Friday, 18 April 2014

Hot microglia: innate inflammation is a part of progressive MS

How hot, is hot, when it comes to microglia in progressive MS? #MSBlog #MSResearch

"Hot microglia the new buzz word in progressive MS. It is hypothesised by a large number of us in the field is that these cells are driving the progressive phase of the disease. The activated or hot mricoglia produce a range of factors that damage axons and neurones. There is now a race on to develop and test drugs that switch these cells off. Hot microglia are not unique to MS and may play a role in other neurodegenerative diseases, for example Alzheimer's disease, therefore there are potentially rich pickings for drugs that work in one disease. Have we found drugs that target these cells? Literally hundreds; laquinimod is the one that is showing the most promise in MS. Interestingly, there is some evidence that BG12, or dimethyl fumarate, may do the same. Sodium channel blocker also down regulate hot microglia. This group of drugs includes oxcarbazepine the drug we are testing in the PROXIMUS trial."

PK11195 imaging in MS

"The study below, using an imaging technique to detect hot microglia, shows what a problem this is in SPMS. This imaging technique will be very useful to test potential therapeutic compounds that target microglia. Now that we have a tool box and many targets let's hope that these insights will lead to a treatment for progressive MS."

Epub: Rissanen et al. In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand 11C-PK11195. J Nucl Med. 2014 Apr 7.

BACKGROUND: SPMSers lack efficient medication to slow down the progression of their disease. PET* imaging holds promise as a method to study, at the molecular level and in vivo, the central nervous system pathology of SPMS. 


*PET = positron emission tomography; PET is a nuclear medicine, functional imaging technique that produces a 3D image of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide(tracer), which is introduced into the body on a biologically active molecule. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis. 

PET might thus help to elucidate potential therapeutic targets and be useful as an imaging biomarker in future treatment trials of progressive MS. The objective of this study was to evaluate whether translocator protein (TSPO)** imaging could be used to visualize the diffuse inflammation located in the periplaque area and in the normal-appearing white matter (NAWM) in the brains of patients with SPMS.


**Translocator protein (TSPO); TSPO is a protein found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. It is upregulated in microglial cells and macrophages in the brain of MSers.

METHODS: This was an imaging study using MR imaging and PET with 11C-PK11195 binding to TSPO, which is expressed in activated, but not in resting, microglia. Ten SPMSers with a mean expanded disability status scale score of 6.3 (SD, 1.5) and eight age-matched healthy controls were studied. The imaging was performed using High-Resolution Research Tomograph PET and 1.5-T MR imaging scanners. Microglial activation was evaluated as the distribution volume ratio (DVR) of 11C-PK11195 from dynamic PET images. DVR estimations were performed with special interest in NAWM and gray matter using region-of-interest and parametric image-based approaches.

RESULTS: The DVR of 11C-PK11195 was significantly increased in the periventricular and total NAWM (P = 0.016 and P < 0.001, respectively) and in the thalamic ROIs (P = 0.027) of SPMSers, compared with the control group. Similarly, parametric image analysis showed widespread increases of 11C-PK11195 in the white matter of SPMSers, compared with healthy controls. Increased perilesional TSPO uptake was present in 57% of the chronic T1 lesions in MR imaging.

CONCLUSION: The finding of increased 11C-PK11195 binding in the NAWM of SPMSers is in line with the neuropathologic demonstration that activated microglial cells are the source of diffuse NAWM inflammation. Evaluating microglial activation with TSPO-binding PET ligands provides a unique tool to assess diffuse brain inflammation and perilesional activity in progressive multiple sclerosis in vivo.

18 comments:

  1. When you say there are hundreds of drugs that affect hot microglia, do we know if natalizumab and alemtuzumab also do this (or any of the other mabs being investigated?), or would people also have to take something else on top such as laquinimod? Have these imaging studies been done in any of these groups of patients?

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    1. I dont think we know how well antibodies get into the CNS i suspect it may be not alott. Do microglia get recruited in a cd49dependent way it has been hypothesised that they replace from within the cns.However if used early enough they may stop the conditions rhat lead to hot microglialia if not maybe one of the others

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    2. Re: ".... do we know if natalizumab and alemtuzumab also do this ..."?

      No we don't, but this is a good reason why we should look. It is assumed if you switch off the inflammatory cascade you will prevent the microglia becoming activated. I would hypothesise that when both these agents are used early you will see less PK11195 binding.

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  2. Any view as to how this process (hot microglia) fits with the B cell / T cell inflammatory process i.e. which comes first?

    I take away some positives from this research. I'm a recipient of Lemtrada (trial participant) which has switched off inflammation (no relapses or activity on MRI). How do I know if my microglia are causing damage? Might this explain why some recipients of highly effective treatments still develop SPMS? Does you definition of NEDA need to be expanded to include no hot microglia?

