Skip to main content
PMC home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2007 Jul;4(3):434–442. doi: 10.1016/j.nurt.2007.05.005

Magnetic resonance imaging of human brain macrophage infiltration

Klaus G Petry 1,✉, Claudine Boiziau 1, Vincent Dousset 1, Bruno Brochet 1
PMCID: PMC7479730  PMID: 17599709

Summary

Macrophage tracking by magnetic resonance imaging (MRI) with iron oxide nanoparticles has been developed during the last decade for numerous diseases of the CNS. Experimental studies on animal models were confirmed by first clinical applications of MRI technology of brain macrophages for multiple sclerosis, ischemic stroke lesions, and tumors. As activated macrophages act in concert with other immune competent cells, this innovative MRI approach provides new functional data on the immune reaction in these CNS diseases. The MRI detection of brain macrophages defines precise spatial and temporal patterns of macrophage involvement that helps to characterize individual neurological disorders. This approach is being explored as an in vivo marker for the clinical diagnosis of cerebral lesion activity, in experimental models for the prognosis of disease development, and to determine the efficacy of immunomodulatory treatments under clinical evaluation. Comparative brain imaging follow-up studies of blood-brain barrier leakage by MRI with gadolinium-chelates, microglia activation by positron emission tomography with radiotracer ligand PK11195 and MRI detection of macrophage infiltration provide more precise information about the pathophysiological cascade of inflammatory events in cerebral diseases. Such multimodal characterization of the inflammatory events should help in the monitoring of patients, in defining precise time intervals for therapeutic interventions, and in developing and evaluating new therapeutic strategies.

Key Words: Macrophages, MRI, brain diseases, multiple sclerosis, stroke, glioma, iron oxide nanoparticles

