Abstract
Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [11C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [11C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging of the brain at baseline and after 1 year of treatment with glatiramer acetate. Parametric maps of [11C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [11C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region-of-interest analysis was also applied to selected subregions. Whole brain [11C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: −0.74, −5.53%) between baseline and 1 year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [11C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.
Similar content being viewed by others
References
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285
Perry VH, Gordon S (1991) Macrophages and the nervous system. Int Rev Cytol 125:203–244
Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75:388–397
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287
Dangond F, Windhagen A, Groves CJ, Hafler DA (1997) Constitutive expression of costimulatory molecules by human microglia and its relevance to CNS autoimmunity. J Neuroimmunol 76:132–138
Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75:165–173
Bauer J, Sminia T, Wouterlood FG, Dijkstra CD (1994) Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J Neurosci Res 38:365–375
Brosnan CF, Bornstein MB, Bloom BR (1981) The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. J Immunol 126:614–620
Huitinga I, van Rooijen N, de Groot CJ, Uitdehaag BM, Dijkstra CD (1990) Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J Exp Med 172:1025–1033
Sriram S, Rodriguez M (1997) Indictment of the microglia as the villain in multiple sclerosis. Neurology 48:464–470
Dubois A, Benavides J, Peny B, Duverger D, Fage D, Gotti B, MacKenzie ET, Scatton B (1988) Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat. Brain Res 445:77–90
Myers R, Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JE (1991) Macrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab 11:314–322
Banati RB, Myers R, Kreutzberg GW (1997) PK (‘peripheral benzodiazepine’)–binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol 26:77–82
Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R (2000) 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
Casellas P, Galiegue S, Basile AS (2002) Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 40:475–486
Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 80:308–322
Debruyne JC, Versijpt J, Van Laere KJ, De Vos F, Keppens J, Strijckmans K, Achten E, Slegers G, Dierckx RA, Korf J, De Reuck JL (2003) PET visualization of microglia in multiple sclerosis patients using [11C]PK11195. Eur J Neurol 10:257–264
Versijpt J, Debruyne JC, Van Laere KJ, De Vos F, Keppens J, Strijckmans K, Achten E, Slegers G, Dierckx RA, Korf J, De Reuck JL (2005) Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study. Mult Scler 11:127–134
Politis M, Giannetti P, Su P, Turkheimer F, Keihaninejad S, Wu K, Waldman A, Reynolds R, Nicholas R, Piccini P (2010) Cortical microglial activation is associated with disability in secondary progressive multiple sclerosis: an in vivo imaging study. Neurology 74:A290
Oh U, Fujita M, Ikonomidou VN, Evangelou IE, Matsuura E, Harberts E, Ohayon J, Pike VW, Zhang Y, Zoghbi SS, Innis RB, Jacobson S (2010) Translocator Protein PET Imaging for Glial Activation in Multiple Sclerosis. J Neuroimmune Pharmacol 6:354–361
Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846
Shiee N, Bazin PL, Ozturk A, Reich DS, Calabresi PA, Pham DL (2010) A topology-preserving approach to the segmentation of brain images with multiple sclerosis lesions. Neuroimage 49:1524–1535
Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, Jonker C, Scheltens P, Lammertsma AA (2007) Evaluation of reference regions for (R)-[(11)C]PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab 27:1965–1974
Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16:834–840
Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113
Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170
Dhib-Jalbut S (2002) Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 58:S3–S9
Kim HJ, Ifergan I, Antel JP, Seguin R, Duddy M, Lapierre Y, Jalili F, Bar-Or A (2004) Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 172:7144–7153
Pul R, Moharregh-Khiabani D, Skuljec J, Skripuletz T, Garde N, Voss EV, Stangel M (2010) Glatiramer acetate modulates TNF-alpha and IL-10 secretion in microglia and promotes their phagocytic activity. J Neuroimmune Pharmacol 6:381–388
Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368
Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489
Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, Reynolds A, Hilton J, Dannals RF, Kassiou M (2009) Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med 50:1276–1282
Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, Fujimura Y, Takano A, Maeda J, Zhang MR, Nakao R, Suzuki K (2007) Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C]DAA1106. J Cereb Blood Flow Metab 27:173–184
Acknowledgments
This study was funded by an independent medical grant from TEVA Neuroscience to Dr. Calabresi. The study sponsor had no role in the design or execution of the study, data analysis, manuscript preparation, or decision to submit the paper for publication.
Conflict of interest
Dr. Ratchford receives research support from the Nancy Davis Foundation for Multiple Sclerosis and support for clinical trials from Novartis and Biogen Idec. Dr. Endres, Dr. Hammoud, Dr. Pomper, Mr. Shiee, Dr. McGready, Dr. Pham have nothing to disclose. Dr. Calabresi has received personal compensation for consulting, serving on scientific advisory boards and speaking activities from Biogen-IDEC, Teva, Merck-Serono, Novartis, Vertex, Vaccinex, Genzyme, and Abbott. He has received research funding from Biogen-IDEC, Teva, EMD-Serono, Vertex, Genentech, Abbott, and Bayer.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ratchford, J.N., Endres, C.J., Hammoud, D.A. et al. Decreased microglial activation in MS patients treated with glatiramer acetate. J Neurol 259, 1199–1205 (2012). https://doi.org/10.1007/s00415-011-6337-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-011-6337-x