Sunday, 5 February 2017

Metabolites and Progressive MS

Lim CK et al. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Scientific Reports 7, Article number: 41473 (2017)doi:10.1038/srep41473

Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Tryptophan is an amino acid which is a Tryptophan is also a precursor to the neurotransmitters serotonin and melatonin. Niacin, also known as vitamin B3, is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates.Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation. Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation and regulating the immune response.


In this study the authors looked for metabolites of the kynurenine pathway of Tpryptophan. They looked in the blood and they
decreases in kynurenic acid and Quinolic acid increases

They looked for metabolites and found a few that may help distinguish different phases of MS. There is am implication that these metabolites are associated with the NMDA glutamate receptor excitotoxicty which is a way that glutamate overload can kill nerves by exciting them to destruction. 
Blocking this stops nerves working properly, but we have a an idea how to block this...watch this space.

However one wonders about the relationship of blood to the CSF?
.

How are we going to use the information?

It could be useful to distinguish RRMS from PPMS as some could use it to perhaps not treat someone predicted to get RRMS with drug X

So whilst interesting they have found correlations at a population level and occurs with the countless imaging studies published are they going to be great to predict what happens to the individual.

As the media claim they are making a product, you can look at patent WO2015/008111 published 2 years ago.



So you do a test what is going to happen to individual in the red circle are they going to get RRMS/PPMS? So how do you base your treatment descisions? 

So you  put a number of differnt tests into the analysis and the predictive value goes up and is not bad for RRMS and PPMS. 

As you would expect SPMS is a bit more wooly, but would you want to be one of the 15% (in some instances) when it it wrong,

Being labelled with SPMS can be a stop singnal for your DMT

However ProfG will claim that making this call ia an art and you have to use many different bits of information to make that call

The key is to find the biology

18 comments:

  1. Here in Oz this piece of research is being hailed as ground breaking and a way that three different types of MS can be classified. However Mouse Superior you seem to intimate "not so much". I am not clear in regard to your crptic comment 'The key is not to find the biology. Could you clarify what you mean by that comment?

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    1. Helen ScottSunday, February 05, 2017 2:19:00 pm
      "Here in Oz this piece of research is being hailed as ground breaking and a way that three different types of MS can be classified."

      for example, http://www.mq.edu.au/newsroom/2017/02/04/first-blood-biomarker-discovered-for-the-prognosis-of-multiple-sclerosis-quick-accurate-and-soon-to-be-available/

      Helen Scott, I wonder if there is some competition in the area ;)

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    2. From the published article: One potential limitation of a blood based biomarker for neurological disease may be that blood parameters may not necessarily mirror those of the CNS. However, a previous study demonstrated that the blood KP profile followed closely with changes of the KP profile in CNS40 and our analysis (which included 3 more KP variables, i.e. K/T ratio, KA and PA) showed generally good to-strong plasma-CNS KP metabolite correlations in the range 65–79.3%. Potential factors limiting these correlations may include the inherent differences in the magnitude of CSF parameters relative to serum values and the fact that the length of storage time (over 10 years) in some of these samples may have led to the partial degradation of some analytes. Although, the key metabolites kynurenine and QA have been reported as relatively stable even after many years of storage41. Notwithstanding these points, the moderately strong correlations between CSF and serum, confirms that the serum KP profile is a suitably sensitive blood-based predictor of disease progression in MS.

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    3. Maybe I should let NeuroDocG do this....Biomarkers are here Thang.

      Maybe she will enthuse that is it is the saviour of MS.

      The data was done in 3 cohorts so it should reproduce easily, so lets see this, before too many miracles are claimed. We have been here below no disrespect to the author.

      Anyway lets thank them for filling in details about CSF and blood and your study.

      Do you want to do a Guest post about it?
      All we ask for is a picture a conflict of interest statement and please send to ProfG g.giovannoni@qmul.ac.uk.

      This will give you an oppertunity to explain what this all means in a language that the readers can understand. What is the significance for the neurologist, understanding of the disease and treatment options.

      Can this be used as a stop indicate for people on failing DMT, is this why the results for SPMS are not so clear cut given that SPMS transitions during RRMS.

      How does this relate to Neurofilament levels



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    4. Dear Helen

      Sorry if my tone was not to your liking, please be gentle with "superior" anon on unreleated blogger comments who said "

      "http://www.nature.com/articles/srep41473 it's a bit technical and boring as all hell, but it clarifies more than the news media"

      The question is how is this information going to be used?

      Does it mean we can throw away MRI scanners as they can't really distinguish the difference between relapsing and progressive MS. Should I enthuse more about those studies

      I do not see the data showing there are three types of MS, PPMS and SPMS look pretty similar which I think is the reality although pharma may want us to thing there are three diseases so that can sell up three differnt drugs to do the same thing.

