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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1
Journal of Neuroinflammation Open Access 12 October 2023
Clinical Neuroradiology Open Access 08 March 2022
Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics
Journal of Neuroinflammation Open Access 10 February 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Baecher-Allan, C., Kaskow, B. J. & Weiner, H. L. Multiple sclerosis: mechanisms and immunotherapy. Neuron 97, 742–768 (2018).
Young, I. R. et al. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 2, 1063–1066 (1981).
Miller, D. H., Grossman, R. I., Reingold, S. C. & McFarland, H. F. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 121 (Pt 1), 3–24 (1998).
Igra, M. S., Paling, D., Wattjes, M. P., Connolly, D. J. A. & Hoggard, N. Multiple sclerosis update: use of MRI for early diagnosis, disease monitoring and assessment of treatment related complications. Br. J. Radiol. 90, 20160721 (2017).
Rio, J., Comabella, M. & Montalban, X. Predicting responders to therapies for multiple sclerosis. Nat. Rev. Neurol. 5, 553–560 (2009).
Bermel, R. A., Fisher, E. & Cohen, J. A. The use of MR imaging as an outcome measure in multiple sclerosis clinical trials. Neuroimaging Clin. N. Am. 18, 687–701.xi (2008).
Mayo, L., Quintana, F. J. & Weiner, H. L. The innate immune system in demyelinating disease. Immunol. Rev. 248, 170–187 (2012).
Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).
Howell, O. W. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134, 2755–2771 (2011).
Machado-Santos, J. et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141, 2066–2082 (2018).
Campbell, G. R., Worrall, J. T. & Mahad, D. J. The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult. Scler. 20, 1806–1813 (2014).
Mahad, D. H., Trapp, B. D. & Lassmann, H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183–193 (2015).
Bruck, W. Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J. Neurol. 252 (Suppl. 5), v10–v15 (2005).
Lassmann, H., van Horssen, J. & Mahad, D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 8, 647–656 (2012).
Matthews, P. M. et al. A practical review of the neuropathology and neuroimaging of multiple sclerosis. Pract. Neurol. 16, 279–287 (2016).
Kutzelnigg, A. & Lassmann, H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb. Clin. Neurol. 122, 15–58 (2014).
Stadelmann, C. Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr. Opin. Neurol. 24, 224–229 (2011).
Peterson, J. W., Bo, L., Mork, S., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001).
Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011).
Kutzelnigg, A. & Lassmann, H. Cortical lesions and brain atrophy in MS. J. Neurol. Sci. 233, 55–59 (2005).
Trapp, B. D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).
Cifelli, A. et al. Thalamic neurodegeneration in multiple sclerosis. Ann. Neurol. 52, 650–653 (2002).
Evangelou, N. et al. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123 (Pt 9), 1845–1849 (2000).
Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).
Hawley, R. J. et al. Neurochemical correlates of sympathetic activation during severe alcohol withdrawal. Alcohol Clin. Exp. Res. 18, 1312–1316 (1994).
Meyer, C., Martin-Blondel, G. & Liblau, R. S. Endothelial cells and lymphatics at the interface between the immune and central nervous systems: implications for multiple sclerosis. Curr. Opin. Neurol. 30, 222–230 (2017).
Man, S., Ubogu, E. E. & Ransohoff, R. M. Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol. 17, 243–250 (2007).
Vercellino, M. et al. Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. J. Neuroimmunol. 199, 133–141 (2008).
McDonnell, G. V., McMillan, S. A., Douglas, J. P., Droogan, A. G. & Hawkins, S. A. Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease. J. Neurol. 246, 87–92 (1999).
Kirk, J., Plumb, J., Mirakhur, M. & McQuaid, S. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J. Pathol. 201, 319–327 (2003).
Alvarez, J. I., Cayrol, R. & Prat, A. Disruption of central nervous system barriers in multiple sclerosis. Biochim. Biophys. Acta 1812, 252–264 (2011).
Leech, S., Kirk, J., Plumb, J. & McQuaid, S. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol. Appl. Neurobiol. 33, 86–98 (2007).
