In Vivo Imaging of Neuroinflammation in Acute Brain Injury

Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR, volume 6)

Abstract

Neuroinflammation is a dynamic process which undergoes significant changes in spatial distribution and intensity within hours and days after an acute brain injury. At present non-invasive in vivo imaging methods like positron emission tomography (PET) offer the only possibility to capture this dynamics longitudinally in the same subject and the entire brain. Amongst the multitude of cellular and non-cellular mechanisms which constitute the complex neuroinflammatory reaction, microglia and macrophages have been the primary targets for developing non-invasive imaging methods. This chapter is an introduction into the basic principles of microglia imaging with PET, its application to ischaemic stroke and traumatic brain injury in both animal models and clinical imaging in patients. Future developments towards magnetic resonance imaging (MRI) of neuroinflammation and imaging of specific enzyme activity in the neuroinflammatory cascade are discussed.

Keywords

Cholesterol Permeability Migration Alanine Alkaloid 

References

  1. 1.
    Wang X, Feuerstein GZ (2004) The Janus face of inflammation in ischemic brain injury. Acta Neurochir Suppl 89:49–54PubMedCrossRefGoogle Scholar
  2. 2.
    Jacobs AH, Tavitian B (2012) Noninvasive molecular imaging of neuroinflammation. J Cereb Blood Flow Metab 32(7):1393–1415PubMedCrossRefGoogle Scholar
  3. 3.
    Schroeter M, Franke C, Stoll G, Hoehn M (2001) Dynamic changes of magnetic resonance imaging abnormalities in relation to inflammation and glial responses after photothrombotic cerebral infarction in the rat brain. Acta Neuropathol 101(2):114–122PubMedGoogle Scholar
  4. 4.
    Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR et al (2009) Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK1. J Cereb Blood Flow Metab 29(6):1216–1225PubMedCrossRefGoogle Scholar
  5. 5.
    Banati RB (2002) Visualising microglial activation in vivo. Glia 40(2):206–217PubMedCrossRefGoogle Scholar
  6. 6.
    Venneti S, Lopresti BJ, Wiley CA (2012) Molecular imaging of microglia/macrophages in the brain. Glia 61(1):10–23PubMedCrossRefGoogle Scholar
  7. 7.
    Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, Kiefer R (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196(2):290–297PubMedCrossRefGoogle Scholar
  8. 8.
    Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapore JJ, Lindemann P et al (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27(8):402–409PubMedCrossRefGoogle Scholar
  9. 9.
    McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 89(8):3170–3174PubMedCrossRefGoogle Scholar
  10. 10.
    Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S et al (2009) 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(3):306–328PubMedCrossRefGoogle Scholar
  11. 11.
    Martin A, Boisgard R, Theze B, Van CN, Kuhnast B, Damont A et al (2010) Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 30(1):230–241PubMedCrossRefGoogle Scholar
  12. 12.
    Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M et al (2008) Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J Neurosci 28(47):12255–12267PubMedCrossRefGoogle Scholar
  13. 13.
    Johansen HL, Wielgosz AT, Nguyen K, Fry RN (2010) Incidence, comorbidity, case fatality and readmission of hospitalized stroke patients in Canada. Can J Cardiol 22(1):65–71CrossRefGoogle Scholar
  14. 14.
    Chauveau F, Boutin H, Van CN, Dolle F, Tavitian B (2008) Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 35(12):2304–2319PubMedCrossRefGoogle Scholar
  15. 15.
    Le FG, Guilloux F, Rufat P, Benavides J, Uzan A, Renault C et al (1983) Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies. Life Sci 32(16):1849–1856CrossRefGoogle Scholar
  16. 16.
    Fujimura Y, Zoghbi SS, Simeon FG, Taku A, Pike VW, Innis RB et al (2009) Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06. J Nucl Med 50(7):1047–1053PubMedCrossRefGoogle Scholar
  17. 17.
    Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S et al (2011) Quantitation of translocator protein binding in human brain with the novel radioligand [lsqb]18F[rsqb]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab 31(8):1807–1816PubMedCrossRefGoogle Scholar
  18. 18.
    Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y et al (2004) Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse 52(4):283–291PubMedCrossRefGoogle Scholar
  19. 19.
    Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH et al (2007) Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med 48(12):2072–2079PubMedCrossRefGoogle Scholar
  20. 20.
    Gulyazs B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K et al (2012) Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [11C]vinpocetine. J Neurol Sci 320(1):110–117CrossRefGoogle Scholar
  21. 21.
    Doorduin J, Klein H, Dierckx R, James M, Kassiou M, Vries E (2009) [11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis. Mol Imaging Biol 11(6):386–398PubMedCrossRefGoogle Scholar
  22. 22.
    Dickstein L, Zoghbi S, Fujimura Y, Imaizumi M, Zhang Y, Pike V et al (2011) Comparison of 18F- and 11C-labeled aryloxyanilide analogs to measure translocator protein in human brain using positron emission tomography. Eur J Nucl Med Mol Imaging 38(2):352–357PubMedCrossRefGoogle Scholar
  23. 23.
    Gulyazs B, Toth M, Vas A, Shchukin E, Kostulas K, Hillert J et al (2012) Visualising neuroinflammation in post-stroke patients: a comparative PET study with the TSPO molecular imaging biomarkers [11C]PK11195 and [11C]vinpocetine. Curr Radiopharm 5(1):19–28CrossRefGoogle Scholar
  24. 24.
    Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M et al (2010) Two binding sites for [(3)H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9):1608–1618PubMedCrossRefGoogle Scholar
  25. 25.
    Owen DRJ, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC et al (2011) Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 52(1):24–32PubMedCrossRefGoogle Scholar
  26. 26.
    Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A et al (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32(1):1–5PubMedCrossRefGoogle Scholar
  27. 27.
    Lammertsma AA (2002) Radioligand studies: imaging and quantitative analysis. Eur Neuropsychopharmacol 12(6):513–516PubMedCrossRefGoogle Scholar
  28. 28.
    Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BN, Luurtsema G, Windhorst AD et al (2005) Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J Cereb Blood Flow Metab 25(7):842–851PubMedCrossRefGoogle Scholar
  29. 29.
    Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4(3):153–158PubMedCrossRefGoogle Scholar
  30. 30.
    Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BN, Lammertsma AA (2006) Evaluation of reference tissue models for the analysis of [(11)C](R)-PK11195 studies. J Cereb Blood Flow Metab 25(11):1431–1441CrossRefGoogle Scholar
  31. 31.
    Thiel A, Heiss WD (2011) Imaging of microglia activation in stroke. Stroke 42(2):507–512PubMedCrossRefGoogle Scholar
  32. 32.
    Dubois A, Benavides J, Peny B, Duverger D, Fage D, Gotti B et al (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(1):77–90PubMedCrossRefGoogle Scholar
  33. 33.
    Stephenson DT, Schober DA, Smalstig EB, Mincy RE, Gehlert DR, Clemens JA (1995) Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat. J Neurosci 15(7 Pt 2):5263–5274PubMedGoogle Scholar
  34. 34.
    Demerle-Pallardy C, Duverger D, Spinnewyn B, Pirotzky E, Braquet P (1991) Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: effect of neuroprotective drugs. Brain Res 565(2):312–320PubMedCrossRefGoogle Scholar
  35. 35.
    Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E et al (2007) Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 27(12):1975–1986PubMedCrossRefGoogle Scholar
  36. 36.
    Gerhard A, Schwarz J, Myers R, Wise R, Banati RB (2005) Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 24(2):591–595PubMedCrossRefGoogle Scholar
  37. 37.
