Wednesday, 21 January 2015

End-organ damage: MRI grey matter atrophy is brain lost

Is it not time to change the way we think about progressive MS? #MSBlog #MSResearch

Protecting the MS Brain #MS2015

"The post-mortem study below shows that loss of gray matter volume, or atrophy, correlates at post-mortem to loss of neurones. This finding is not new; we have known about it for sometime in MS and in particular other neurodegenerative diseases. This study supports MS being a progressive neurodegenerative disease that is not limited to the white matter, but clearly involves the gray matter to a large extent. The loss of gray matter also explains why cognition is affected so early in MS and why MS given time causes dementia."

"Our current understanding of MS is that the loss of gray matter is driven by focal inflammatory events. However, if inflammation causes too much damage it then primes the surviving neurons to die off over time. This is why if we want to have a major impact on the prognosis of MS we need to switch off inflammation as soon as possible before too  much damage accrues. The corollary is that if we want to have an impact on progressive MS we need additional therapies to add-on to anti-inflammatory therapies; simply switching of inflammation won't do the job at least in the short-term. The latter explains why anti-inflammatory therapies have not worked in progressive MS in short-term studies. I have proposed the therapeutic lag hypothesis to explain why it will take much longer for anti-inflammatory therapies to have an effect in progressive MS."

"A few days ago someone made a comment that we know nothing about progressive MS. I don't agree with them. I think we have a good idea about a large number of the pathological processes underpinning progressive MS and how to target them. What we haven't worked out is how to do trials in progressive MS. This is why the Progressive MS Alliance (PMSA) is trying to do with their new funding call. They are trying to catalyse and new wave of innovation focusing on progressive MS. I still think we need wider adoption of early effective treatment in relapsing MS as a preventive strategy to try and prevent or delay the onset of progressive MS. There are still many MSers with no access to DMTs or with smouldering MS on DMTs. We need to change this. We also need to go beyond NEDA (no evident disease activity), which at present mainly targets focal inflammation, and start focusing on DMTs that reduce end-organ damage; yes. reduce or normalise brain atrophy rates. We have a responsibility to protect the MS brain; we can do this with DMTs and a brain health programme. 'Protecting the MS brain' is my new mantra for 2015 and to achieve this we need a fresh, new, holistic approach."



Epub: Popescu e al. What drives MRI-measured cortical atrophy in multiple sclerosis? Mult Scler. 2015 Jan 12. pii: 1352458514562440.

BACKGROUND: Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown.

OBJECTIVE: We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology.

METHODS: MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model.

RESULTS: Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume.

CONCLUSIONS: In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

CoI: multiple

18 comments:

  1. 'The loss of gray matter also explains why cognition is affected so early in MS and why MS given time causes dementia.'
    'Protecting the MS brain' is my new mantra for 2015 and to achieve this we need a fresh, new, holistic approach."

    Yes, we get it, really we do, I don't need to read this every flipping time I look at this blog. If you are taking a holistic approach then surely this means being mindful of the anxiety that being told you will get dementia induces (well it does in me) and that the symptoms of anxiety are akin to that of cognitive deficits. So right now I've no idea if I have cognitive decline or it is the anxiety.

    Is it not possible to direct these comments (and i'm not disputing that it needs very serious consideration but what the heck can someone with MS do about it?) to NICE etc through a different means?

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  2. As ever, the disease is much worse than we thought. The research community has spent decades trying to understand the disease mechanisms and now have some understanding. Good news? No wait, they now need more time to develop the right types of trials. We are probably looking at the next decade before and anti-progression drug hits the market. Slow? Like a tortoise with no legs with Prof Mouse sitting on its back.

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    Replies
    1. So true. We have to accept that MS will not be cured in our lifetime.

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    2. If it was easy, we'd have done it already.
      It isn't but we (and others) on it and things are moving on apace.
      Watch this space my little bundle of joy.

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    3. I've been watching this space (blog) for the last five years. Actions speak louder than words. While I don't doubt you've all be working hard, I've not seen one benefit to me i.e. something tangible that improves my circumstances and gives me hope for a better future. Stopping neurodegeneration should be the only goal of MS research - anything else should be put on the backburner.