Kwon, E. E. & Prineas, J. W. Blood-brain barrier abnormalities in longstanding multiple sclerosis lesions. An immunohistochemical study. J. Neuropathol. Exp. Neurol. 53, 625–636 (1994).
Lee, N. J. et al. Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination. Brain 141, 1637–1649 (2018).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21, 1380–1391 (2018).
Rasmussen, M. K., Mestre, H. & Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol. 17, 1016–1024 (2018).
Simon, M. J. & Iliff, J. J. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochim. Biophys. Acta 1862, 442–451 (2016).
Wicken, C., Nguyen, J., Karna, R. & Bhargava, P. Leptomeningeal inflammation in multiple sclerosis: insights from animal and human studies. Mult. Scler. Relat. Disord. 26, 173–182 (2018).
Magliozzi, R., Columba-Cabezas, S., Serafini, B. & Aloisi, F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 148, 11–23 (2004).
Sellebjerg, F. et al. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 73, 2003–2010 (2009).
Festa, E. D. et al. Serum levels of CXCL13 are elevated in active multiple sclerosis. Mult. Scler. 15, 1271–1279 (2009).
Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).
Carassiti, D. et al. Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol. Appl. Neurobiol. 44, 377–390 (2018).
Wegner, C. & Matthews, P. M. A new view of the cortex, new insights into multiple sclerosis. Brain 126, 1719–1721 (2003).
Wegner, C., Esiri, M. M., Chance, S. A., Palace, J. & Matthews, P. M. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67, 960–967 (2006).
Nylander, A. & Hafler, D. A. Multiple sclerosis. J. Clin. Invest. 122, 1180–1188 (2012).
Correale, J., Gaitan, M. I., Ysrraelit, M. C. & Fiol, M. P. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 140, 527–546 (2017).
Smyth, L. J., Kirby, J. A. & Cunningham, A. C. Role of the mucosal integrin alpha(E)(CD103)beta(7) in tissue-restricted cytotoxicity. Clin. Exp. Immunol. 149, 162–170 (2007).
Kuhlmann, T. et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 133, 13–24 (2017).
Stangel, M., Kuhlmann, T., Matthews, P. M. & Kilpatrick, T. J. Achievements and obstacles of remyelinating therapies in multiple sclerosis. Nat. Rev. Neurol. 13, 742–754 (2017).
Frischer, J. M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).
Reynolds, R. et al. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 122, 155–170 (2011).
Hametner, S. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74, 848–861 (2013).
Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).
Zrzavy, T. et al. Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913 (2017).
Savarin, C. et al. Astrocyte response to IFN-gamma limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis. J. Neuroinflammation 12, 79 (2015).
Metz, I. et al. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann. Neurol. 75, 728–738 (2014).
Frischer, J. M. et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann. Neurol. 78, 710–721 (2015).
Luchetti, S. et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 135, 511–528 (2018).
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
van der Valk, P. & Amor, S. Preactive lesions in multiple sclerosis. Curr. Opin. Neurol. 22, 207–213 (2009).
Ingram, G. et al. Complement activation in multiple sclerosis plaques: an immunohistochemical analysis. Acta Neuropathol. Commun. 2, 53 (2014).
Singh, S. et al. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol. 125, 595–608 (2013).
Prineas, J. W. et al. Immunopathology of secondary-progressive multiple sclerosis. Ann. Neurol. 50, 646–657 (2001).
Costantini, E., D'Angelo, C. & Reale, M. The role of immunosenescence in neurodegenerative diseases. Mediators Inflamm. 2018, 6039171 (2018).
Khademi, M. et al. Intense inflammation and nerve damage in early multiple sclerosis subsides at older age: a reflection by cerebrospinal fluid biomarkers. PLOS ONE 8, e63172 (2013).
Djikic, J. et al. Age-associated changes in rat immune system: lessons learned from experimental autoimmune encephalomyelitis. Exp. Gerontol. 58, 179–197 (2014).
Zrzavy, T. et al. Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts. Brain Pathol. 28, 791–805 (2018).
