Tuesday, 6 December 2016

#NewsSpeak: blowing our own trumpet

MS Reporters if you haven't watched them you are missing out! #MSReporters #NewsSpeak #MSBlog

Some of you may know that Barts-MS are part of the MS-Reporters project run by Shift.MS. The following are our annual figures that have been supplied by the charity. Good or bad we don't know. We would like to take this opportunity to than the Wellcome Trust for generoulsy funding this work. 

Advent Calendar 6



An alternative MRI - MRS and PET imaging in MS

Mult Scler. 2016 Nov 30. pii: 1352458516681504. [Epub ahead of print]

Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis.


Datta G, Violante IR, Scott G, Zimmerman K, Santos-Ribeiro A, Rabiner EA, Gunn RN, Malik O, Ciccarelli O, Nicholas R, Matthews PM.


Abstract

BACKGROUND:

Multiple sclerosis (MS) is characterised by a diffuse inflammatory response mediated by microglia and astrocytes. Brain translocator protein (TSPO) positron-emission tomography (PET) and [myo-inositol] magnetic resonance spectroscopy (MRS) were used together to assess this.

OBJECTIVE:

To explore the in vivo relationships between MRS and PET [11C]PBR28 in MS over a range of brain inflammatory burden.

METHODS:

A total of 23 patients were studied. TSPO PET imaging with [11C]PBR28, single voxel MRS and conventional magnetic resonance imaging (MRI) sequences were undertaken. Disability was assessed by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC).

RESULTS:

[11C]PBR28 uptake and [myo-inositol] were not associated. When the whole cohort was stratified by higher [11C]PBR28 inflammatory burden, [myo-inositol] was positively correlated to [11C]PBR28 uptake (Spearman's ρ = 0.685, p = 0.014). Moderate correlations were found between [11C]PBR28 uptake and both MRS creatine normalised N-acetyl aspartate (NAA) concentration and grey matter volume. MSFC was correlated with grey matter volume (ρ = 0.535, p = 0.009). There were no associations between other imaging or clinical measures.

CONCLUSION:

MRS [myo-inositol] and PET [11C]PBR28 measure independent inflammatory processes which may be more commonly found together with more severe inflammatory disease. Microglial activation measured by [11C]PBR28 uptake was associated with loss of neuronal integrity and grey matter atrophy.

Figure: Representation of combining MRS and PET imaging in this work.
Placement of spectroscopy voxel shown in (a) sagittal, (b) coronal and (c) axial image planes. (d) A parametric PET [11C]PBR28 distribution volume ratio (DVR) image overlaid with an outline of the placement spectroscopy voxel in the axial MRI plan corresponding to (c) is shown. (e) A representative MR spectrum for a patient. Ins: myo-inositol; Cho: choline; Cr+PCr: creatinine and phosphocreatinine; NAA: N-acetyl aspartate; p.p.m.: parts per million.

To be frank standard MRI imaging research is on its last legs as far as potential goes; possibly with the exception of high-field MRI imaging (since it provides better image resolution). As physicists look for new avenues of research, one of the untapped potentials has been PET (Positron Emission Tomography) and MRS (Magnetic Resonance Spectroscopy) imaging modalities. These modes of imaging have little value in terms of individual risk stratification, but on a population scale can add value to understanding the MS disease process. Paul Matthews group, in this paper attempt a combined analysis of both PET and MRS in a small group of RRMS and SPMS PwMS (by no means a cheap technology!).

Their rationale is to look at the innate immune system (microglia and astrocytes), as opposed to classical MRI where you are to large extent looking at the adaptive immune system (T cells and B cells). They hypothesize that the slow burn neurodegeneration may be related to the innate immune system activation - we know, that this isn't the only contributing factor!

Using MRS you can measure a metabolite in the brain called myo-inositol, which has been proposed as a glial marker, and corresponds to activated astrocytes in the MS brain. Whilst, using PET imaging and a ligand ([11C]PBR28) which binds to the mitochondrial translocator protein (TSPO), co-localises with activated microglia. When looking for a relationship between the two measures, the group did not find a relationship between MRS [myo-inositol] and PET [11C]PBR28, and therefore conclude that the two cells are involved in two distinct processes or to elements of a common process with different time courses!

Not sure if I agree with this, a lack of statistical correlation doesn't mean that there is no association, the cells are present at the same time and therefore must be interacting in some form or another, as well as with their surrounding environment, probably in a more biological way than appreciated by these two measures!! Some of this is apparent in their finding that in those with high inflammatory load there was an association. It is therefore likely that the signal has been diluted out by the case variation with varying degrees of inflammation.

There is interestingly, higher TSPO uptake within white matter of MS lesions, associated with grey matter volume loss, as well as loss of neuronal integrity (represented by the MRS measure N-acetyl aspartate or NAA, which is synthesized in mitochondria of neurons). Based on these findings, they suggest that microglial activation in MS lesions is associated with neurodegeneration. Of course, an association does not imply causality and more work needs to be done to look at this in more depth.

NB: both microglia and astrocytes have important functions in the brain. Any attempt to block this, should be considered carefully.

Monday, 5 December 2016

#ClinicSpeak & #NeuroSpeak: when to rebaseline?

Cherry-picking data; responders need to be analysed differently to delayed-responders or non-responders. #ClinicSpeak #NeuroSpeak

When we discuss NEDA (no evident disease activity) I always make the point of rebaselining. The reason is if you don't rebaseline then you will be taking into account disease activity that occurs before the drug works and blaming the drug for being ineffective when it may not be. With maintenance therapies the rebaselining needs to be done quite early, typically 3-6 months after starting the treatment, with the exception of glatiramer acetate that takes longer to have a full impact on MRI activity. In reality, an for pragmatic, reasons rebaseling at 6 or 12 months is fine.

When it comes to PIRTs, rebaselining needs to be done much later. Why? The mode of action of pulsed immune reconstitution therapies (PIRTs) is due to both depletion and reconstitution. The depletion may happen quickly, for example in the case of alemtuzumab and HSCT, or be more delayed in the case of cladribine. However, most consider the mode of action to be what happens post-reconstitution, i.e. when the immune system resets itself with new regulatory mechanisms. The reconstitution takes many months, if not years, to occur. Therefore it only makes sense to rebaseline at a point in time when you can do something about ongoing disease activity, i.e. in the case of alemtuzumab and cladribine offer another course of treatment. This is why we recommend 24 months in our Barts-MS algorithm.


Not all people agree with using the 24 months for rebaseling with alemtuzumab. Some have suggested using 12 months, i.e. before the second course has had time to work. The advantage of using the second year is that it at least allows you to compare alemtuzumab with other maintenance therapies. In the NEDA study below we simply looked at what happened to the 50% (175/349) of subjects who were rendered NEDA in year 2 (prior to alemtuzumab having had a chance to have its full effect). The other 50% of subjects had activity and hence should be looked at in year-3 and beyond; this analysis is being done. What this study tells you that if you are in the 50% of subjects that responds quickly to alemtuzumab by being NEDA in year 2 (prior to full activity) then you have 60% chance of being NEDA over the whole time period to year 5. That is all this poster says; it is not trying to make any other claim but that. Clearly, what happens to the other 50% is important and this information will be presented in a future publication. But more importantly is what happens to all these subjects over the next 10-15 years. This information will tell us if the promise of a 'potential cure' is real or not. 


People need to realise that PIRTs are not necessarily miracle drugs; all they offer is a different apporach to treating MS. What is clear is that the way we use them and monitor their activity is very different. 

CoI: multiple

Advent Calendar 5