Wednesday, 24 July 2013

Damage occurs early in MS

Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Brück W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain. 2002;125:2202-12.

Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP‐positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP‐positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so‐called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP‐positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8‐positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon‐protective treatment should start as early as possible and include strategies preventing T cell/macrophage‐mediated axon destruction and leading to remyelination of axons.

Amyloid precursor protein (APP) is shuttled down the nerve from the head to the feet, if there is a break the APP goes down the nerve then accumulates at the cut and makes a bleb. You can count the blebs. 

Bruce Trapps group did this and found 11,000 in the active lesion and < 1 in health nerve areas. This was mentioned on the brain shred post by ProfG. This says that damage is associated with the amount of active inflammation, block this and you block the nerve damage. This current post says the same thing, that nerve damage correlates with the amount and duration of inflammation. They findmore active damage early on and less later in disease. This is what we would expect because inflammatory disease is more active early in disease. This we know from MRI where gadolinium enhancing lesions are more common early in disease. This study also shows that the amount of damage correlates with the amount of inflammation. This is associated with T cells and microglia. Therefore it makes sense to think the anti-inflammatory approach within the CNS is a way to go. Target this aspect and block it and then let's see if it stops nerve transections. The doubting minnnies will say they are clearing up the damage. Let's see. 

They show that this damage occurs early so lets start treating this early. That is what we are trying with some of the optic neuritis trials. Protecting the nerves from the effects of inflammation, put this on top of stopping the inflammatory cells getting into the brain and you get a double whammy. This is what we are doing with the PROXIMUS trial. My gut feeling is that this early activity takes out the vulnerable nerve pools leaving the more sturdy nerves and these are damaged more slowly. Let's see what the trials bring.

19 comments:

  1. MouseDoc, this so-called "current" paper is more than a decade old.

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    1. But it gives the rationale for doing the clinical trial (as have our own research results). It's an oldie but goldie!

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    2. Whilst you aee chastising i suggest that you read the comments on the M2 remyelination post on 27th july and then you may understand the reasons for the post.

      Questions are questions if one person thinks it. So Does another. Regards as always :-)

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  2. MD2,these new wonder DMTs will be swell for newbies, but what happens to us oldie MSers? Where is the momentum for us?

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    1. The momentum is totally with you...it just takes time to show itself

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  3. After 10+ years still haven't learned....;"Hit hard and early" is the take home message. Yet there tends to be complacency when it comes to prescribing DMTs based on the initial clinical symptoms that resolve on there own. Why isn't there a mandate for prescribing aggressively? (I realize its $ but waiting until disability sets in is even more costly).Patients need to know that early treatment is critical even though their symptoms may be minimal. Wait and see attitude should not be an option.

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  4. MD, MD2, these are excerpts from the study above:
    1. "The PPWM (n = 81) showed no signs of demyelination."
    2. "APP‐positive axons can be detected in all stages of demyelinating activity and also in the PPWM"

    where PPWM = PeriPlaque White Matter

    Combining proposistions 1 & 2 leads to a clear conclusion: That immediate axonal damage is NOT the result of demyelination. Instead, axonal damage and demyelination inside and around a new lesion are the result of another preceeding process. Thus all these talking about early treatment is just the "immune-mediated"-Bias speaking.

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    1. More likely is the axonal damage in the PPWM is as a result of the diffusion of toxic cytokines etc from areas where there are/have been inflammatory demyelinating lesions. The early treatment proposed is not "immune-mediated bias", the report recommends we need a combination of efective DMTs combined with the early administration of neuroprotectants to save as many nerves as possible. Surely that's a good thing?

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    2. "...the axonal damage in the PPWM is as a result of the diffusion of toxic cytokines..." - can you prove this?

      Read carefully the second proposition: damaged axons are visible in ALL stages of demyelinating activity, which means even in the early stages. How is this possible? Are axons so very delicate to get truncated right in the beginning of demyelination?

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    3. "We found APP‐positive axons in the PPWM without any signs of demyelination. These findings indicate that axonal damage occurs without visible demyelination or even precedes demyelination."

      Your readers might find this confusing, since they have been always told that axons die as a result of demyelination. If axons can die without demyelination in sight then MS is progressive right from the beginning. And since no drug is effective in progressive stages then none is going to be effective in any stage.

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    4. The axons are dying as a result of toxic factors released by infiltrating inflammatory cells (which cause demyelination locally in MS). The clue is the APP-positive axons are right next to lesions (PPWM).
      We have never said that axons die solely as a result of demyelination, though this can make them more vulnerable to death down the line. So, stop the inflammation and you should stop the axons dying and since there are many drugs that can now do this then certainly where inflammation is ongoing these should be effective particularly combined with neuroprotective therapies.
      The challenge is to prevent axons dying in PPMS and SPMS and here it is plain that DMTs are less/not effective so neuroprotective agents are indicated here.

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    5. MD2 you need to remind VV that a central axon can be up to a metre, or more, in length. Therefore a lesion at a subcortical level, say 1 cms from the cell body, can cause enough axonal dysfunction in the remainder of the 99cm of axon so that when you section it proximal or distal to the demyelinating lesion it looks sick. So if you section the axon at say 15 cm it will look sick with delay axonal transport causing a traffic jam (bulbs or early bulbs) that are biologically miles away from the proximal lesion that is likely to be demyelinating.

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    6. Wise words there Gavin. I hope VV takes note. I've been thinking about this and in conjunction with some work we've done previously I've come up with a new project!

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    7. Let's see.
      APP is measurable in sites of recent and violent axon injury, not just mere axonal dysfunction. A sick axon wouldn't be APP visible. That's why APP is detectable for less than a month. At least that is what the authors say:

      "...we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of RECENT axon TRANSECTION or DAMAGE."

      So what the researchers measured was the number of violently broken apart axons within a lesion. Since the size of a lesion is way smaller than the length of an axon (1cm to 100cm in your example), the demyelination within the lesion can not account for the extent of damage necessary to produce detectable APP levels. So there must be a different mechanism transecting the axons inside a lesion.

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    8. What exactly is a 'central axon'?

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  5. Axonal damage without demyelination is just one potential mechanism you see it in eae all the time.

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    1. Why should we care about the way axons die in a fabricated mouse disease?

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    2. You posed the question not me

      Why......because it is biology

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