Bar-Or, A. & Antel, J. P. Central nervous system inflammation across the age span. Curr. Opin. Neurol. 29, 381–387 (2016).
Mundt, S. et al. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci. Immunol. 4, eaau8380 (2019).
Duszczyszyn, D. A. et al. Thymic involution and proliferative T-cell responses in multiple sclerosis. J. Neuroimmunol. 221, 73–80 (2010).
Raz, L., Knoefel, J. & Bhaskar, K. The neuropathology and cerebrovascular mechanisms of dementia. J. Cereb. Blood Flow Metab. 36, 172–186 (2016).
Geraldes, R., Esiri, M. M., DeLuca, G. C. & Palace, J. Age-related small vessel disease: a potential contributor to neurodegeneration in multiple sclerosis. Brain Pathol. 27, 707–722 (2017).
Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007).
Conde, J. R. & Streit, W. J. Microglia in the aging brain. J. Neuropathol. Exp. Neurol. 65, 199–203 (2006).
Ohrfelt, A. et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult. Scler. 22, 1587–1595 (2016).
Zrzavy, T. et al. Pro-inflammatory activation of microglia in the brain of patients with sepsis. Neuropathol. Appl. Neurobiol. 45, 278–290 (2019).
Wendeln, A. C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).
Rao, V. T. et al. MicroRNA expression patterns in human astrocytes in relation to anatomical location and age. J. Neuropathol. Exp. Neurol. 75, 156–166 (2016).
Thompson, A. J. et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann. Neurol. 29, 53–62 (1991). A highly important, pioneering study that still deserves reading for its clear demonstration that substantial inflammatory activity can be found in patients with chronic MS.
Sormani, M. P. et al. Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets. J. Neurol. Neurosurg. Psychiatry 70, 494–499 (2001).
Geurts, J. J. et al. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236, 254–260 (2005).
Kober, T. et al. MP2RAGE multiple sclerosis magnetic resonance imaging at 3 T. Invest. Radiol. 47, 346–352 (2012).
Harel, A. et al. Phase-sensitive inversion-recovery MRI improves longitudinal cortical lesion detection in progressive MS. PLOS ONE 11, e0152180 (2016).
Tofts, P. S. & Kermode, A. G. Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn. Reson. Med. 17, 357–367 (1991). An elegant framework for the quantitative interpretation of dynamic gadolinium contrast MRI that has informed all efforts to assess chronic blood–brain barrier breakdown with MRI that have come since.
Soon, D., Tozer, D., Altmann, D., Tofts, P. & Miller, D. Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes. Mult. Scler. 13, 884–894 (2007).
Cramer, S. P., Simonsen, H., Frederiksen, J. L., Rostrup, E. & Larsson, H. B. Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI. Neuroimage Clin. 4, 182–189 (2014).
Pasquini, L. et al. Gadolinium-based contrast agent-related toxicities. CNS Drugs 32, 229–240 (2018).
Marti-Bonmati, L. & Marti-Bonmati, E. Retention of gadolinium compounds used in magnetic resonance imaging: a critical review and the recommendations of regulatory agencies. Radiologia 59, 469–477 (2017).
Elliott, C. et al. Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions. Mult. Scler. https://doi.org/10.1177/1352458518814117 (2018). This article describes convincing evidence for the slow expansion of some chronic T2 hyperintense lesions and makes the powerful inference that this relates to neuropathologically chronic active lesions.
Truyen, L. et al. Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47, 1469–1476 (1996).
Harrison, D. M. et al. Lesion heterogeneity on high-field susceptibility MRI is associated with multiple sclerosis severity. AJNR Am. J. Neuroradiol. 37, 1447–1453 (2016).
Dal-Bianco, A. et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 133, 25–42 (2017). Extending the work of Elliott et al. (2018), this report provides additional evidence that slowly expanding MRI lesions represent the neuropathologically chronic active plaques by demonstrating that the rims of these MRI lesions show evidence for pathological iron accumulation, corresponding to iron-rich macrophages/microglia in these plaques.