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    1. Re: "I take away some positives from this research. I'm a recipient of Lemtrada (trial participant) which has switched off inflammation (no relapses or activity on MRI). How do I know if my microglia are causing damage? Might this explain why some recipients of highly effective treatments still develop SPMS? Does you definition of NEDA need to be expanded to include no hot microglia?"

      I have addressed this question already. I suspect that if you have advanced MS the hot microglia may become autonomous and independent of T and B-cell mediated inflammation. This is what Hans Lasmann the MS pathologist like to refer to as a 2-staged disease with the second stage being driven by inflammation behind the blood-brain-barrier and being driven by the innate immune system (microglia).

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  3. The image you display shows PET scans of a healthy control, a RRMSer and a SPMSer. The accompanying article says nothing about RRMS.

    I don't know what the image is? Is the image from a RRMSer who is on treatment or not? Clearly neuro-degeneration happens even in RRMS and the microglia is an innate immune response to clean up the debris. Therefore it would be of the upmost importance to show a PET scan from an RRMSer who is treatment naive as well as one who is on treatment and stable (one post HSCT would be my suggestion). Or did you just pull this picture from Google Images?

    So, if neuro-degeneration is a function of chronic demeylination it seems that activated microglia would not be prominent in a RRMSer who has had the autoimmune process shut off before neuro-degeneration has taken hold.

    I think this would be a worthwhile endeavor to find out what is going on in ms instead of waiting for the 20 year experiment to be complete.

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    1. The progressive phase of MS is there from the start. The idea that there is a major difference between RRMS and SPMS is wrong. Even in asymptomatic MS or RIS (radiologically-isolated syndrome) there is evidence of disease progression. What defines SPMS is that compensatory mechanisms are exhausted, i.e. there is no reserve capacity left.

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    2. This is quite depressing. So we are all progressive MSers from the start. I took the risk of early aggressive treatment to try and prevent the shift to the progressive stage - looks like I'd already lost the battle! Perhaps it's time to focus on repair / boosting the compensatory mechanisms!

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    3. I never said there was a difference between SPMS and RRMS. The key thing to know is if SPMS can be prevented in RRMS with therapies in current use. So far it seems to be the case in certain therapies such as HSCT as well as Copaxone super-responders and possibly others. This PET scan method would be insightful to see what's going on in these st able RRMS patients.

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    4. I am glad I listen to my neurologist as well as do my own research on what is an effective drug:

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478150/

      Reading this blog you would come away with the notion you should be on Tysabri or Lemtrada. If these treatments don't work in the long run, they made a mistake for which I'm sure they will apologize for creating such unsupported positions about short term results and longterm effectiveness. It is no wonder there are legions of neurologists who disagree with Giovannoni.

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  4. This is a good post to follow up on february's "Hot chillies in the brain: activated microglia". As stated, alemtuzumab induction therapy will provide evidence on whether autoimmune t-cells or primary neurodegeneration is driving disease progression. In addition to other neurodegenerative diseases such as Alzheimer's, HIV-1 associated neuro-cogntive disorder (HAND) is driven by "hot" microglia, activated by a viral protein tat, may be treated with ibudilast. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018633.
    Charcot project may also shed some light on the underlying process. It is exciting that microglia have taken center stage in progressive disease. Suppress the activated microglia and directly reduce infiltrating lymphocytes/ reduce infiltrating lymphocytes and suppress microglial activation? Is this chicken and the egg or a combo chicken/egg omelet:-)

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    1. http://www.nature.com/ni/journal/v15/n5/full/ni.2872.html
      Also, good paper on endogenous retro-elements and the innate immune response and implications on autoimmunity. Seems to support dysfunctional immune response to cDNA, more ammunition for Charcot project?

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  5. Something has to control microglia. It is disconcerning that people think that restricting the adaptive immune system from the CNS is a good approach (Tysabri). But this could just be opening a whole new problem:

    http://www.ncbi.nlm.nih.gov/pubmed/23758741

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    1. RE: "Something has to control microglia. It is disconcerning that people think that restricting the adaptive immune system from the CNS is a good approach (Tysabri). But this could just be opening a whole new problem.."

      I agree, This is why we need to move into the combination therapy era and start testing treatments that target different pathological processes separately. How about a trial of natalizumab in combination with laquinimod? Compared to natalizumab alone? This study would need to use an MRI outcome as the clinical outcome we use would take to long to read-out.

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  6. The images are images do link them to the post, sometimes they link

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  7. Sorry MD, not so clear to me,but is this also the same for PPMS? The use of the term progressive ms means different things to different people.
    Also,if it is for PPMS people,is laqunimad available?

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    1. To me progressive ms means both ppms and spms and ag thd moment laquinimod is not yet available

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  8. Would it be worth trialling placebo versus say laquinimod and assessing outcomes with this PET technique?

    Also if the statins do work, would they also be worth a try?

    How much would a trial of this sort really cost given that it would potentially require fairly small numbers of participants?

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