Theories: "Auto-Immune" vs. Not

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

Postby bromley » Sun May 29, 2005 2:55 pm

Harry,

On the grey matter issue. The following is an extract from an article from the UK MS MRI Unit on the UK MS Society website.

We are trying to find markers of prognosis (a prediction of disease progression) early on because this will help decide who will most likely benefit from new treatments. MRI lesion volume has some effect on the long term course but is a relatively weak predictor. We are now investigating other measures that show a more extensive abnormality than just the visible lesions. There are intrinsic abnormalities in the normal appearing white matter and grey matter that show up with measures including magnetisation transfer ratio (MTR) - specific types of MRI scans allowing more precise detection of damage, and MR spectroscopy. There is also loss of tissue in both the white and grey matter.


The following article is also from the UK MS Society website:

Damage in the Grey Matter in Multiple Sclerosis (MS)
March 2005, we look at Professor Margaret Esiri's study of grey matter in MS.


The brain can be divided into grey and white matter. Grey matter is the area where nerve cells communicate with each other. White matter acts as the wiring between different areas of the brain. Traditionally MS researchers focused on damage in the white matter because damage in this area appeared to explain all the characteristic relapsing remitting character of the earlier stages of disease. However, white matter damage cannot explain disability progression in a simple way. It alone also does not easily explain memory problems in MS, which can be found in roughly half of the patients.

Damage in the grey matter in MS provides an alternative explanation for these symptoms. We are interested in investigating changes in the grey matter in MS. Although damage in the grey matter was recognised many years ago, these changes were not widely appreciated. Recent studies have re-examined the grey matter and suggest that we may have underestimated the importance of damage in this area.

A study conducted at our department focused on nerve cells and their junctions in one grey matter area. This work demonstrated that there was a loss of nerve cells and their junctions within damaged grey matter in MS. These observations that nerve cells and their junctions are damaged in MS could help us to explain psychological findings such as memory problems. Our findings could be relevant for new treatments for MS that protect nerve cells and their junctions.


What's not clear is why the grey matter is being damaged. Is it from the inflammation that occurs when the myelin (white matter) is damaged or is there another reason (neuro-degeneration?). Much recent research has revealed that this disease is even worse than first imagined. On the plus, the more the scientists know about it the better they should become at identifying strategies to combat it. By the time they have solved the mystery I will have probably lost so much grey matter that I would have forgotten that I promised to buy you a drink.

Ian
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Postby raven » Sun May 29, 2005 4:10 pm

Don't worry Ian,

We'll just turn up and remind you that you promised to buy the first 2 rounds :wink:

Just to throw a little more confusion into the pot....

Presented at ACTRIMS 2004

EFFECT OF INTERFERON BETA-1A ON GREY MATTER ATROPHY PROGRESSION IN RELAPSING-REMITTING MULTIPLE SCLEROSIS

R Zivadinov1, L Locatelli2, B Srinivasaraghavan1, M Ukmar2, A Bratina2, C Maggiore2, A Bosco2, A Grop2, R Pozzi-Mucelli2, M Catalan2 and M Zorzon

University of Buffalo, Neurology, Buffalo, New York, USA; University of Trieste, Neurology, Trieste, Italy

Keywords: brain atrophy; grey matter atrophy; interferon
beta-1a; longitudinal; MRI; trial

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) that involves most prominently the white matter (WM) of the brain. It has been demonstrated that substantial gray matter (GM) damage in the brain occurs from the earliest stages of the disease. Two recently concluded clinical trials showed that Avonex® (IFN beta-1a; Biogen, Inc., Cambridge, MA) slows down the rate of brain atrophy progression in the second and third year of the trial. However, more detailed information on the effect of this disease-modifying treatment (DMT) on the topography of CNS atrophy has not been provided yet.

Objectives: To determine whether Avonex® slows down progression of brain atrophy by reducing predominantly GM or WM damage, or both.

Methods: Thirty-one patients with MS have been included in the study and followed for 3 years. The inclusion criteria were: relapsing-remitting (RR) MS, Expanded Disability Status Scale (EDSS) 0–5.5 and one exacerbation in the 12 months prior to study entry. At study entry, the therapy with Avonex® has been offeredto all patients. Fourteen patients started treatment with Avonex®, whereas 17 decided to delay the start of DMT and served as study controls. Both groups had quantitative cranial MRI scans at study entry and after three years, and standardized clinical assessments every 6 months. Brain parenchymal fraction (BPF), grey matter fraction (GMF) and white matter fraction (WMF) percent changes were calculated using SPM99 software program.

Results: Three patients in the control arm have been excluded from the study, because they started DMT before the study conclusion. Baseline demographic, clinical, and MRI measures were well matched between the two study arms. None of the patients on Avonex® developed neutralizing antibodies during the study. Mean percent change in BPF ( -1.2% vs. -2.2%, p = 0.003) and GMF (+3.6% vs. -4.2%, p < 0.0001) favored the Avonex® treatment arm. Both treatment groups developed similar amounts of WM atrophy over 3 years (p = NS).