    Weinstein J, Koerner I, Moller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246PubMedCrossRefGoogle Scholar
  38. 38.
    Schroeter M, Jander S, Witte OW, Stoll G (1999) Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex. Neuroscience 89(4):1367–1377PubMedCrossRefGoogle Scholar
  39. 39.
    Schmitt AB, Brook GA, Buss A, Nacimiento W, Noth J, Kreutzberg GW (1998) Dynamics of microglial activation in the spinal cord after cerebral infarction are revealed by expression of MHC class II antigen. Neuropathol Appl Neurobiol 24(3):167–176PubMedCrossRefGoogle Scholar
  40. 40.
    Radlinska B, Ghinani S, Lyon P, Jolly D, Soucy JP, Minuk J et al (2009) Multi-modal microglia imaging of fiber tracts in acute sub-cortical stroke. Ann Neurol 66:825–832PubMedCrossRefGoogle Scholar
  41. 41.
    Thiel A, Radlinska B, Paquette C, Sidel M, Soucy JP, Schirrmacher R et al (2010) The temporal dynamics of post-stroke neuroinflammation: a longitudinal DTI-guided PET-study with [11C]-PK11195 in acute sub-cortical stroke. J Nucl Med 51:1404–1412PubMedCrossRefGoogle Scholar
  42. 42.
    Keiner S, Wurm F, Kunze A, Witte OW, Redecker C (2008) Rehabilitative therapies differentially alter proliferation and survival of glial cell populations in the perilesional zone of cortical infarcts. Glia 56(5):516–527PubMedCrossRefGoogle Scholar
  43. 43.
    Rao VL, Dogan A, Bowen KK, Dempsey RJ (2000) Traumatic brain injury leads to increased expression of peripheral-type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol 161(1):102–114CrossRefGoogle Scholar
  44. 44.
    Venneti S, Wagner AK, Wang G, Slagel SL, Chen X, Lopresti BJ et al (2007) The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging. Exp Neurol 207(1):118–127PubMedCrossRefGoogle Scholar
  45. 45.
    Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM et al (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70(3):374–383PubMedCrossRefGoogle Scholar
  46. 46.
    Folkersma H, Boellaard R, Vandertop WP, Kloet RW, Lubberink M, Lammertsma AA et al (2009) Reference tissue models and blood–brain barrier disruption: lessons from (R)-[11C]PK11195 in traumatic brain injury. J Nucl Med 50(12):1975–1979PubMedCrossRefGoogle Scholar
  47. 47.
    Folkersma H, Boellaard R, Yaqub M, Kloet RW, Windhorst AD, Lammertsma AA et al (2011) Widespread and prolonged increase in (R)-11C-PK11195 binding after traumatic brain injury. J Nucl Med 52(8):1235–1239PubMedCrossRefGoogle Scholar
  48. 48.
    Venneti S, Lopresti BJ, Wang G, Slagel SL, Mason NS, Mathis CA et al (2007) A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem 102(6):2118–2131PubMedCrossRefGoogle Scholar
  49. 49.
    Cagnin A, Myers R, Gunn RN, Lawrence AD, Stevens T, Kreutzberg GW et al (2001) In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. Brain 124(Pt 10):2014–2027PubMedCrossRefGoogle Scholar
  50. 50.
    Shukuri M, Takashima-Hirano M, Tokuda K, Takashima T, Matsumura K, Inoue O et al (2011) In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. J Nucl Med 52(7):1094–1101PubMedCrossRefGoogle Scholar
  51. 51.
    Antunes IF, Doorduin J, Haisma HJ, Elsinga PH, van Waarde A, Willemsen ATM et al (2012) 18F-FEAnGA for PET of ß-glucuronidase activity in neuroinflammation. J Nucl Med 53(3):451–458PubMedCrossRefGoogle Scholar
  52. 52.
    McAteer M, von Zur Muhlen C, Anthony D, Sibson N, Choudhury R (2011) Magnetic resonance imaging of brain inflammation using microparticles of iron oxide. In: Shah K (ed) Molecular imaging, 680 edn. Humana Press, p 103–15Google Scholar
  53. 53.
    Rosenberg JT, Sachi-Kocher A, Davidson MW, Grant SC (2012) Intracellular SPIO labeling of microglia: high field considerations and limitations for MR microscopy. Contrast Media Mol Imaging 7(2):121–129PubMedCrossRefGoogle Scholar
  54. 54.
    Nighoghossian N, Wiart M, Cakmak S, Berthezene Y, Derex L, Cho TH et al (2007) Inflammatory response after ischemic stroke. Stroke 38(2):303–307PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Neurology and NeurosurgeryMcGill UniversityMontrealCanada

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