Axonal loss

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Axonal loss

Postby bromley » Sat Apr 15, 2006 8:51 am

In recent years it has been recognised that axonal loss is the main cause of permanent disability. The traditional view is that attacks by the immune sytem result in demyelination and that the underlying nerve fibres (axons) degenerate. The damage is considered to take place under the lesions which form where de-myelination has occurred. As with everything connected with this disease - nothing is straightforward. Attached is an article which suggestes that demyelination and axonal loss are not necessarily linked. One of the authors is Professor Esiri and I have been following her work for some time. She is funded by the UK MS Society to study the damage caused by MS and its cause. I think this research may well turn out to be a turning point. It might be that axonal damage / loss occurs before the immune response. It's not comfortable reading but the sooner the researchers get a better understanding of what is happening and why, the sooner they can identify ways to address the problem.

Ian


http://www.msif.org/en/research/researc ... ution.html
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Postby mrhodes40 » Sat Apr 15, 2006 9:43 am

Great Paper thanks for posting it. If you go to that paper and click the link called related articles in the upper right corner, you get a list of other older material talking about axon loss compared to myelin/lesion load and it all is saying much the same thing. Sadly this is less "new" than it seems....
It dovetails nicely with Prineas and Barnett's paper though. If the nerves die then the immune system comes in what other damage might occur? IT is known that things in the periphery which would damage myelin are kept out by the bbb, and according to my neurologist this includes myelin active antibodies which are molecular mimics. He said everyone has myelin active antibodies in their blood ( I was asking why we can't test for the myelin active antibodies), the problem is most people keep them out of their brains.

The bbb can be opened on purpose by activated microglia, say if a cell dies, in order to have peripheral monocytes t-cells etc in to clean up .

warning speculation: maybe the nerves die as suggested by P&B, the microglia activate and open the BBB, peripheral immune cells enter, and bring with them accidentally these molecular mimics that damage the myelin, causing a secondary myelin issue. Kind of like if you get a cold you might get an earache secondary. And interestingly did you know that b-cells are often infected with EBV and carry it in to where they go? I stumbled into this in the RA world. There is high levels of ebv in RA joints but it is thught to be secondary to b-cell presence not the primary cause of the joint problem.

Speculation and more speculation! God I wish there was more solved/
I certainly hope it is a good year for MS!
Marie
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Postby bromley » Sat Apr 15, 2006 11:43 pm

Marie,

The real breakthrough will come when the experts work out the chain of events. The B cell angle is very interesting as Rituximab reduces the number of B cells (being trialled in PP, SP and RR). The drug has also recently been approved for RA has it has shown good results for RA cases where other drugs did not.

All the best

Ian
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Re: Axonal loss

Postby HarryZ » Sun Apr 16, 2006 6:35 am

Ian,

Thanks for that very interesting article.

I think that many comments have been made that demyelination is a reaction by the immune system to something else far more destructive going on when it comes to MS. Yet we all know where the vast majority of MS research continues to center around....more powerful immune system altering drugs that try and prevent this secondary action.

I fear that unless this line of research changes, the real culprit isn't going to be discovered for quite some time.

Harry
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Inside Out or Outside In Demyelination?

Postby Shayk » Sun Apr 16, 2006 8:12 pm

Ian

Welcome back....I'm fascinated by this research on axonal loss and whether or not it's related to demyelination. I think you're absolutely right that once they know the injury cascade we're much closer to better interventions.

Here are some abstracts about axonal loss that may, or, as the case may be when you have no medical or scientific background, may not :wink: be related.

Inside Out vs. Outside In Models of Virus Induced Demyelination: Axonal Damage Triggering Demyelination
The primary target in multiple sclerosis (MS) is believed to be either myelin itself (myelinopathy) or the myelin-forming cell, the oligodendrocyte (oligodendrogliopathy). Although axonal injury occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from myelin (outside) to the axon (inside) (Outside-In model). Recently, gray matter lesions and axonal injury in normal-appearing white matter have also been reported in MS. This raises two questions. 1) Is axonal injury exclusively secondary to myelin damage or from a direct insult to the axon or neurons (axonopathy)? (2) Is the injured axon regarded as only an end result of pathology or disease, or can axonal injury contribute to the spread of secondary damage, including demyelination? ...spinal cord sections demonstrates that axonal injury with oligodendrocyte apoptosis also precedes demyelination in an animal model for MS....This implies that axonal injury could trigger demyelination. In this instance, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).


The same researchers later reported: Axonal injury heralds virus induced demyelination
The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.


And, lastly, there's this. Axonal loss in normal-appearing white matter in a patient with acute MS
Confocal and electron microscopy revealed myelin sheaths without axonal content....CONCLUSIONS: These studies confirm axonal degeneration in the absence of myelin loss as one histopathologic correlate to abnormal MR findings in patients with MS.

The "inside out" model of axonal loss actually makes some sense to me on the surface. It could help explain (or so it seems) why men (with that thicker myelin from testosterone :wink: ) generally have less inflammation than women and tend to be diagnosed at a later age.

This same research group has also found a relationship with COX-2 in a model of viral induced demyelination. Pathological Role for COX-2
COX-2 is an enzyme that is tightly coupled to neuronal excitotoxic death.....The presence of the cell death marker (activated caspase 3) with COX-2 in oligodendrocytes is direct evidence linking COX-2 with cell death of oligodendrocytes in these demyelinating diseases.

Hopefully some line of research will make 2006 a very good year for MS. I'm optimistic progress is being made.

Sharon
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Postby bromley » Mon Apr 17, 2006 12:31 am

Thanks Sharon,

Dr Esiri's work is due to report in June - she is a neuropathologist.
I imagine that we will also see another instalment in the Lesion Project overseen by Dr Luccinetti.

The inside v outside issue seems to be key. MS, or some forms of it, may be like a car rusting from the inside and every now and then some paint flakes off. Patching up the area where the paint flakes off will never address the undelying problem.

I do see a shift in the research. The recent research on Testosterone talks about tissue loss rather than myelin. But there's an industry focussed on the myelin / auto-immune theory and it will take time to shift them.

Ian
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