Thursday, 18 October 2012

MS - a disease of nerve pathways?

Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. 

In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement inmultiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems.

Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a 'tract-specific' pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.

This study by a team in Oxford further underpins the suspicion that ‘inflammatory demyelination’ is only a fraction of what underlies disease progression in MS.  In a combined MRI and histology study using whole brains donated to the UK MS Society’s Tissue Bank the authors detected correlation between various measures of neurodegeneration ‘within connected pathways’ in the brain, however no such association ‘between different areas’ of the brain.  Measures of neurodegeneration included cortical thickness, neuronal cell and nerve fibre counts.  The two pathways included were tracts connecting specific nerve cell populations in the thalamus (a major ‘switchboard’ of information in the brain) and (i) the visual and (ii) the pre-frontal cortex. Demyelinating lesions had virtually no impact on the detected relationships.

What is the significance of these results?
According to this data MS leads to preferential damage of directly connected areas in the brain suggesting MS is a systemic neurodegenerative disease leading to nerve cell and fibre loss irrespective of demyelinating lesions.

What needs to be done next?
We need to better understand the mechanisms underlying neurodegeneration in MS to enable development of new treatments targeting these mechanisms!

This study is open access so you can all read it.


  1. Fascinating post. Always good to learn something new.
    Thanks Klaus!

  2. Dr K or Dr S? Does this support the comments and opinions expressed on this blog that MS is a neurodegenerative disease and not an autoimmune disease and that powerful anti-inflammatory drugs will have no effect on disease progression? I am particularly worried about cognitive impairment. I need to know whether or not to take up the option of having alemtuzumab ASAP or waiting for my disease to become more active in the future. Thank you.

    1. Anon, do you know that alemtuzumab has been withdrawn from the market? You will have to wait for the relaunch of the drug and even then access may be denied to you based on its license and NICE guidance; that's assuming you live in the UK.

    2. It's probably both, where neurodegenration and inflammation are intimately linked. Suppressing relapses can have an effect on progression (slowing neurodegenration)as seen with alemtuzumab. This indicates that inflammation does play at least some part in the degenerative process.

  3. Replies
    1. Klaus is part of the Team G clinical arm. He's an MS MRI/pathology expert.

  4. Replies
    1. Put the captcha back. It may help

  5. again MD2 - please cancel the possibility to post anonymously.

    No point in begging people not to post, they will always do.

  6. If proven this is really, really BAD NEWS. We will progress regardless of what treatment we decide to take. This research will lead to another 20 years of further research.If you've go MS now it's a grim situation. I always looked for hope on this site, but the primarily neuro-degenerative scenario was always the worse (as its most things with this disease). Only the researchers can be pleased with the findings form this study. I'm sick to death how, in 2012, we still ahve not treatments to really address this dreadful disease!

    1. Anonymous 4.36
      It's not as bleak as you suggest. The degeneration is linked to inflammatory lesions so the more of those you stop, the better the outcome is likely to be. see the alemtuzumab link I posted upthread.
      What is clear is that we also need to be also using neuroprotective agents in combination with DMTs so any neurodegeneration can be reduced as well as new lesions. Studies on neuroprotectants in MS are now ongoing.

  7. When nerves are attacked they can die and this can include all of the nerve this prossess is often term Wallerian degeneration. So if you have damage to a nerve say by inflammation in one part of the nerve tract its effects will eventually be seen in another part, where there may be no inflammation in sight. However inflammation could be critical to the process. We see this in the beasties also where we know what the cause is

    1. MD and MD 2,

      Thanks for the response. My post was a bit OTT, bu it's pretty tough thinking about progression.

      "Studies on neuroprotectants in MS are now ongoing" - are these research studies or actual trials of agents? I was so hopeful for lamotrigine and then the CUPID trail, but have been left jaded. Do the agents currently being examined offer promise of protecting nerves? Are we talking 5, 10, 15 years before they are on the shelf in Boots?

      How does the above study fit with Prof G's EBV theory?

    2. Studies on neuroprotectants in MS are now ongoing are these actual trials...Yes these are actual trials, we are doing doing a few new ones and will be recruiting soon and there are some other ones that are round the corner....I cannot say anything as not sure all i's have been dotted you you will hear soon. as the Novartis plug indicated there is a new trial on SPMS with a Gilenya me too I will post some new info related to this the title sound interesting I need to check out content. There are Gilenya, nataluzimab trials in PPMS and others. Then there are is the amiloirde trial etc etc ......

      Now to the lamotrigine trial if you speak to the Neuros who did the trial, they believe it worked, but they cocked-up in their trial design. It was not long enough and the wrong endpoint was selected.
      Likewise we have yet to see the publication of the data of CUPID but it has been presented. Again trial design was part of the problem. This is common in MS history. The first trials fail as neuros work out how best to do trials to show effects...This was the cases with DMT for RRMSers and now the trial well developed. In CUPID the problem was that people did too well. If you are in a trial you do better even if you are on placebo and so Progressive MSers on the trial did not deteriorate at the predicted rate making it almost impossible to show a slowing of deterioration. However if you only look at the group of less disabled Msers who where at a stage of EDSS that is known to progress quicker (showing that EDSS in not linear meaning a change from 4 to 5 is not the same as say a change from 7 to 8) then the drug appeared to work.

      However, in clinical trials you have to say what your drug is going to do before you start to consider it positive. If it does not do that this is a failure and you have to do another study to show it works. This is done to stop pharma moving the goal posts after the trial has finished to get a positive result. They wouldn't do that would they?.

      Are we talking 5, 10, 15 years....yes probably to all of them. Different drugs will appear at different times. Many of the drugs being tested by academics are already on the shelf at Boots but they just have to be designated for use in MS rather than other diseases such as epilepsy. It depends on the trials if it is a big trial over three year it is going to take 5 years to do some of Prof Gs trials it may be 2 years,if they work and then convincing NICE. I won't make promises because that is not in my power to control.

    3. How does the above study fit with Prof G's EBV theory?

      This is part of the equation the EBV comes earlier as a "trigger" and "cause" the neuroprotection studies are a "consequence" down the line.


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.