn/journal/v13/n ... n3275.html
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Re: Will the real multiple sclerosis please stand up?

Postby cervocuit » Tue Jul 10, 2012 3:24 am

I totally agree that MS has a progressive compound even for RR. But I’m not sure that inflammation is not involved from my experiment.

I have had MS for 14 years (probably more). About 20 relapses.The minor relapses goes entierly by themselves. But the major relapses leaves major sequels, that are a part of the disability. Sclerotic plaques seen on autopsy since 1850 are a part of the disability. we would not say that watching Dr. Stys graphics.
http://www.nature.com/nrn/journal/v13/n ... 75_F2.html

Rather than undelying neurodegeneration, I’m conviced that their is also imperceptible relapses that leaves imperceptiple sequels, that we call progressive MS.
I remember having joint pain on morning for many years. Doctors told me that this was inflammatory pain, but not related to MS ( :?: ). But it was not every morning, and some days it was stronger than others. So the inflammation seems to not be constant. MS is a long term process and patients don’t do blood test every day to detect inflammation.
Since I do nutrition for MS, I never had those pain since almost two years (nor MS progression)
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Re: Will the real multiple sclerosis please stand up?

Postby cheerleader » Wed Jul 11, 2012 1:29 pm

Cervocuit--
Dr. Stys would certainly agree with you...no one is saying inflammation and immune activation are not important and destructive in MS. But they are not necessarily all of MS---and we cannot understand pathogenesis without understanding cytodegeneration.

Dr. Stys explains his theory of why the inflammation appears prominenently in RRMS, as opposed to other neurodegenerative diseases--

In MS, the situation is reversed: inflammation occurs early and is very prominent in many patients, so it was naturally assumed that autoimmunity might be causal; but, as we argue throughout this Perspective, such an assumption may be incorrect. If MS is primarily a degenerative disorder in line with an inside-out mechanism, why would this disease be unique in engendering such prominent and cyclic inflammation? The differences may be related to age: Alzheimer’s disease and Parkinson’s disease present decades later than MS, and immune responsiveness wanes with age through a process of ‘immune senescence’ Indeed, the responsiveness of T cells, which are known to be centrally involved in the immunopathogenesis of MS 88, appears to be particularly altered with age 87. Moreover, it is conceivable that the putative cytodegeneration involving the myelinating unit (oligodendroglia, their processes and myelin) in MS releases debris that is more antigenic 35,36,66 than the debris that is shed from the mainly synaptic and neuronal degeneration in Alzheimer’s disease and other traditional neurodegenerative disorders.

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Re: Will the real multiple sclerosis please stand up?

Postby cervocuit » Thu Jul 12, 2012 1:44 am

It’s an interesting theory, but does dr Stys explains in his paper what we can see on MRI ?
Does he think that the neurodegeneration is disseminated in time and space (not the case in Alzheimer) ? Otherwise, the neurodegeneration is global and for those who have a reactiv immune systetm (the youngs), it clean up only selected debris between whiles for some reason ?

There is also evidences that people with MS has more chance to develop other autoimmune deseases. It’s hard to believe that a slow neurodegeneration would create acute inflammation in bowel or joints. The only one person with MS that I know personally had hashimoto’s thyroidis 5 years before the first symptom of MS.
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Re: Will the real multiple sclerosis please stand up?

Postby jimmylegs » Thu Jul 12, 2012 4:56 am

prions and protein misfolding seemed to enjoy a few mentions here a few years ago, off my radar entirely until this year. thoughts on that angle?
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Re: Will the real multiple sclerosis please stand up?

Postby HarryZ » Thu Jul 12, 2012 6:29 am

There is also evidences that people with MS has more chance to develop other autoimmune deseases. It’s hard to believe that a slow neurodegeneration would create acute inflammation in bowel or joints. The only one person with MS that I know personally had hashimoto’s thyroidis 5 years before the first symptom of MS.


Interesting comment about other autoimmune diseases. My wife, who had MS for 36 years, rarely had a cold or any kind of viral problem after her first attack. I can remember her neuro telling her years ago that they thought MS patients had an overactive immune system and, as a result, didn't come down with other viral diseases nearly as often as other people. Yet, as a teenager, she had the measles 3 times! Go figure.
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