      Lastly Sorry " The key is not to find the biology" is a typo should be
      "The key is find the biology" my mistake I'll change

      I am abit frazzled from pulling a virutal all nighter as grant deadline looms

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    5. "first-blood-biomarker-discovered-for-the-prognosis-of-multiple-sclerosis-quick-accurate-and-soon-to-be-available/"

      This is the same story so not competition, however this is the story saying that the authors are commerciallising their discovery

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    6. PPS High neurofilament (can be sometimes used with blood analysis) is an indicator of poor prognosis and has been around for a while.

      Hopefully it shows us that excitotoxicty is the problem for MS, I've invented a drug that can block it...Yes i'm excited.

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    7. MD you've been working flat out this weekend by the sounds of it and still found time to keep this wonderful blog updated. Take a break you must, an exhausted mouse we don't want ;-)
      Re high nfl, this is from LP? So we need something neuroprotective to add onto dmt? Sounds like PROXIMUS trial?
      I'm not sure what the fuss is about bio markers, Prof G keeps saying MS is MS. A few are lucky (10%?) and it never comes to much before they die at old age, most are not :-(

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    8. My competition comment was aimed at this statement - "Blocking this stops nerves working properly, but we have a an idea how to block this...watch this space."

      I saw a comment somewhere from powers that are to the effect that the test won't be used on those who have MS already. The comment made no sense at the time, but in hindsight I wonder if it was a reference to the differences in between blood and CNS markers and to the changes some or all DMTs lead to between bloods and CNS...

      And I understand (I follow enough) to get how this is a marker for distinguishing between the types of MS, but not so much for evaluating treatment efficacy (are they saying treatment should be reducing the levels of whatever they're measuring and using as biomarker)?

      The actual study when one reads it repeatedly and consistently uses the word "may"... the study consisted of 3 cohorts, the biggest one of which i think had 150 participants, including control groups and then numbers in the cohorts following the first one were reduced.

      so how do go from that to a test to be available in 2 years that diagnoses ms, distinguishes between 3 types of ms and is going to help guide treatment decisions? And is not going to be used for people who currently have MS (maybe I'm confused and imagined that comment... I can't be bothered looking for it right now but I am fairly sure it was made)...

      I'm genuinely confused.

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    9. Dear Judy
      Thanks for your concerning I have done all I can its ready to go, I'll get a bit of kip today

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    10. Competition...Oh I see "us" verses "them" to find a solution, so we may win that one I suspect...Blocking NMDA has been tried in MS a number of times using a drug called memantine. Blocking glutamate receptors induces side effects

      In short they look for a number of chemicals in the blood and they believe that if you look for 6 of more chemicals related to tryptophan metabolism they claim they can distinguish between health, MS relapising MS and primary and secondary progressive. The data however shows that in many cases SPMS and PPMS is similar.

      Perhaps you could use the test to help confirm your diagnosis.

      Although this was not shown I would suspect that the metabolite concentrations will change with therapy. This is probably their next paper.

      Will it diagnose MS I suspect not as other nurological problems will show some similarity

      It can only guide between RRMS and PPMS as SPMS occurs after RRMS or in relativity they transition from RRMS.

      If you believe the test shows progressive MS then NICE would argue that some treatments should stop as they dont work in progressive MS.

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    11. thank you for the explanations!!!!

      ps. go win please :)

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  2. What I found to be "different" was to say that there are 3 forms of MS. Maybe if they had said that there are 3 "stages" of MS would sound better. Because if you have RRMS you will have SPMS in the future, and perhaps because of excess of excitocity the Primary Progressive MS already starts degenarative, ie, the disease is one, what would define the stages of it would be this excitocity that leads to neural death.
    Now that a blood test is much more practical than an LCR or an MRI, the practicality of rapid diagnosis and knowing about the evolution of the disease itself, and cheapening the costs with exams (here in Brazil MRI and CSF are still very expensive tests).

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  3. MD,are you serious about having invented a drug for excotocity?

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  4. Hi MD,

    Thanks for your thoughts on this study. I wrote a summary on this yesterday as well and shared some of my own opinions, I've included the link below. This has been hugely hyped by media and organisations here in Australia, so I thought it was really important that more detail was provided. It seems that we have raised very similar questions about the results and how it could proceed to a clinical setting. Would love to hear your feedback on our summary, in particular, your thoughts on how disease duration may be the prevailing factor leading to the differences observed, rather than disease stage?

    http://www.mstranslate.com.au/can-blood-test-determine-type-of-ms/

    Thanks,

    Brett (MS Researcher, Science Communicator and Co-Founder - MStranslate)

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    1. Dear Brett
      Your version is more readable that mine . well done. Maybe NDG will take up the banner Biomarkers are more her and ProfGs thing...I've been too tied up with memory B cell week and planning for the next part of the trilogy.

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