Absinta, M. et al. Identification of chronic active multiple sclerosis lesions on 3T MRI. AJNR Am. J. Neuroradiol. 39, 1233–1238 (2018).
Hametner, S. et al. The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation — a biochemical and histological validation study. Neuroimage 179, 117–133 (2018).
Corot, C. et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest. Radiol. 39, 619–625 (2004).
Tourdias, T. et al. Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging. Radiology 264, 225–233 (2012). A pioneering demonstration of the potential utility of superparamagnetic iron oxide particle contrast for the assessment of cell trafficking into inflammatory lesions in MS. This remains the single robust approach for direct assessment of inflammatory cell trafficking into the brains of humans.
Vellinga, M. M. et al. Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI to demonstrate diffuse inflammation in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients: an exploratory study. J. Magn. Reson. Imaging 29, 774–779 (2009).
Neuwelt, A. et al. Iron-based superparamagnetic nanoparticle contrast agents for MRI of infection and inflammation. AJR Am. J. Roentgenol. 204, W302–W313 (2015).
Lu, M., Cohen, M. H., Rieves, D. & Pazdur, R. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am. J. Hematol. 85, 315–319 (2010).
Bailie, G. R. Comparison of rates of reported adverse events associated with i.v. iron products in the United States. Am. J. Health Syst. Pharm. 69, 310–320 (2012).
Daldrup-Link, H. E. Ten things you might not know about iron oxide nanoparticles. Radiology 284, 616–629 (2017).
Zarghami, N. et al. Optimization of molecularly targeted MRI in the brain: empirical comparison of sequences and particles. Int. J. Nanomedicine 13, 4345–4359 (2018).
Geurts, J. J. et al. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am. J. Neuroradiol. 26, 572–577 (2005). An important study validating the MRI detection of cortical lesions using postmortem brains. Conceptually even more important, however, was the demonstration of limited sensitivity to these lesions, suggesting that in vivo imaging may capture only the ‘tip of the iceberg’ of cortical demyelination with MS.
Geurts, J. J. et al. Does high-field MR imaging improve cortical lesion detection in multiple sclerosis? J. Neurol. 255, 183–191 (2008).
Wiggermann, V., Hernandez-Torres, E., Traboulsee, A., Li, D. K. & Rauscher, A. FLAIR2: a combination of FLAIR and T2 for improved MS lesion detection. AJNR Am. J. Neuroradiol. 37, 259–265 (2016).
Kilsdonk, I. D. et al. Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR. AJNR Am. J. Neuroradiol. 34, 791–796 (2013).
Calabrese, M. et al. Regional distribution and evolution of gray matter damage in different populations of multiple sclerosis patients. PLOS ONE 10, e0135428 (2015).
Calabrese, M. et al. Imaging distribution and frequency of cortical lesions in patients with multiple sclerosis. Neurology 75, 1234–1240 (2010).
Puthenparampil, M. et al. Cortical relapses in multiple sclerosis. Mult. Scler. 22, 1184–1191 (2016).
Calabrese, M. et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch. Neurol. 64, 1416–1422 (2007).
Scalfari, A. et al. The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis. Neurology 90, e2107–e2118 (2018).
Papadopoulou, A. et al. Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis. Mult. Scler. 19, 1290–1296 (2013).
Calabrese, M. et al. Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study. Neuroimage 42, 1324–1328 (2008). An important characterization of cortical lesions in vivo with demonstration of the frequency of their appearance, emphasizing that cortical lesions are associated with all stages of MS.
Calabrese, M. et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology 72, 1330–1336 (2009).
Zurawski, J., Lassmann, H. & Bakshi, R. Use of magnetic resonance imaging to visualize leptomeningeal inflammation in patients with multiple sclerosis: a review. JAMA Neurol. 74, 100–109 (2017).
Bergsland, N. et al. Leptomeningeal contrast enhancement is related to focal cortical thinning in relapsing-remitting multiple sclerosis: a cross-sectional MRI study. AJNR Am. J. Neuroradiol. 40, 620–625 (2019).
