Chillies in the brain: microglial activation in MS

Chillies in the brain: Is progressive MS due to hot microglia? #MSblog #MSResearch

"If you are a regular reader of this blog you will know that we believe that two processes underlie MS disease progression."

"(1) Acute or sudden inflammatory events that transect or shred axons and nerves. This occurs acutely in a narrow time window that probably lasts days to weeks; we refer to this as the inflammatory penumbra. We are testing acute neuroprotection in this widow with our phenytoin in acute optic neuritis trial. This acute damage occurs in association with with relapses and focal MRI lesions."

Hot microglia are like chillies in the brain!

"(2) The second process is more delayed and occurs over months to years. We think this second process may be primed by acute focal autoimmune inflammation, or by another process - possibly a viral infection. In other words we still don't know if this is a primary or secondary event. What is important is that this delayed slow neurodegeneration appears to independent of the focal autoimmune process and is driven by cells in the brain called microglia. We refer to them as 'hot microglia', hence the analogy with chillies in the brain. What is emerging is that we now have drugs that work downstream of autoimmune inflammation and target these hot microglia; examples are laquinimod, ibudilast, sodium channel blockers, BG12, etc. This is why we are testing these compounds on the neurodegenerative processes that drive progressive MS. We are about to start testing oxcarbazepine, as sodium channel blocker, in the PROXIMUS trial, and ibudilast in the MS-SMART and NIH funded studies. Teva announced last year that they are taking laquinimod forward in progressive MS. Biogen-Idec have yet to commit to testing BG12 in progressive MS, but I suspect they will. If any Biogen-Idec employees are reading this post may you would be prepared to comment on this?"

"The study below helps confirm the 'hot microglia' hypothesis. It uses a very clever imaging technique that is able to detect hot micoglia in the brains of MSers. I was actually on the original paper looking at this marker in MSers. I recall recruiting, examining and consenting all the subjects for that study; that was almost 20 years ago when I was doing my PhD."

Banati et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000 Nov;123 ( Pt 11):2321-37.

Activated or hot microglia

"What this study below shows is that the black holes on T1 MRI are hot with activated microglia. We know that black hole lesions on T1 MRI are more destructive lesions with greater loss of axons and nerves and in progressive MSers the amount of hot microglia correlated with disability. What was interesting is that in the relapsing MSer group hot microglia were everywhere and correlated inversely with lesion volume; the more hot microglia the fewer and smaller the focal lesions. This is a result that is counter intuitive. I wonder what it means? It could mean that the hot microglia are the primary pathology, the initial event, and that the focal lesions are secondary in response to what is causing the diffuse pathology. This interpretation would support the hypothesis that MS is due to some diffuse neurodegenerative process and that the focal autoimmune lesions are secondary. How can we test this hypothesis? We are already doing this in the alemtuzumab extension studies. If MSers treated early with alemtuzumab and are rendered NEDA (no evident disease activity) for decades and never come back with SPMS then it is unlikely that MS is a diffuse neurodegenerative disease; in other words these MSers will be cured of their autoimmune disease by early induction therapy. This why alemtuzumab is such and important treatment. If on the other hand MSers treated early with alemtuzumab and are rendered NEDA (no evident disease activity) for decades and then present later with SPMS, MS is likely to be an primary neurodegenerative disease and the autoimmune response is secondary. I sincerely hope the former pans out to be the case, but will not be surprised if the latter turns out to be the reality. I am an autoimmune sceptic when it comes to MS. I hope this post makes sense to you."

Epub: Giannetti et al. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study. Neurobiol Dis. 2014 Feb 5.

Background: The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. 


Objectives: In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. 

Methods: Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. 

Results: Out of a total of 1,242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; p<0.05) only in the progressive group. In the relapsing MSers there was an inverse correlation between PKBPND and BH total lesion volume in whole brain (r=-0.781; p<0.05). When progressive MSers were grouped according to the disability outcome at 2years from the PK-PET scan, the total PKBPND in BHs was found to be a significant outcome predictor of disability (p<0.01). 

Conclusions: Our findings show that relapsing and progressive MSers have heterogeneous patterns of PKBPND in T1 BHs and indicate that BHs are not just "holes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression.

The 20-year alemtuzumab experiment; are you prepared to wait for the answer?

CoI: multiple

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