Tuesday, 6 December 2016

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.



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.


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


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).


[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.


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

Sunday, 4 December 2016

#ResearchSpeak: remyelination study suggests small positive effect

Another successful remyelination study: is progress in MS unstoppable? #MSBlog #ResearchSpeak

One of the big questions out there is how do we do remyelination and repair/neurorestorative trials? In phase 2, or early proof-of-concept, remyelination studies we have tended to rely on the optic nerve and an improvement in conduction speed using the so called visual evoked potential. Another strategy is anatomical and to study individual lesions with an MRI, or imaging, technique called MTR. MTR, or magnetization transfer ratio, is one technique that can be used to detect changes in the structural status of brain parenchyma that may, or may, not be visible with standard MR techniques. Use of MTR allow subcategorization of multiple sclerosis lesions into those with very low MTR (demyelinated lesions) and slightly decreased MTR (oedematous lesions) and it can show how these lesions evolve over time. If the a lesion with a low MTR improves over time this would indicate that it has been remyelinated. 

In this proof-of-concept study below, of a novel compound that works by blocking histamine H3 receptors, the investigators show a small, but signficant improvement, in lesions in pwMS treated with the H3-blocker, compared to those treated with placebo. This trial therefore shows that H3-blockade using GSK239512 is able to improve the MTR of demyelinated MS lesions; the interpretation being that this drug may be be an effective remyelination therapy in MS. 

Where to from here? Now that is the question we are trying to answer. As you are aware when Biogen moved from optic neuritis to MS with opicinumab, their anti-lingo-1 antibody, into a larger add-on phase 2b study the results were negative. Can we learn something from the negative opicinumab study? Yes, I am sure we can and let's hope Biogen publish their results soon. In a similar way that not all people respond to certain drugs, not all pwMS with disabilities will have reversible disabiities as a result of demyelinated lesions. Some disabilities will be fixed due to axonal loss and not modfiable with remyelination. We are therefore going to have work out who is more likely to respond to a remyelination therapy and who is not. We simply don't want to include the latter people in clinical trials as they won't respond or be informative. Remyelination therapy may finally bring precision medicine to MS. 

Background: Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). 

Objective: The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. 

Methods: This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. 

Results: Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. 

Conclusions: A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

CoI: multiple

Measuring Spasticity

Illomei G, Spinicci G, Locci E, Marrosu MG. Muscle elastography: a new imaging technique for multiple sclerosis spasticity measurement.961

Multiple sclerosis (MS) spasticity is currently evaluated on the basis of neurological examinations such as Ashworth Scale (AS) and 0-10 NRS. Severity of spasticity is difficult to quantify. We investigated the use of real time elastography (RTHE) ultrasounds for evaluating objectively the muscle fibers status in MS spasticity patients and their changes after a new antispasticity treatment. Two studies were performed. In study A, 110 MS patients underwent a neurological evaluation based on the AS and RTHE. The RTHE images were scored with the new 1-5 muscle fibres rigidity imaging scale, here called MEMSs (Muscle Elastography Multiple SclerosisScore). The correlation between AS and MEMSs was found to be statistically significant. In study B, 55 MS patients treated with THC:CBD oromucosal spray for their resistant spasticity were followed prospectively. MS spasticity was evaluated by the 0-10 NRS scale at baseline and after 4 weeks of treatment. MEMSs' figures were obtained at both timepoints. Responders to THC:CBD oromucosal spray (pre-defined as an improvement ≥20% in their 0-10 NRS spasticity score vs. baseline) were 65% of sample. These patients had a mean 0-10 NRS reduction of 1.87 and a MEMSs reduction of 1.97 (P values <0.0001). The remaining 35% of patients, classified as clinically non-responders, showed still a significant mean reduction in MEMSs (0.8, P = 0.002). Our overall results showed that RTHE, operativized throughout MEMSs, could be an objective gold standard to evaluate MS muscle spasticity as well as the effectiveness of antispasticity therapy

Unfortunately the gold standard is the Ashworth Scale with the FDA and failure to hit this endpoint is a failed drug candidate. Something that measures spasticity is highly desirable.

COI. We are testing an anti-spasctic agent