References

  • 1.Mosser DM. The many faces of macrophage activation. J Leuk Biol. 2003;73:209–212. doi: 10.1189/jlb.0602325. [DOI] [PubMed] [Google Scholar]
  • 2.Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342–349. doi: 10.4049/jimmunol.175.1.342. [DOI] [PubMed] [Google Scholar]
  • 3.Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015. [DOI] [PubMed] [Google Scholar]
  • 4.Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ. Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology. 1990;175:494–498. doi: 10.1148/radiology.175.2.2326475. [DOI] [PubMed] [Google Scholar]
  • 5.Corot C, Petry KG, Trivedi R, et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol. 2004;39:619–625. doi: 10.1097/01.rli.0000135980.08491.33. [DOI] [PubMed] [Google Scholar]
  • 6.Corot C, Robert P, Idee JM, Port M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev. 2006;58:1471–1504. doi: 10.1016/j.addr.2006.09.013. [DOI] [PubMed] [Google Scholar]
  • 7.Cagnin A, Kassiou M, Meikle SR, Banati RB. Positron emission tomography imaging of neuroinflammation. Neurotherapeutics. 2007;4:443–452. doi: 10.1016/j.nurt.2007.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52:61–76. doi: 10.1016/j.neuron.2006.09.011. [DOI] [PubMed] [Google Scholar]
  • 9.Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging of the brain, spinal cord, and optic nerve. Neurotherapeutics. 2007;4:401–413. doi: 10.1016/j.nurt.2007.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Deloire-Grassin MS, Brochet B, Quesson B, et al. In vivo evaluation of remyelination in rat brain by magnetization transfer imaging. J Neurol Sci. 2000;178:10–16. doi: 10.1016/S0022-510X(00)00331-2. [DOI] [PubMed] [Google Scholar]
  • 11.Brochet B, Dousset V. Pathological correlates of magnetization transfer imaging abnormalities in animal models and humans with multiple sclerosis. Neurology. 1999;53(suppl 3):S12–S17. [PubMed] [Google Scholar]
  • 12.Bauer J, Ruuls SR, Huitinga I, Dijkstra CD. The role of macrophage subpopulations in autoimmune disease of the central nervous system. Histochem J. 1996;28:83–97. doi: 10.1007/BF02331413. [DOI] [PubMed] [Google Scholar]
  • 13.Dousset V, Ballarino L, Delalande C, et al. Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. AJNR Am J Neuroradiol. 1999;20:223–227. [PMC free article] [PubMed] [Google Scholar]
  • 14.Rausch M, Hiestand P, Baumann D, Cannet C, Rudin M. MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. Magn Reson Med. 2003;50:309–314. doi: 10.1002/mrm.10541. [DOI] [PubMed] [Google Scholar]
  • 15.Floris S, Blezer EL, Schreibelt G, et al. Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain. 2004;127:616–627. doi: 10.1093/brain/awh068. [DOI] [PubMed] [Google Scholar]
  • 16.Boulleme AI, Rodriguez JJ, Touil T, et al. Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neurosci. 2002;22:123–132. doi: 10.1523/JNEUROSCI.22-01-00123.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Vignes JR, Deloire MS, Petry KG, Nagy F. Characterization and restoration of altered inhibitory and excitatory control of micturition reflex in experimental autoimmune encephalomyelitis in rats. J Physiol (Lond.) 2007;578:439–450. doi: 10.1113/jphysiol.2006.117366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Dousset V, Gomez C, Petty KG, Delalande C, Caille JM. Dose and scanning delay using USPIO for central nervous system macrophage imaging. MAGMA. 1999;8:185–189. doi: 10.1007/BF02594597. [DOI] [PubMed] [Google Scholar]
  • 19.Bendszus M, Stoll G. Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J Neurosci. 2003;23:10892–10896. doi: 10.1523/JNEUROSCI.23-34-10892.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol. 2006;27:1000–1005. [PMC free article] [PubMed] [Google Scholar]
  • 21.Manninger SP, Muldoon LL, Nesbit G, Murillo T, Jacobs PM, Neuwelt EA. An exploratory study of ferumoxtran-10 nanoparticles as a blood-brain barrier imaging agent targeting phagocytic cells in CNS inflammatory lesions. ANJR Am J Neuroradiol. 2005;26:2290–2300. [PMC free article] [PubMed] [Google Scholar]
  • 22.Lassmann H, Brück W, Luchinetti CF. Heterogeneity of multiple sclerosis pathogenesis. Implications for diagnosis and therapy. Trends Mol Med. 2001;7:115–121. doi: 10.1016/S1471-4914(00)01909-2. [DOI] [PubMed] [Google Scholar]
  • 23.Boven LA, Van Meurs M, Van Zwam M, et al. Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain. 2006;129:517–526. doi: 10.1093/brain/awh707. [DOI] [PubMed] [Google Scholar]
  • 24.Mikita J, Deloire MS, Canron MH, et al. Prediction of macrophage phenotypes in inflammatory CNS lesions of relapsing EAE disease by MRI with iron nanoparticles. Fifth forum of European Neuroscience Vienna-Austria; July 8–12 2006. A096.13 (abstract).
  • 25.Heyn C, Ronald JA, Mackenzie LT, et al. In vivo magnetic resonance imaging of single cells in mouse brain with optical validation. Magn Reson Med. 2006;55:23–29. doi: 10.1002/mrm.20747. [DOI] [PubMed] [Google Scholar]
  • 26.Slotkin JR, Cahill KS, Tharin SA, Shapiro EM. Cellular magnetic resonance imaging: Nanometer and micrometer size particles for noninvasive cell localization. Neurotherapeutics 4:428–433. [DOI] [PMC free article] [PubMed]
  • 27.Crane IJ, Forrester JV. Th1 and Th2 lymphocytes in autoimmune disease. Crit Rev Immunol. 2005;25:75–102. doi: 10.1615/CritRevImmunol.v25.i2.10. [DOI] [PubMed] [Google Scholar]
  • 28.Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petty KG. Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment. Mult Scler. 2004;10:540–548. doi: 10.1191/1352458504ms1090oa. [DOI] [PubMed] [Google Scholar]
