Inflammation vs. neurodegeneration

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

Postby Lyon » Tue Jul 24, 2007 9:12 am

Hi finn,
finn wrote:Btw, I have decided to quit using smileys and give people an opportunity to interpret my posts just the way they want. I'd like to serve my humour dry.
Fine...I'm an old man whose time and smileys are short. I'm going to use the heck out of them until Arron prys them from my cold, dead fingers :lol:

finn wrote: I'd suggest that our disease could always be called "progressive MS", a slowly progressive neurodegenerative process followed by demyelination.8O (thought you snuck that one by me eh?) When there is inflammation present in our CNS, the progression of neurodegeneration (and permanent disability) is slower, and the disease can be called RRMS (or SPMS).
I agree that MS in any stage or phase (even "CIS" and "benign") can be considered progressive but the existance of the separate definitions of PPMS and SPMS implies that some people don't go through the RRMS phase and instead collect $50 and go straight to PPMS.

I think it's a LOT more sensible to consider that EVERYONE goes through RRMS but around 10% (the 10% now diagnosed as PPMS) don't experience symptoms until the limits of plasticity are reached and symptoms become evident in the SPMS phase, rather than the "normal" RRMS phase.

Not a big deal in itself but the existance of the PPMS phase is just another misconception to needlessly complicate things.

Lyon wrote:So.....you are going to add another diamond and “simultaneous two-component” to your list?

Most likely there is an unknown relationship between the two of them, but I'd say the option is more or less covered when stated that "Inflammation and neurodegeneration are seperate and independent processes".[/quote]I somewhat agree finn but the "simultaneous" describes the fact that, whether separate or not, the inflammation and neurodegeneration are acting at the same time. On the other hand the "simultaneous" might hint that neurodegeneration and inflammation start at the same time and I don't want to touch that one because the information doesn't yet exist to prove either way.

Bob
Last edited by Lyon on Tue Jul 24, 2007 12:33 pm, edited 1 time in total.
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Postby finn » Tue Jul 24, 2007 11:05 am

Bob,

in the light of current knowledge it should be quite certain that if there was inflammation, there is also neurodegeneration present at the same time in the pathology of MS (not necessary vice versa, though).

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby Lyon » Tue Jul 24, 2007 12:51 pm

finn wrote:in the light of current knowledge it should be quite certain that if there was inflammation, there is also neurodegeneration present at the same time in the pathology of MS (not necessary vice versa, though).
Hi finn,
Your English is fine and I'm not trying to purposely frustrate you but to my understanding
(not necessary vice versa, though)
means that there might not necessarily be neurodegeneration without inflammation.

Is that what you mean to imply? Unless I'm not understanding properly that seems contrary to everything the old finn has ever stood for.

Bob
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Postby finn » Wed Jul 25, 2007 12:09 am

Bob,

Since I got you confused, I must have used the phrase the wrong way. What I meant was that
  • when there is inflammation, there is also neurodegeneration.
  • there can be neurodegeneration without inflammation.
I hope this clarifies the way I see it.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby Lyon » Wed Jul 25, 2007 6:32 am

Thanks for clarifying finn and I don't disagree.
Bob
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Postby dignan » Sat Aug 18, 2007 9:34 am

Always looking for a chance to kickstart this thread...the abstract below includes information on the role of inflammation in the brain.



Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins.

Int Rev Neurobiol. 2007;82:29-55
Griffiths M, Neal JW, Gasque P.
Brain Inflammation and Immunity Group (BIIG), Department of Medical Biochemistry, School of Medicine, Cardiff University, CF144XN Cardiff, United Kingdom.

Brain inflammation due to infection, hemorrhage, and aging is associated with activation of the local innate immune system as expressed by infiltrating cells, resident glial cells, and neurons. The innate immune response relies on the detection of "nonself" and "danger-self" ligands behaving as "eat me signals" by a plethora of pattern recognition receptors (PRRs) expressed by professional and amateur phagocytes to promote the clearance of pathogens, toxic cell debris (amyloid fibrils, aggregated synucleins, prions), and apoptotic cells accumulating within the brain parenchyma and the cerebrospinal fluid (CSF). These PRRs (e.g., complement, TLR, CD14, scavenger receptors) are highly conserved between vertebrates and invertebrates and may represent the most ancestral innate scavenging system involved in tissue homeostasis. However, in some diseases, these protective mechanisms lead to neurodegeneration on the ground that several innate immune molecules have neurocytotoxic activities. The response is a "double-edged sword" representing a fine balance between protective and detrimental effects. Several key regulatory mechanisms have now been evidenced in the control of CNS innate immunity, and these could be harnessed to explore novel therapeutic avenues. We will herein provide new emphasis on the role of neuroimmune regulatory proteins (NIRegs), such as CD95L, TNF, CD200, CD47, sialic acids, CD55, CD46, fH, C3a, HMGB1, which are involved in silencing innate immunity at the cellular and molecular levels and suppression of inflammation. For instance, NIRegs may play an important role in controlling lymphocyte/macrophage/microglia hyperinflammatory responses, while sparing host defense and repair mechanisms. Moreover, NIRegs have direct beneficial effects on neurogenesis and contributing to brain tissue remodeling.

