Brain microglial activity predicts faster progression of MS

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Prof Laura Airas is based in Turku PET Centre, Turku, Finland and writes about their recent paper.

Disclosures

 She has received honoraria from Biogen, Roche., Genzyme, Merck Serono and Teva, and institutional research grant support from Finnish Academy, Sigrid Juselius Foundation, Nancy Davis Foundation, Biogen, Genzyme, Merck Serono and Novartis.

Laura Airas | University of Turku
Prof Laura Airas writes

Brain microglial activity predicts faster progression of MS

Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis.Sucksdorff M, Matilainen M, Tuisku J, Polvinen E, Vuorimaa A, Rokka J, Nylund M, Rissanen E, Airas L.Brain. 2020 Oct 2:awaa275. doi: 10.1093/brain/awaa275.

A study conducted at the National Turku PET Centre, Turku, Finland, found that higher microglial cell activity in areas surrounding the focal inflammatory lesions in the brain predicts a faster progression of MS disease. It is the first study to show that the active innate immune cells in the brain predict progression of MS.

There are a number of effective drugs to prevent the exacerbations associated with relapsing-remitting MS, but yet there is no medication that would efficiently prevent the steady worsening associated with the disease. The pathological processes associated with the progressive forms of the disease take place behind the blood-brain barrier in the brain, and affecting these processes is challenging.

– First of all, it is difficult to accurately examine the brain in living patients. Following this, the mechanisms leading to neuronal degeneration are poorly understood. Due to this, it is difficult to directly slow down the neural degeneration process in any brain disease. An effective drug also needs to get through a tight blood-brain barrier, and developing a drug capable of this has its own challenges, explains Professor Laura Airas from the University of Turku.

The study was able to predict the disease progression with 95% accuracy

Neuropathological studies have identified an inflammatory reaction outside of focal inflammatory lesions in the brain of patients with progressive MS. Such diffuse brain inflammation, which sweeps across the entire brain tissue, is thought to be one of the factors contributing to chronic degeneration of the nervous system in MS and other degenerative diseases of the central nervous system.

Diffuse inflammation involves the harmful activation of the brain innate immune cells, microglial cells, which can be measured using positron emission tomography (PET) imaging, but not conventional MRI.

In a study conducted at the National Turku PET Centre, the link between microglial cell activity to later disease progression was modeled by stepwise logistic regression analysis. This model tested 21 different factors potentially contributing to disease progression, and of all these factors the microglial activity measured using PET imaging was recognized as the most significant.

— Regardless of relapses, the model predicted disease progression with 95% accuracy. The study carefully controlled for confounding factors such as medication, sex, age and duration of the disease, Airas says.

The findings are from an extensive dataset of 69 MS patients and 18 healthy controls. All subjects underwent an initial MRI and a TSPO-PET scan of the brain using a microglial cell binding radioligand [11C]-PK11195. The clinical severity of the disease was assessed using EDSS scoring, both at baseline and after an average of four years follow-up.

— This is the first study to show that the active, TSPO-PET detectable phenotype of microglial cells predicts progression of MS. The study proves the harmful nature of that particular microglial cell type. It demonstrates that PET imaging, with its molecular-level specificity, is a powerful research tool to investigate specific aspects of brain pathology in vivo. Importantly, it allows linking a given brain cell phenotype to the clinical status of the patients.

TSPO-PET imaging has excellent potential to be used as a biomarker in drug development targeted for progressive MS disease in the future.

The study was published in the distinguished journal Brain: https://doi.org/10.1093/brain/awaa275

For more information, please contact: Laura Airas Professor of Neuroimmunology, University of Turku, +358 50 3294321, laura.airas@utu.fi

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10 comments

  • Dear Prof. Airas,

    95% CI is convincing enough by my standards. Would you use PET scanning and microglial cell monitoring as a biomarker to change/escalate a licensed DMD ?

    And thank you for this highly interesting work!

    Tony

    • Thanks Tony.
      We can not yet monitor patients at large scale using PET. However, if highly activated microglia were detected, it would be a signal of too much inflammation in brain, and one way to reduce this (the only way presently) is to treat more efficiently with licenced DMD. We have evidence that treatment with high-efficacy DMD reduces PET-measurable microglial activation. BR -Laura

  • After 20 years of your findings and then getting confirmation of YOIR discovery from a junior colleague. Do you think this will inspire hope or frustration in people with MS. Do you understand the paranoia this creates that promising MS research is deliberately being burried by pharama in order to prevent a cure from being found? If I was the researcher that made a discovery and allowed nothing to happen for 20 years to end the suffering caused by this disease to patients and their families. I would find my culpability in this sad states of affairs undeniable and spend what time I have making things right. But I am well aware the lure of money and the things we will do to get it and by no means a perfect angel myself. But well done for being vindicated after 20 years and whatever kudos that it gives you.

  • I do not agree with “the study proves the harmful nature of that particular microglial cell type”. The other explanation is still possible. Maybe microglia is doing its job, but gets activated harder in patients with a worse virus infection , or whatever the MS underlying condition is.

    • True. We know that the TSPO-PET detectable activated innate immune cell phenotype is bad news, as it predicts faster MS progression. We do not know what promotes the persisting activated phenotype. This we need to study next. Importantly, it is known that the activated microglia/macrophage phenotype in MS brain has harmful, neuron-damaging characteristics, for example they produce toxic proinflammatory cytokines, reactive oxygen species and promote increased release of toxic glutamate. It would be interesting also to do a study to see if reversing this phenotype with a CNS-penetrating drug would reduce neural damage and progression.

  • ‘This study points strongly to a key role for activated microglia in initial demyelination in multiple sclerosis……If this is so, therapeutic strategies to inhibit macrophage activity……my be of greater benefit than efforts to inhibit T cells or other immune reactions.
    The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis.Identification and characterisation of the primary demyelinating lesion’ ( Gay et al Brain 1997,120,1461-1483)

    And the cause of microglial activation?

    Staphylococcal immune complexes and myelinolytic toxin in early acute multiple sclerosis lesions-An immunohistological study supported by multifactorial cluster analysis and antigen-imprint isoelectric focusing. (Gay F MSARD 2013,2 213-232)

    Lumsden C 1970 ‘Pathology is st ill the indispensable compass with which experimental and epidemiological research must be steered, and without which that research will be wasteful and meaningless’

    ‘Go to the tissues, they will tell you what the answer is’ John Vane.

    Sorry about this MD, the answer really is in the MS tissues, and its up to the pathologists to find it.

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