Absinta, M. et al. Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis. Neurology 85, 18–28 (2015). This important paper both introduces the concept of leptomeningeal enhancement for assessment of chronic inflammation in MS and validates it with an autopsy case study.
Zivadinov, R. et al. Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: a retrospective, pilot, observational longitudinal study. Mult. Scler. 23, 1336–1345 (2017).
Zivadinov, R. et al. Evaluation of leptomeningeal contrast enhancement using pre- and postcontrast subtraction 3D-FLAIR imaging in multiple sclerosis. AJNR Am. J. Neuroradiol. 39, 642–647 (2018).
Magliozzi, R., Reynolds, R. & Calabrese, M. MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course. Brain Pathol. 28, 735–742 (2018).
Owen, D. R. et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J. Cereb. Blood Flow Metab. 37, 2679–2690 (2017).
Cosenza-Nashat, M. et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol. Appl. Neurobiol. 35, 306–328 (2009).
Vowinckel, E. et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J. Neurosci. Res. 50, 345–353 (1997).
Banati, R. B. 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 123 (Pt 11), 2321–2337 (2000). While not the first report, this is the most influential early TSPO PET report. It includes a first effort to validate the signal using postmortem autoradiography and highlights both the heterogeneity in tracer uptake across lesions and the involvement of grey matter. While the significance of all of the observations was not fully appreciated at the time, it describes the full range of phenomena that have been explored since.
Datta, G. et al. Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis. Brain 140, 2927–2938 (2017).
Datta, G. et al. 11C-PBR28 and 18F-PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis. J. Nucl. Med. 58, 1477–1482 (2017). This paper represents the first effort to consolidate observations in the TSPO PET ‘subfield’ by showing the quantitative correspondence between observations conducted over similar patient populations using the same analytical methodology. It also describes lesion heterogeneity in detail for the first time, proposing correspondences with neuropathological classifications of potential clinical significance.
Rissanen, E. et al. In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the radioligand 11C-PK11195. J. Nucl. Med. 55, 939–944 (2014).
Colasanti, A. et al. In vivo assessment of brain white matter inflammation in multiple sclerosis with 18F-PBR111 PET. J. Nucl. Med. 55, 1112–1118 (2014).
Herranz, E. et al. Neuroinflammatory component of gray matter pathology in multiple sclerosis. Ann. Neurol. 80, 776–790 (2016).
Betlazar, C., Harrison-Brown, M., Middleton, R. J., Banati, R. & Liu, G. J. Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. Int. J. Mol. Sci. 19, E2707 (2018).
Horti, A. G. et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc. Natl Acad. Sci. USA 116, 1686–1691 (2019).
Kolb, H. et al. Preclinical evaluation and non-human primate receptor occupancy study of 18F-JNJ-64413739, a novel PET radioligand for P2X7 receptors. J. Nucl. Med. https://doi.org/10.2967/jnumed.118.212696 (2019).
Kim, M. J. et al. Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys. J. Nucl. Med. 59, 1907–1912 (2018).
Spinelli, F., Mu, L. & Ametamey, S. M. Radioligands for positron emission tomography imaging of cannabinoid type 2 receptor. J. Labelled Comp. Radiopharm. 61, 299–308 (2018).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Takata, K. et al. 11C-acetate PET imaging in patients with multiple sclerosis. PLOS ONE 9, e111598 (2014). An underappreciated paper that provides an interesting proof-of-principle for imaging astrocyte activation in neurodegenerative disease.
Engler, H. et al. Imaging astrocytosis with PET in Creutzfeldt-Jakob disease: case report with histopathological findings. Int. J. Clin. Exp. Med. 5, 201–207 (2012).
Carter, S. F. et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J. Nucl. Med. 53, 37–46 (2012).
Tyacke, R. J. et al. Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding site in human brain. J. Nucl. Med. 59, 1597–1602 (2018).
Chang, L., Munsaka, S. M., Kraft-Terry, S. & Ernst, T. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J. Neuroimmune Pharmacol. 8, 576–593 (2013).
Vrenken, H. et al. MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn. Reson. Med. 53, 256–266 (2005).
Bitsch, A. et al. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am. J. Neuroradiol. 20, 1619–1627 (1999).