Pubmed link
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Thanks Dignan!

Postby Smilingface » Sat Aug 18, 2007 11:28 am

Thanks for the attention to this topic! It's my favorite topic to ponder. I interpret this article as support for a dual mechanism in MS which fits in nicely with my current theory, of course.
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Postby jackD » Thu Aug 30, 2007 1:01 am

How Green Tea's EGCG helps the MS situation has recently been published. It is in my web storage area shown below.

It also has good material related to this topic.

jackD


http://home.ix.netcom.com/~jdalton/egcg-neorond-ms.pdf
.
.
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Postby ewizabeth » Thu Aug 30, 2007 8:36 pm

Inflammation is the enemy, not just for people with MS but many others as well. I try to eat a lot of the natural anti-inflammatory types of foods: veggies, fruits, lean meats omega 3 fats, etc...

It's no wonder that many of the DMD's fight inflammation. JackD, I wish I could tolerate green tea, but tea of any kind gives me a migraine and nausea.
Take care, Ewizabeth Previously Avonex, Rebif & Copaxone RRMS ~Tysabri, 31 infusions, ended 9/09. Starting Copaxone 12/09, waiting for Cladribine to be approved in 2010.
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Pathology of MS

Postby Shayk » Thu Jan 03, 2008 7:52 pm

Finn

Just wanted to let you know that an “MS Expert” has quite explicitly highlighted similar questions about the pathology of MS that you’ve been posing for several years now.

The MS Care Organization has a CME program that includes a presentation (audio/visual) by Bruce Cohen entitled Evolving Views of MS Pathogenesis . It concludes with the following:
Important questions remain regarding the pathogenesis of MS.

It is still not known whether the inflammation directed at CNS antigens is the primary process in MS or an intermediate process.

Is there a parallel degenerative process that might precede and progress only partly in relation to inflammatory events?

It is also unclear to what extent MS represents one disease with stages, a series of phenotypes with diverse causes, or a genetically influenced variable response to inciting factors.

The temporal relationship between inflammation and disability remains to be elucidated, as well as the reasons why inflammatory events appear to recede in later stages of MS.

I bet the questions look really familiar to you. :) I grinned when I arrived at the conclusion of the presentation thinking mmmm I think I’ve read this before. Maybe 2008 will bring us the beginning of some answers—here’s hoping.

Take care

Sharon
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Postby finn » Sat Jan 05, 2008 2:32 am

Sharon, thank you for making my day :-)

It is really great to see this old thread getting bumped up again, and I appreciate your feedback very much.

Thanks for sharing Dr Cohen's presentation, too. It was good.

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby dignan » Sun Jan 06, 2008 8:35 pm

The abstract below alludes to an interesting way of looking at MS pathogenesis:

...in the early stage of acute and relapsing multiple sclerosis, focal plaques in the white matter are formed by relapsing waves of inflammation. With chronicity, however, the inflammatory response becomes trapped behind the blood-brain barrier, giving rise to slowly progressive inflammatory damage that affects the brain and spinal cord in a global sense.



New concepts on progressive multiple sclerosis.

Curr Neurol Neurosci Rep. 2007 May;7(3):239-44.
Lassmann H.
Centre for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien, Austria. hans.lassmann@meduniwien.ac.at

Multiple sclerosis is generally regarded as a putative autoimmune disease of the central nervous system in which a chronic T-cell-mediated inflammation leads to focal plaques of demyelination in the white matter of the central nervous system. This plaque-centered view of the disease, however, fails to explain clinical deterioration of the patients when they have reached the progressive stage of the disease. It was thus postulated during the past few years that besides inflammation there is a neurodegenerative component of the disease that leads to progressive and global brain damage.