Conclusions: The results of this preliminary study indicate that Avonex® may slow down brain atrophy progression preventing predominantly the development of GM atrophy.

Disclosures: R Zivadinov has nothing to disclose.

Funding: No funding reported.


http://www.nationalmssociety.org/pdf/forpros/ACTRIMS04.pdf

Robin
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Postby finn » Mon May 30, 2005 7:58 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:14 pm, edited 1 time in total.
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Postby reed » Mon May 30, 2005 9:09 am

finn wrote:Robin, Ian, Harry, Reed

You guys made an offer no Finn can refuse. Once this thing is solved I'll take the first plane to London. A couple of drinks after a long dry season (some balance problems at the moment, you know) sounds like an excellent idea. Btw, Harry, Reed, is it ok with you if we meet in the UK?


Surely. We should also ask Sarah and David if they would join us. (And maybe strawberries at Wimbleton, to boot?)
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Postby SarahLonglands » Mon May 30, 2005 10:04 am

Nah, I don't think most of those people would want to see us, for some reason. And strawberries at Wimbledon are way overpriced!

However, if they did, I do know a nice little micro-brewery, though, fairly nearby :wink:

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Postby bromley » Mon May 30, 2005 10:22 am

Reed & co,

I don't mind buying a few beers but you're pushing it with strawberries and Wimbledon. What next - tea with the Queen?

If they ever solve the mystery (and more importantly how to get us back to normal) I'll hire the ****ing Millennium Dome in London and invite the 2,000 users of this site. The bill for the event will be forwarded to Biogen and the other ms drug companies. Guest of honour will be Arron.


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Postby HarryZ » Mon May 30, 2005 11:29 am

Finn,

OK, I'll jump on an airplane (easy to do being a retired airline employee)and fly to London. But I warn you , that trip will make me VERY thirsty :D

Brain wrote:An increase in lesion load (LL), a decrease of brain volume (BV) and a reduction of N-acetylaspartate (NAA) are all thought to reflect disease progression in MS.


Now that's interesting about N-actylaspartate. In the one and only Prokarin double-blind clinical trial, Dr. Richards did a side study on the level of N-actylaspartate levels he saw on the MR Sptectroscopies that were done on all the patients. In the end, all the patients on Prokarin had much higher NAct levels than before they started the trial. But what totally surprised him was that these increased levels were seen after only 3 months as opposed to the normal 9-12 month minimum period that it usually takes to see these increases. When my wife started using Prokarin some 5 years ago, that so called "brain fog" symptom that she had soon went away and left her far more alert. So the histamine therapy (Prokarin) that she is using likely had a dramatic, positive effect on N-Act which I guess is very good.

Harry
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Postby kareng7 » Sat Jun 11, 2005 11:11 am

HarryZ wrote:The reason that Prineas and Barrett's autopsy work has caused such a stir in MS circles is because it is the first time that someone has actually been able to scientifically look at a lethal lesion so quickly after the patient died. They were able to see something very different to what the researches have thought for years..


I know I asked this question before but I literally lost the thread. Did Prineas and Barrett prove conclusively that they were examining deceased patients with MS, and not another similar but more notoriously lethal disease, such as Devic's Syndrome?

http://www.mult-sclerosis.org/Devicssyndrome.html

When I brought their research up to my neurologist, that was her first question.
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Postby HarryZ » Sat Jun 11, 2005 12:00 pm

kareng7 wrote:
HarryZ wrote:The reason that Prineas and Barrett's
I know I asked this question before but I literally lost the thread. Did Prineas and Barrett prove conclusively that they were examining deceased patients with MS, and not another similar but more notoriously lethal disease, such as Devic's Syndrome?


I can only go by the paper that Prineas and Barrett published and they stated that the patients they examined did indeed have MS. The young lady that died from a severe exacerbation gave them the opportunity of examining a lethal lesion within 18 hours after death which apparently was a "first". I can only assume that these 2 notable MS researchers looked into other possible causes of death.

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Postby SarahLonglands » Sat Jun 11, 2005 3:27 pm

I'm afraid it was MS: We have a full copy of the paper, which was sent by Dr. Prineas when my husband, also a pathologist, showed much interest.


I posted this in the thread entitled "Scientists in NZ say they have a cure!" It took me ages to find it. I will just reiterate what Harry said, with the addition that I have read the full paper more than once. It has some very excellent images.

'night all,

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More on Not Auto-Immune

Postby Shayk » Tue Jul 26, 2005 8:56 pm

Hi all

Now that you’ve had this great discussion, here’s an abstract I just saw today and a couple I don’t think I’ve seen posted yet that seem relevant to the “not auto-immune” discussion.

