Chronic inflammation in multiple sclerosis — seeing what was always there

Abstract

Activation of innate immune cells and other compartmentalized inflammatory cells in the brains and spinal cords of people with relapsing–remitting multiple sclerosis (MS) and progressive MS has been well described histopathologically. However, conventional clinical MRI is largely insensitive to this inflammatory activity. The past two decades have seen the introduction of quantitative dynamic MRI scanning with contrast agents that are sensitive to the reduction in blood–brain barrier integrity associated with inflammation and to the trafficking of inflammatory myeloid cells. New MRI imaging sequences provide improved contrast for better detection of grey matter lesions. Quantitative lesion volume measures and magnetic resonance susceptibility imaging are sensitive to the activity of macrophages in the rims of white matter lesions. PET and magnetic resonance spectroscopy methods can also be used to detect contributions from innate immune activation in the brain and spinal cord. Some of these advanced research imaging methods for visualization of chronic inflammation are practical for relatively routine clinical applications. Observations made with the use of these techniques suggest ways of stratifying patients with MS to improve their care. The imaging methods also provide new tools to support the development of therapies for chronic inflammation in MS.

Key points

  • Advanced MRI and PET methods enable visualization of features related to chronic inflammation in progressive and relapsing–remitting forms of multiple sclerosis (MS).

  • Quantitative analysis of uptake of gadolinium contrast agent and ultra-small paramagnetic particles provide in vivo evidence of chronic, low-grade inflammation in people with progressive or relapsing–remitting MS (RRMS).

  • Lesions associated with activated macrophages/microglia (slowly expanding T2 hyperintense lesions and lesions with high susceptibility-weighted MRI signals at their rims) are more common in progressive MS than in RRMS.

  • Persistent focal leptomeningeal inflammation, detectable with gadolinium contrast-enhanced T2 fluid attenuation inversion recovery MRI in many people with MS (particularly progressive MS), is associated with cortical lesions and accelerated cortical atrophy.

  • Translocator protein PET can detect increased innate immune activation in brains of people with MS; typically, activation is greater in secondary progressive MS than in RRMS.

  • Indirect evidence suggests that magnetic resonance spectroscopy measures of myo-inositol and some recently introduced PET measures can reflect contributions of astrocyte activation to brain innate immune responses.

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Fig. 1: Leptomeningeal inflammation in multiple sclerosis.
Fig. 2: Macrophages in a mixed active–inactive multiple sclerosis lesion.
Fig. 3: A slowly expanding multiple sclerosis lesion.
Fig. 4: PET imaging of microglial activation in secondary progressive multiple sclerosis.

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Acknowledgements

P.M.M. acknowledges the early input of ideas from L. Steinman and H. Lassmann, who emphasized the potential importance of long-lived B cells in the brain parenchyma of people with MS. This and related work has been supported by the Imperial College Healthcare Trust – National Institute for Health Research (NIHR) Biomedical Research Centre. P.M.M. has also been in receipt of generous personal and research support from the Edmond J. Safra Foundation and Lily Safra, an NIHR Senior Investigator’s Award, the Medical Research Council and the UK Dementia Research Institute, which is supported by the Medical Research Council, The Alzheimer’s Society and Alzheimer’s Research UK.

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Correspondence to Paul M. Matthews.

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P.M.M. acknowledges consultancy fees from Adelphi Communications, Biogen, Celgene and Roche. He has received honoraria or speakers’ honoraria from Biogen, Novartis and Roche, and has received research or educational funds from Biogen, GlaxoSmithKline, Nodthera and Novartis. He is a paid member of the Scientific Advisory Board for Ipsen Pharmaceuticals.

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