This article reviews recent findings that suggest a different explanation. It describes that in the early stage of acute and relapsing multiple sclerosis, focal plaques in the white matter are formed by relapsing waves of inflammation. With chronicity, however, the inflammatory response becomes trapped behind the blood-brain barrier, giving rise to slowly progressive inflammatory damage that affects the brain and spinal cord in a global sense. This is mainly reflected by extensive cortical demyelination and diffuse axonal injury within the normal-appearing white matter. This process seems to be driven by the aberrant formation of ectopic lymphatic tissue within the brain compartment.

Pubmed link
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Postby Jamie » Tue Apr 15, 2008 8:01 pm

TwistedHelix wrote:First of all, and just to prove I don't know what the hell I'm talking about, I made a mistake in the previous post: I didn't mean potassium and sodium; I should have said calcium -- I woke up at 3 o'clock in the morning realising this, which just goes to show that even my dreams are boring!

Finn, I take what you said as a real compliment, especially coming from someone who obviously has an excellent understanding in this field. And as for your English: I would NEVER have guessed you weren't a native English speaker... I'd always assumed you were an English person living in Finland!
I don't have any specialist knowledge about the nervous system: I just do exactly as you guessed; just take various bits of information about research and piece together the ones that seem to fit. A specialist would probably demolish anything I have to say in a few seconds.

Bob, I think what the research was getting at was maintenance. As you know, every cell and structure in the body is regularly repaired, maintained and replaced, and in the case of axons the strength, and possibly frequency, of electrical impulses seems to be a crucial signal to the body to continue that maintenance. If those impulses weaken and stop, so will any effort to repair and tissue, (both axons and myelin), will wither away.
Of course, this still doesn't answer the question about which comes first: myelin damage or axonal decay, or indeed what is the root cause of these events, but I suppose if we knew that this website could close down :roll:
That was a really good point you made about seeing the whole length of an axon -- a bit like trying to see an entire piece of spaghetti in a plate full of bolognese. It made me think: the discovery that unmyelinated Grey matter axons also die in MS made everyone revise the theory that demyelination was the key factor. But what if those axons are only kept alive by the constant stimulation they are supposed to receive from their myelinated neighbours? Demyelination occurs, this weakens the "please keep me maintained" electrical signal in every axon down the line , and we see atrophy in both grey and white matter .

I'm just thinking out loud here as I'm writing, and haven't really thought this through, but my head's spinning so I think I'd better go and concentrate on something simple like quantum physics.

Bob, thanks again for the information you sent me: you've definitely got me convinced about helminths!

Dom.[/i]



I think this is the single most intelligent comment I've ever read on here.
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Postby rainer » Mon Apr 21, 2008 7:29 pm

Inflammation Triggers Cell Fusions That Could Protect Neurons, Stanford Research Shows

Chronic inflammation triggers bone marrow-derived blood cells to travel to the brain and fuse with a certain type of neuron up to 100 times more frequently than previously believed, according to a new study from the Stanford University School of Medicine.
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Postby dignan » Sat May 03, 2008 11:32 am

I think this abstract sounds interesting, although it would be more interesting if we could read the whole article...Anway, they hypothesize that "primary oligodendrocyte dysfunctions" can trigger the secondary immune response.


Oligodendroglial impact on axonal function and survival - a hypothesis.

Demyelinating diseases
Current Opinion in Neurology. 21(3):235-241, June 2008.
Kassmann, Celia Michele; Nave, Klaus-Armin

Abstract:
Purpose of review: Although multiple sclerosis is considered the prototype of a primary autoimmune disease in the central nervous system, there is emerging evidence that primary oligodendrocyte dysfunctions can suffice to trigger a secondary immune response in the nervous system. This short review focuses on the possible primary role of oligodendrocytes in axon loss and inflammatory demyelination.

Recent findings: The analysis of natural and engineered mouse mutants has provided unexpected insight into oligodendrocyte function beyond that of axonal myelination for rapid impulse propagation. Specifically, mutations in some genes thought to be required for myelin assembly revealed an additional role of oligodendrocytes in supporting long-term axonal function and survival. Other mutations have been reported that cause both central nervous system demyelination and neuroinflammation, with pathological features known from human leukodystrophy patients. In human multiple sclerosis, demyelination leads invariably to axon loss, but the underling pathomechanisms may not be restricted to that of a primary immune-mediated disorder.

Summary: Collectively, experimental and pathological findings point to a primary role of myelinating glia in long-term axonal support and suggest that defects of lipid metabolism in oligodendrocytes contribute to inflammatory myelin diseases.
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