The first abstract appears to support that axonal injury may precede inflammation. Finn, I think you first suggested that inflammation might be secondary and perhaps neuroprotective. ;-)
Astrocyte-associated axonal damage in pre-onset stages of experimental EAE

Recent studies of axon-glia and glia-glia communication have emphasized interactivity and interdependence between central nervous system (CNS) components. Concurrently, data from imaging, biochemical, and morphological studies have changed the view of multiple sclerosis (MS) from a neuroinflammatory condition with primary demyelination to one in which cumulative axonal damage drives progression. We therefore studied axonal damage in the context of inflammation and glial responses, from the pre-clinical to onset stage of murine experimental autoimmune encephalomyelitis (EAE), an established MS model. We report three major findings: (1) the first evidence of axonal injury before significant T-cell entry into the parenchyma, (3) coincidence of the earliest manifestation of axonal damage and astrocytic responses, and (3) an association between accumulation of axonal and astrocytic changes and specific forms of MS. These data demonstrate the relationship between the initiation of axonal injury and early inflammation. Significantly, we show that, in common with a growing number of neurodegenerative conditions, the pathology of murine EAE is characterized by early active contribution from astrocytes. This marks a change in the understanding of the role of astrocytes in MS pathogenesis and has important implications for the development of neuroprotective strategies.


These next two abstracts seem to reinforce the notion that inflammatory lesions may not be the primary and/or only cause of axonal degeneration and disability in MS.

Diffusion-Tensor Magnetic Resonance Imaging Detects Normal-Appearing White Matter Damage Unrelated to Short-term Disease Activity in Patients at the Earliest Clinical Stage of Multiple Sclerosis

CONCLUSIONS: In patients with multiple sclerosis at the earliest clinical stage, the severity of NAWM damage does not predict new lesion formation in the short term, suggesting that the "diffuse" component of tissue damage is, at least partially, independent of the "discrete," predominantly inflammatory aspects of the disease since its clinical onset.


Axonal Injury and Overall Tissue Loss Are Not Related in Primary Progressive Multiple Sclerosis

CONCLUSIONS: Axonal-neuronal damage in the brain of patients with PPMS seems to occur, at least partially, independently of the burden of magnetic resonance imaging-visible lesions.


The answer is out there somewhere. Take care everyone.

Sharon (btw-I think everyone will be drinking hormone laced designer cocktails at the party. :-) )
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Postby finn » Tue Jul 26, 2005 11:13 pm

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:15 pm, edited 2 times in total.
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Postby bromley » Wed Jul 27, 2005 2:29 am

Sharon / Finn,

Thanks for the post Sharon.

There are so many questions still unanswered by the MS research professions.

On the issue of the different sub-types of MS, you get different responses from different 'experts'. My MS nurse (who sees hundreds of people with MS) believes that PPMS is a totally different disease. But one of the MS neurologists I met believed it to be the same disease. He also believed that by using very heavy immune suppressing drugs you could actually change RRMS into PPMS i.e little inflammatory activity but the disease still progresses. I have also seen papers comparing Secondary Progressive MS and PPMS. The conclusion was that they are pretty much the same in terms of time to different levels of disability.

There are the other sub-types 'benign' and 'malignant'. But there have been questions over the term benign. Malignant covers those poor souls like Jacqueline Du Pre who have a very rapid decline (and pass away).
I suppose theses different sub-types might all be the same but its the way our bodies react to them - I suppose a bit like flu.

The other fly in the ointment is the improvements in disability seen by sufferers who have taken Campath and Tovaxin. How does this match to the view that MS is primarily a neuro-degenerative disease as these treatments target the immune system?

I'm also confused by the inflammation bad v inflammation good issues. For years, relapses have been treated with steroids to dampen inflammation and generally this has positive results i.e getting back functions etc. But now some say that inflammation is neuro-protective. So should we stop taking the steroids? Should we be encouraging more inflammation if it's so good?

Sharon might be right on the importance of hormones. MS is more common in women (I have seen two times and three times more women get MS than men). But women (on average) tend to have a better prognosis than men.


The annual ACTRIMS and ECTRIMS meeting is taking place in Greece at the end of September. This draws together the top MS researchers and experts. I wonder if the presentations and papers will address any of these questions?

The one thing they all seem to agree on is to protect what we have got. Neuro-protection - i.e stop what's destroying our nerves.

Bromley
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Postby raven » Wed Jul 27, 2005 7:55 am

We need a unified field theory for ms....

With reference to Campath (a subject obviously close to my heart!) It may be that the immune system is subtly altered in a way that promotes axonal regeneration.

Interestingly, after Campath-1H the immune cells do seem to encourage nerve cells to grow. Now we have to find out how!

-Alasdair Coles

http://www.mssociety.org.uk/research/research_we_fund/project_of_the_month/alasdair_coles.html

Robin
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Postby finn » Wed Jul 27, 2005 9:38 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:17 pm, edited 1 time in total.
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