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    4. "We have to accept that MS will not be cured in our lifetime?"

      Why accept this?

      The people who have long-term NEDA after early effective treatment may already disagree.

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    5. "I've not seen one benefit to me."

      Please read through the blog again. There is information in the blog from which everyone can benefit. It may not be the earth shattering change you want and may just be a life style change you can to have a positive impact but this is not nothing.

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    6. I find this blog very helpful, and plan to try a few things based on what I have read here (below comment on statins). I think the pace of MS research is going as about as fast as it can given the nature of science, regulations, etc. I do think that some things could be changed, and that its surprising that with 100,000's of people affected there are not more trials / experiments done by patients. Information is shared faster via the internet, though most of it is anecdotal. I think there has been a missed opportunity for patients to conduct experiments using already approved medicines, vitamins, or the like.

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  3. In regards to your post about Therapeutic lag, it seems interferon may have a benefit in progressive disease. It also seems that this may be the case for Copaxone (at least in the male population).

    So why are progressive MSers on these therapies? It seems like all MSers should be diagnosed with RRMS to allow access to drugs as there is some evidence of benefit.

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  4. Happy days! You certainly know hoe to cheer an MSer up! All in the name of openness and honesty. While I eat my lunch and reflect on the disability and dementia which is coming my way, please can I ask one question - in what timescale are we likely to see effective treatments for neurodegeneration become available? A best guess will suffice. I need some hope as this blog keeps kicking me where it hurts.

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    Replies
    1. It depends where you are. If you are in the UK, then get on a trial and it can be there in a couple of months.

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    2. Thanks. When you get back from the pub please can you tell me the name of the trial and where I sign on (please no white knights gibberish, just a straightforward answer).

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    3. We're off to the pub tonight funnily enough. We'll get back to you if we're in any fit state but a list of current UCLP trials is at the top of the blog.

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    4. SMART MS, SWIFT MS in USA, PROXIMUS etc

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  5. I may be late on this, but what is a "brain health programme" ?

    Is there anything besides high efficiency DMT that can improve the course of their disease?

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  6. I'm thinking whether to ask my doctor about taking Simvastatin as I have high cholesterol (and if I didn't I would eat lots of chocolate until I did!) Perhaps not 80 mg; though whatever is the safe level.

    http://multiple-sclerosis-research.blogspot.com/2014/03/politics-lessons-from-simvastatin-trial.html

    Folks seems to do well on LDN - which seems to help a lot of thing, though since there is not coordination of this and only anecdotes, its hard to know if this slows down things. I just need to know if its safe to take both LDN and Simvastatin together.

    Are there any other things that have helped slow brain atrophy? in other neuro-related diseases or the like? What about neuro-stimilulation? I saw where there is a couple companies that have devices on the market. Seems neuro-stimulation has had mixed results; though perhaps worth trying all of the above.

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    Replies
    1. Re taking Simvastin and LDN - if you use the internet to find the full prescribing information for ordinary Naltrexone you should be able to find out something about this. The maximum LDN dose used with MS (and other auto-immune diseases) is less than one tenth of the dose at which Naltrexone is generally used for alcohol and other substance abuse treatment. As Naltrexone has been around for many years there should be information available i.e. if there are any contraindications. Unfortunately with Naltrexone being out of patent no drug company is going to bother doing any trials to verify the benefits reported by the many many thousands of MSers taking LDN. However, with LDN causing virtually no side effects at all, your have nothing to lose by giving it a try.

      If you want to look at modifying your diet to try and address your cholesterol issues, do some serious research and do not just swallow holus bolus the "good ol' food pyramid" stuff that has been shovelled at us for years - much of the "evidence" supporting the Food Pyramid" is now being shown to have been cherry picked to support the hypotheses put forward, and the involvement of Big Food Industry (Big Pharma's bad cousin) interests in promoting it. Newer research (and even some old research) is producing quite a lot of evidence that the culprits which have been blamed for the obesity epidemic in Western affluent countries are not necessarily those which the "experts" have been warning us about for years.

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