Datta, G. et al. Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis. Mult. Scler. 23, 1469–1478 (2017).
Rae, C. D. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem. Res. 39, 1–36 (2014).
Wattjes, M. P., Steenwijk, M. D. & Stangel, M. MRI in the diagnosis and monitoring of multiple sclerosis: an update. Clin. Neuroradiol. 25 (Suppl. 2), 157–165 (2015).
Vagberg, M. et al. Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society. Acta Neurol. Scand. 135, 17–24 (2017).
Suthiphosuwan, S., Kim, D., Bharatha, A. & Oh, J. Imaging markers for monitoring disease activity in multiple sclerosis. Curr. Treat. Options Neurol. 19, 18 (2017).
Oreja-Guevara, C. & Paradig, M. S. G. Overview of magnetic resonance imaging for management of relapsing-remitting multiple sclerosis in everyday practice. Eur. J. Neurol. 22 (Suppl. 2), 22–27 (2015).
Magliozzi, R. et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477–493 (2010).
Sormani, M. P. & Pardini, M. Assessing repair in multiple sclerosis: outcomes for phase II clinical trials. Neurotherapeutics 14, 924–933 (2017).
Ontaneda, D. & Fox, R. J. Imaging as an outcome measure in multiple sclerosis. Neurotherapeutics 14, 24–34 (2017).
Bodini, B., Louapre, C. & Stankoff, B. Advanced imaging tools to investigate multiple sclerosis pathology. Presse Med. 44, e159–e167 (2015).
Filippi, M. MRI measures of neurodegeneration in multiple sclerosis: implications for disability, disease monitoring, and treatment. J. Neurol. 262, 1–6 (2015).
Tur, C. & Montalban, X. Progressive MS trials: lessons learned. Mult. Scler. 23, 1583–1592 (2017).
Ontaneda, D., Fox, R. J. & Chataway, J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 14, 208–223 (2015).
Ciotti, J. R. & Cross, A. H. Disease-modifying treatment in progressive multiple sclerosis. Curr. Treat. Options Neurol. 20, 12 (2018).
Alam, M. M., Lee, J. & Lee, S. Y. Recent progress in the development of TSPO PET ligands for neuroinflammation imaging in neurological diseases. Nucl. Med. Mol. Imaging 51, 283–296 (2017).
Owen, D. R. et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J. Cereb. Blood Flow Metab. 32, 1–5 (2012).
Kobayashi, M. et al. 11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195. J. Cereb. Blood Flow Metab. 38, 393–403 (2018).
Owen, D. R. et al. Determination of [11C]PBR28 binding potential in vivo: a first human TSPO blocking study. J. Cereb. Blood Flow Metab. 34, 989–994 (2014).
Feeney, C. et al. Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain. Eur. J. Nucl. Med. Mol. Imaging 43, 2201–2210 (2016).
Vomacka, L. et al. TSPO imaging using the novel PET ligand [18F]GE-180: quantification approaches in patients with multiple sclerosis. EJNMMI Res. 7, 89 (2017).
Unterrainer, M. et al. TSPO PET with [18F]GE-180 sensitively detects focal neuroinflammation in patients with relapsing-remitting multiple sclerosis. Eur. J. Nucl. Med. Mol. Imaging 45, 1423–1431 (2018).
Hagens, M. H. J. et al. In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET. J. Neuroinflammation 15, 314 (2018).
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.
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.
Peer review information
Nature Reviews Neurology thanks J. Geurts and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Matthews, P.M. Chronic inflammation in multiple sclerosis — seeing what was always there. Nat Rev Neurol 15, 582–593 (2019). https://doi.org/10.1038/s41582-019-0240-y
This article is cited by
Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1
Journal of Neuroinflammation (2023)
Neuroscience Bulletin (2023)
Current Neurology and Neuroscience Reports (2023)
Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics
Journal of Neuroinflammation (2022)
Rim lesions are demonstrated in early relapsing–remitting multiple sclerosis using 3 T-based susceptibility-weighted imaging in a multi-institutional setting