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.