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.

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