  • 29.von Adrian UH, Engelhardt B. Alpha 4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348:68–72. doi: 10.1056/NEJMe020157. [DOI] [PubMed] [Google Scholar]
  • 30.Kappos L, Antel J, Comi G, et al. FTY720 D2201 Study Group. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–1140. doi: 10.1056/NEJMoa052643. [DOI] [PubMed] [Google Scholar]
  • 31.Rausch M, Hiestand P, Foster CA, Baumann DR, Cannet C, Rudin M. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ulttasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2004;20:16–24. doi: 10.1002/jmri.20057. [DOI] [PubMed] [Google Scholar]
  • 32.Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–1608. doi: 10.1016/S0140-6736(04)16205-3. [DOI] [PubMed] [Google Scholar]
  • 33.Toft-Hansen H, Buist R, Sun XJ, Schellenberg A, Peeling J, Owens T. Metalloproteinases control brain inflammation induced by Pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system. J Immunol. 2006;177:7242–7249. doi: 10.4049/jimmunol.177.10.7242. [DOI] [PubMed] [Google Scholar]
  • 34.Berger C, Hiestand P, Kindler-Baumann D, Rudin M, Rausch M. Analysis of lesion development during acute inflammation and remission in a rat model of experimental autoimmune encephalomyelitis by visualization of macrophage infiltration, demyelination and blood-brain barrier damage. NMR Biomed. 2006;19:101–107. doi: 10.1002/nbm.1007. [DOI] [PubMed] [Google Scholar]
  • 35.Brochet B, Deloire MS, Touil T, et al. Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage. 2006;32:266–274. doi: 10.1016/j.neuroimage.2006.03.028. [DOI] [PubMed] [Google Scholar]
  • 36.Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW. Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev. 1999;30:77–105. doi: 10.1016/S0165-0173(99)00007-7. [DOI] [PubMed] [Google Scholar]
  • 37.Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26:248–254. doi: 10.1016/S0166-2236(03)00071-7. [DOI] [PubMed] [Google Scholar]
  • 38.Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol. 2003;183:25–33. doi: 10.1016/S0014-4886(03)00082-7. [DOI] [PubMed] [Google Scholar]
  • 39.Tanaka R, Komine-Kobayashi M, Mochizuki H, et al. Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience. 2003;117:531–539. doi: 10.1016/S0306-4522(02)00954-5. [DOI] [PubMed] [Google Scholar]
  • 40.Rausch M, Sauter A, Fröhlich J, Neubacher U, Radu EW, Rudin M. Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage. Magn Reson Med. 2001;46:1018–1022. doi: 10.1002/mrm.1290. [DOI] [PubMed] [Google Scholar]
  • 41.Rausch M, Baumann D, Neubacher U, Rudin M. In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO. NMR Biomed. 2002;15:278–283. doi: 10.1002/nbm.770. [DOI] [PubMed] [Google Scholar]
  • 42.Saleh A, Wiedermann D, Schroeter M, Jonkmanns C, Jander S, Hoehn M. Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging. NMR Biomed. 2004;17:163–169. doi: 10.1002/nbm.881. [DOI] [PubMed] [Google Scholar]
  • 43.Schroeter M, Saleh A, Wiedermann D, Hoehn M, Jander S. Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia. Magn Reson Med. 2004;52:403–406. doi: 10.1002/mrm.20142. [DOI] [PubMed] [Google Scholar]
  • 44.Kleinschnitz C, Bendszus M, Frank M, Solymosi L, Toyka KV, Stoll G. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab. 2003;23:1356–1361. doi: 10.1097/01.WCB.0000090505.76664.DB. [DOI] [PubMed] [Google Scholar]
  • 45.Wiart M, Davoust N, Pialat JB, et al. MRI monitoring of neuroinflammation in mouse focal ischemia. Stroke. 2007;38:131–137. doi: 10.1161/01.STR.0000252159.05702.00. [DOI] [PubMed] [Google Scholar]
  • 46.Saleh A, Schroeter M, Jonkmanns C, Hartung HP, Mödder U, Jander S. In vivo MRI of brain inflammation in human ischaemic stroke. Brain. 2004;127:1670–1677. doi: 10.1093/brain/awh191. [DOI] [PubMed] [Google Scholar]
  • 47.Nighoghossian N, Wiart M, Cakmak S, et al. Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke. 2007;38:303–307. doi: 10.1161/01.STR.0000254548.30258.f2. [DOI] [PubMed] [Google Scholar]
  • 48.Stoll G, Jander S, Schroeter M. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J Neural Transm Suppl. 2000;59:81–89. doi: 10.1007/978-3-7091-6781-6_11. [DOI] [PubMed] [Google Scholar]
  • 49.Jander S, Schroeter M, Saleh A. Imaging inflammation in acute brain ischemia. Stroke. 2007;38:642–645. doi: 10.1161/01.STR.0000250048.42916.ad. [DOI] [PubMed] [Google Scholar]
  • 50.Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [1c](r)-pk11195 PET study. Neuroimage. 2005;24:591–595. doi: 10.1016/j.neuroimage.2004.09.034. [DOI] [PubMed] [Google Scholar]
  • 51.Zimmer C, Weissleder R, Poss K, Bogdanova A, Wright SC, Enochs WS. MR imaging of phagocytosis in experimental gliomas. Radiology. 1995;197:533–538. doi: 10.1148/radiology.197.2.7480707. [DOI] [PubMed] [Google Scholar]
  • 52.Varallyay P, Nesbit G, Muldoon LL, et al. Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors. AJNR Am J Neuroradiol. 2002;23:510–519. [PMC free article] [PubMed] [Google Scholar]
  • 53.Neuwelt EA, Varallyay P, Bago AG, Muldoon LL, Nesbit G, Nixon R. Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours. Neuropathol Appl Neurobiol. 2004;30:456–471. doi: 10.1111/j.1365-2990.2004.00557.x. [DOI] [PubMed] [Google Scholar]
  • 54.Murillo TP, Sandquist C, Jacobs PM, Nesbit G, Manninger S, Neuwelt EA. Imaging brain tumors with ferumoxtran-10, a nano-particle magnetic resonance contrast agent. Therapy. 2005;2(6):871–882. doi: 10.2217/14750708.2.6.871. [DOI] [Google Scholar]
  • 55.Taschner CA, Wetzel SG, Tolnay M, Froehlich J, Merlo A, Radue EW. Characteristics of ultrasmall superparamagnetic iron oxides in patients with brain tumors. AJR. 2005;185:1477–1486. doi: 10.2214/AJR.04.1286. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES