Advertisement

Journal of Neural Transmission

, Volume 125, Issue 5, pp 847–867 | Cite as

In vivo PET imaging of neuroinflammation in Alzheimer’s disease

  • Julien Lagarde
  • Marie Sarazin
  • Michel Bottlaender
Neurology and Preclinical Neurological Studies - Review Article

Abstract

Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer’s disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia. In the present review, we describe the most widely used PET tracers targeting the TSPO, the methodological issues in tracer quantification and summarize the results obtained by TSPO PET imaging in AD, as well as in neurodegenerative disorders associated with AD, in psychiatric disorders and ageing. We also briefly describe alternative PET targets and imaging modalities to study neuroinflammation. Lastly, we question the meaning of PET imaging data in the context of a highly complex and multifaceted role of neuroinflammation in neurodegenerative diseases. This overview leads to the conclusion that PET imaging of neuroinflammation is a promising way of deciphering the enigma of the pathophysiology of AD and of monitoring the effect of new therapies.

Keywords

Neuroinflammation Alzheimer’s disease PET imaging TSPO Microglia 

Notes

Compliance with ethical standards

Conflict of interest

Hoffmann-La Roche Ltd partly supported a study conducted by the authors. During the last 2 years, M.S. has received speaker honorarium from Société Générale.

References

  1. Ahamed M, van Veghel D, Ullmer C, Van Laere K, Verbruggen A, Bormans GM (2016) Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [11C]MA2 and [18F]MA3. Front Neurosci 10:431PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ahmad R, Postnov A, Bormans G, Versijpt J, Vandenbulcke M, Van Laere K (2016) Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 43(12):2219–2227PubMedCrossRefGoogle Scholar
  3. Albrecht DS, Granziera C, Hooker JM, Loggia ML (2016) In vivo imaging of human neuroinflammation. ACS Chem Neurosci 7(4):470–483PubMedPubMedCentralCrossRefGoogle Scholar
  4. Anderson AN, Pavese N, Edison P, Tai YF, Hammers A, Gerhard A, Brooks DJ, Turkheimer FE (2007) A systematic comparison of kinetic modelling methods generating parametric maps for [11C]-(R)-PK11195. Neuroimage 36(1):28–37PubMedCrossRefGoogle Scholar
  5. Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217PubMedCrossRefGoogle Scholar
  6. 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):2321–2337PubMedCrossRefGoogle Scholar
  7. Belloli S, Moresco RM, Matarrese M, Biella G, Sanvito F, Simonelli P, Turolla E, Olivieri S, Cappelli A, Vomero S, Galli-Kienle M, Fazio F (2004) Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration. Neurochem Int 44:433–440PubMedCrossRefGoogle Scholar
  8. Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD (2016) Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11C]PBR28 PET brain imaging study. Am J Psychiatry 173(1):44–52PubMedCrossRefGoogle Scholar
  9. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB (2001) In-vivo measurement of activated microglia in dementia. Lancet 358(9280):461–467PubMedCrossRefGoogle Scholar
  10. Cagnin A, Rossor M, Sampson EL, Mackinnon T, Banati RB (2004) In vivo detection of microglial activation in frontotemporal dementia. Ann Neurol 56(6):894–897PubMedCrossRefGoogle Scholar
  11. Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci 124(5):307–321PubMedCrossRefGoogle Scholar
  12. Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, Nordberg A (2012) 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(1):37–46PubMedCrossRefGoogle Scholar
  13. Casellas P, Galiegue S, Basile AS (2002) Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 40:475–486PubMedCrossRefGoogle Scholar
  14. Chauveau F, Van Camp N, Dollé F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M, Tavitian B (2009) Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med 50(3):468–476PubMedCrossRefGoogle Scholar
  15. Ching AS, Kuhnast B, Damont A, Roeda D, Tavitian B, Dollé F (2012) Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases. Insights Imaging 3(1):111–119PubMedCrossRefGoogle Scholar
  16. Choo IL, Carter SF, Schöll ML, Nordberg A (2014) Astrocytosis measured by 11C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging 41(11):2120–2126PubMedCrossRefGoogle Scholar
  17. Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J, Nicolas G, Venel Y, Hommet C, Baulieu JL, Cottier JP, Roussel C, Kassiou M, Guilloteau D, Ribeiro MJ (2012) Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One 7(12):e52941PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, Lee SC (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
  19. Cunningham VJ, Hume SP, Price GR, Ahier RG, Cremer JE, Jones AK (1991) Compartmental analysis of diprenorphine binding to opiate receptors in the rat in vivo and its comparison with equilibrium data in vitro. J Cereb Blood Flow Metab 11(1):1–9PubMedCrossRefGoogle Scholar
  20. Di Grigoli G, Monterisi C, Belloli S, Masiello V, Politi LS, Valenti S, Paolino M, Anzini M, Matarrese M, Cappelli A, Moresco RM (2015) Radiosynthesis and preliminary biological evaluation of [18F]VC701, a radioligand for translocator protein. Mol Imaging. doi: 10.2310/7290.2015.00007 PubMedCrossRefGoogle Scholar
  21. Diorio D, Welner SA, Butterworth RF, Meaney MJ, Suranyi-Cadotte BE (1991) Peripheral benzodiazepine binding sites in Alzheimer’s disease frontal and temporal cortex. Neurobiol Aging 12(3):255–258PubMedCrossRefGoogle Scholar
  22. Doble A, Malgouris C, Daniel M, Daniel N, Imbault F, Basbaum A, Uzan A, Guérémy C, Le Fur G (1987) Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H]PK 11195: anatomical and subcellular distribution. Brain Res Bull 18(1):49–61PubMedCrossRefGoogle Scholar
  23. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50(11):1801–1807PubMedCrossRefGoogle Scholar
  24. Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, Tai YF, Fox N, Kennedy A, Rossor M, Brooks DJ (2008) Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32(3):412–419PubMedCrossRefGoogle Scholar
  25. Edison P, Ahmed I, Fan Z, Hinz R, Gelosa G, Ray Chaudhuri K, Walker Z, Turkheimer FE, Brooks DJ (2013) Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology 38(6):938–949PubMedPubMedCentralCrossRefGoogle Scholar
  26. 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 50:1276–1282PubMedPubMedCentralCrossRefGoogle Scholar
  27. Esposito G, Giovacchini G, Liow JS, Bhattacharjee AK, Greenstein D, Schapiro M, Hallett M, Herscovitch P, Eckelman WC, Carson RE, Rapoport SI (2008) Imaging neuroinflammation in Alzheimer’s disease with radiolabeled arachidonic acid and PET. J Nucl Med 49(9):1414–1421PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fan Z, Aman Y, Ahmed I, Chetelat G, Landeau B, Ray Chaudhuri K, Brooks DJ, Edison P (2015a) Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson’s disease dementia. Alzheimers Dement 11(6):608–621.e7PubMedCrossRefGoogle Scholar
  29. Fan Z, Harold D, Pasqualetti G, Williams J, Brooks DJ, Edison P (2015b) Can studies of neuroinflammation in a TSPO genetic subgroup (HAB or MAB) be applied to the entire AD cohort? J Nucl Med 56(5):707–713PubMedCrossRefGoogle Scholar
  30. Fan Z, Okello AA, Brooks DJ, Edison P (2015c) Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain 138(Pt 12):3685–3698PubMedCrossRefGoogle Scholar
  31. Fan Z, Calsolaro V, Atkinson RÁ, Femminella GD, Waldman A, Buckley C, Trigg W, Brooks DJ, Hinz R, Edison P (2016) Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein. J Nucl Med 57(11):1753–1759PubMedCrossRefGoogle Scholar
  32. Fan Z, Brooks DJ, Okello A, Edison P (2017) An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain. doi: 10.1093/brain/aww349 PubMedCentralCrossRefPubMedGoogle Scholar
  33. Femminella GD, Ninan S, Atkinson R, Fan Z, Brooks DJ, Edison P (2016) Does microglial activation influence hippocampal volume and neuronal function in Alzheimer’s disease and Parkinson’s disease dementia? J Alzheimers Dis 51(4):1275–1289PubMedCrossRefGoogle Scholar
  34. García-Lorenzo D, Lavisse S, Leroy C, Wimberley C, Bodini B, Remy P, Veronese M, Turkheimer F, Stankoff B, Bottlaender M (2017) Validation of an automatic reference region extraction for the quantification of [18F]DPA-714 in dynamic brain PET studies. J Cereb Blood Flow Metab. doi: 10.1177/0271678X17692599 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gauberti M, Montagne A, Quenault A, Vivien D (2014) Molecular magnetic resonance imaging of brain-immune interactions. Front Cell Neurosci 8:389PubMedPubMedCentralCrossRefGoogle Scholar
  36. Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (1999) Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 51:629–650PubMedGoogle Scholar
  37. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn N, Schwarz J, Brooks DJ (2003) [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 61(5):686–689PubMedCrossRefGoogle Scholar
  38. Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ (2004) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 19(10):1221–1226PubMedCrossRefGoogle Scholar
  39. Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 21(1):89–93PubMedCrossRefGoogle Scholar
  40. Gershen LD, Zanotti-Fregonara P, Dustin IH, Liow JS, Hirvonen J, Kreisl WC, Jenko KJ, Inati SK, Fujita M, Morse CL, Brouwer C, Hong JS, Pike VW, Zoghbi SS, Innis RB, Theodore WH (2015) Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol 72(8):882–888PubMedPubMedCentralCrossRefGoogle Scholar
  41. Golla SS, Boellaard R, Oikonen V, Hoffmann A, van Berckel BN, Windhorst AD, Virta J, Haaparanta-Solin M, Luoto P, Savisto N, Solin O, Valencia R, Thiele A, Eriksson J, Schuit RC, Lammertsma AA, Rinne JO (2015) Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer’s disease patients. J Cereb Blood Flow Metab 35(5):766–772PubMedPubMedCentralCrossRefGoogle Scholar
  42. Golla SS, Boellaard R, Oikonen V, Hoffmann A, van Berckel BN, Windhorst AD, Virta J, Te Beek ET, Groeneveld GJ, Haaparanta-Solin M, Luoto P, Savisto N, Solin O, Valencia R, Thiele A, Eriksson J, Schuit RC, Lammertsma AA, Rinne JO (2016) Parametric binding images of the TSPO ligand 18F-DPA-714. J Nucl Med 57(10):1543–1547PubMedCrossRefGoogle Scholar
  43. Groom GN, Junck L, Foster NL, Frey KA, Kuhl DE (1995) PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer’s disease. J Nucl Med 36(12):2207–2210PubMedGoogle Scholar
  44. Gulyas B, Toth M, Vas A, Shchukin E, Kostulas K, Hillert J, Halldin C (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):19–28PubMedCrossRefGoogle Scholar
  45. Gulyás B, Makkai B, Kása P, Gulya K, Bakota L, Várszegi S, Beliczai Z, Andersson J, Csiba L, Thiele A, Dyrks T, Suhara T, Suzuki K, Higuchi M, Halldin C (2009) A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. Neurochem Int 54(1):28–36PubMedCrossRefGoogle Scholar
  46. Gulyás B, Pavlova E, Kása P, Gulya K, Bakota L, Várszegi S, Keller E, Horváth MC, Nag S, Hermecz I, Magyar K, Halldin C (2011a) Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-l-deprenyl using whole hemisphere autoradiography. Neurochem Int 58(1):60–68PubMedCrossRefGoogle Scholar
  47. Gulyás B, Vas A, Tóth M, Takano A, Varrone A, Cselényi Z, Schain M, Mattsson P, Halldin C (2011b) Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine. Neuroimage 56(3):1111–1121PubMedCrossRefGoogle Scholar
  48. Guo Q, Colasanti A, Owen DR, Onega M, Kamalakaran A, Bennacef I, Matthews PM, Rabiner EA, Turkheimer FE, Gunn RN (2013) Quantification of the specific translocator protein signal of 18F-PBR111 in healthy humans: a genetic polymorphism effect on in vivo binding. J Nucl Med 54(11):1915–1923PubMedCrossRefGoogle Scholar
  49. Haarman BC, Riemersma-Van der Lek RF, de Groot JC, Ruhé HG, Klein HC, Zandstra TE, Burger H, Schoevers RA, de Vries EF, Drexhage HA, Nolen WA, Doorduin J (2014) Neuroinflammation in bipolar disorder—a [11C]-(R)-PK11195 positron emission tomography study. Brain Behav Immun 40:219–225PubMedCrossRefGoogle Scholar
  50. Hafizi S, Tseng HH, Rao N, Selvanathan T, Kenk M, Bazinet RP, Suridjan I, Wilson AA, Meyer JH, Remington G, Houle S, Rusjan PM, Mizrahi R (2017) Imaging microglial activation in untreated first-episode psychosis: a pet study with [18F]FEPPA. Am J Psychiatry 174:118–124PubMedCrossRefGoogle Scholar
  51. Hagens M, van Berckel B, Barkhof F (2016) Novel MRI and PET markers of neuroinflammation in multiple sclerosis. Curr Opin Neurol 29(3):229–236PubMedCrossRefGoogle Scholar
  52. Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, de Souza LC, Corne H, Dauphinot L, Bertoux M, Dubois B, Gervais P, Colliot O, Potier MC, Bottlaender M, Sarazin M, Clinical IMABio3 Team (2016) Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139(Pt 4):1252–1264PubMedCrossRefGoogle Scholar
  53. Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, Pittman B, Lee JY, O’Connor KC, Pelletier D, Carson RE (2013) The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [11C]PBR28 PET study. Brain Behav Immun 33:131–138PubMedPubMedCentralCrossRefGoogle Scholar
  54. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405PubMedCrossRefPubMedCentralGoogle Scholar
  55. Henkel K, Karitzky J, Schmid M, Mader I, Glatting G, Unger JW, Neumaier B, Ludolph AC, Reske SN, Landwehrmeyer GB (2004) Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration. Mov Disord 19(7):817–821PubMedCrossRefGoogle Scholar
  56. Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6):358–372PubMedCrossRefGoogle Scholar
  57. Herranz E, Hooker JM, Izquierdo-Garcia D, Loggia ML, Mainero C (2017) Reply. Ann Neurol 81(2):324–325PubMedCrossRefGoogle Scholar
  58. Hickman SE, El Khoury J (2014) TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharmacol 88(4):495–498PubMedCrossRefGoogle Scholar
  59. Hillmer AT, Li S, Zheng MQ, Scheunemann M, Lin SF, Nabulsi N, Holden D, Pracitto R, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Esterlis I, Cosgrove KP, Brust P, Carson RE, Huang Y (2017) PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]-ASEM and [18F]-DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans. Eur J Nucl Med Mol Imaging. doi: 10.1007/s00259-017-3621-8 PubMedCrossRefPubMedCentralGoogle Scholar
  60. Hinz R, Boellaard R (2015) Challenges of quantification of TSPO in the human brain. DOI, Clin Transl Imaging. doi: 10.1007/s40336-015-0138-7 CrossRefGoogle Scholar
  61. Hirvonen J, Kailajärvi M, Haltia T, Koskimies S, Någren K, Virsu P, Oikonen V, Sipilä H, Ruokoniemi P, Virtanen K, Scheinin M, Rinne JO (2009) Assessment of MAO-B occupancy in the brain with PET and [11C]-l-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther 85(5):506–512PubMedCrossRefGoogle Scholar
  62. Hommet C, Mondon K, Camus V, Ribeiro MJ, Beaufils E, Arlicot N, Corcia P, Paccalin M, Minier F, Gosselin T, Page G, Guilloteau D, Chalon S (2014) Neuroinflammation and β amyloid deposition in Alzheimer’s disease: in vivo quantification with molecular imaging. Dement Geriatr Cogn Disord 37(1–2):1–18PubMedCrossRefGoogle Scholar
  63. Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S, Gelsomino G, Moresco RM, Perani D (2013) In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat Disord 19(1):47–52PubMedCrossRefGoogle Scholar
  64. Ikawa M, Lohith TG, Shrestha S, Telu S, Zoghbi SS, Castellano S, Taliani S, Da Settimo F, Fujita M, Pike VW, Innis RB (2017) 11C-ER176, a radioligand for 18-kDa translocator protein (TSPO), has adequate sensitivity to robustly image all three affinity genotypes in human brain. J Nucl Med 58:320–325PubMedPubMedCentralCrossRefGoogle Scholar
  65. Janssen B, Vugts DJ, Funke U, Spaans A, Schuit RC, Kooijman E, Rongen M, Perk LR, Lammertsma AA, Windhorst AD (2014) Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation. J Label Comp Radiopharm 57(8):509–516CrossRefGoogle Scholar
  66. Kalkman HO, Feuerbach D (2016) Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci 73(13):2511–2530PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kenk M, Selvanathan T, Rao N, Suridjan I, Rusjan P, Remington G, Meyer JH, Wilson AA, Houle S, Mizrahi R (2015) Imaging neuroinflammation in gray and white matter in schizophrenia: an in vivo PET study with [18F]-FEPPA. Schizophr Bull 41(1):85–93PubMedCrossRefGoogle Scholar
  68. Kim S, Nho K, Risacher SL, Inlow M, Swaminathan S, Yoder KK, Shen L, West JD, McDonald BC, Tallman EF, Hutchins GD, Fletcher JW, Farlow MR, Ghetti B, Saykin AJ (2013) PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer’s disease. Multimodal Brain Image Anal 8159:150–158CrossRefGoogle Scholar
  69. Kincaid E (2016) Picture imperfect: going beyond imaging amyloid in Alzheimer’s disease. Nat Med 22(10):1067–1068PubMedCrossRefGoogle Scholar
  70. Korkhov VM, Sachse C, Short JM, Tate CG (2010) Three-dimensional structure of TspO by electron cryomicroscopy of helical crystals. Structure 18(6):677–687PubMedPubMedCentralCrossRefGoogle Scholar
  71. Koshimori Y, Ko JH, Mizrahi R, Rusjan P, Mabrouk R, Jacobs MF, Christopher L, Hamani C, Lang AE, Wilson AA, Houle S, Strafella AP (2015) Imaging striatal microglial activation in patients with Parkinson’s disease. PLoS One 10(9):e0138721PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P, Hong J, Morse CL, Zoghbi SS, Gladding RL, Jacobson S, Oh U, Pike VW, Innis RB (2010) Comparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. Neuroimage 49(4):2924–2932PubMedCrossRefGoogle Scholar
  73. Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB, Biomarkers Consortium PET Radioligand Project Team (2013a) A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab 33(1):53–58PubMedCrossRefGoogle Scholar
  74. Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, Corona W, Morse CL, Zoghbi SS, Pike VW, McMahon FJ, Turner RS, Innis RB, Biomarkers Consortium PET Radioligand Project Team (2013b) In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 136(Pt 7):2228–2238PubMedPubMedCentralCrossRefGoogle Scholar
  75. Kreisl WC, Lyoo CH, Liow JS, Wei M, Snow J, Page E, Jenko KJ, Morse CL, Zoghbi SS, Pike VW, Turner RS, Innis RB (2016) 11C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol Aging 44:53–61PubMedPubMedCentralCrossRefGoogle Scholar
  76. Kreisl WC, Lyoo CH, Liow JS, Snow J, Page E, Jenko KJ, Morse CL, Zoghbi SS, Pike VW, Turner RS, Innis RB (2017) Distinct patterns of increased translocator protein in posterior cortical atrophy and amnestic Alzheimer’s disease. Neurobiol Aging 51:132–140PubMedCrossRefGoogle Scholar
  77. Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BN, Luurtsema G, Windhorst AD, Lammertsma AA (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
  78. 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)-[11C]PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab 27(12):1965–1974PubMedCrossRefGoogle Scholar
  79. Lagarde J, Sarazin M, Chauviré V, Stankoff B, Kas A, Lacomblez L, Peyronneau MA, Bottlaender M (2016) Cholinergic changes in aging and Alzheimer disease: an [18F]-F-A-85380 exploratory PET study. Alzheimer Dis Assoc Disord. doi: 10.1097/WAD.0000000000000163 CrossRefGoogle Scholar
  80. Laube M, Kniess T, Pietzsch J (2013) Radiolabeled COX-2 inhibitors for non-invasive visualization of COX-2 expression and activity—a critical update. Molecules 18(6):6311–6355PubMedCrossRefGoogle Scholar
  81. Lavisse S, Guillermier M, Hérard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dollé F, Delzescaux T, Bonvento G, Hantraye P, Escartin C (2012) Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci 32(32):10809–10818PubMedCrossRefGoogle Scholar
  82. Lavisse S, García-Lorenzo D, Peyronneau MA, Bodini B, Thiriez C, Kuhnast B, Comtat C, Remy P, Stankoff B, Bottlaender M (2015) Optimized quantification of translocator protein radioligand 18F-DPA-714 uptake in the brain of genotyped healthy volunteers. J Nucl Med 56(7):1048–1054PubMedCrossRefGoogle Scholar
  83. Liu GJ, Middleton RJ, Hatty CR, Kam WW, Chan R, Pham T, Harrison-Brown M, Dodson E, Veale K, Banati RB (2014) The 18 kDa translocator protein, microglia and neuroinflammation. Brain Pathol 24(6):631–653PubMedCrossRefGoogle Scholar
  84. Lockhart A, Davis B, Matthews JC, Rahmoune H, Hong G, Gee A, Earnshaw D, Brown J (2003) The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker. Nucl Med Biol 30:199–206PubMedCrossRefGoogle Scholar
  85. Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW, Fujita M, Innis RB, Kreisl WC (2015) Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. J Nucl Med 56(5):701–706PubMedPubMedCentralCrossRefGoogle Scholar
  86. Matthews PM, Datta G (2015) Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis. Expert Opin Drug Discov 10(5):557–570PubMedCrossRefGoogle Scholar
  87. 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 89:3170–3174PubMedPubMedCentralCrossRefGoogle Scholar
  88. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126(4):479–497PubMedCrossRefGoogle Scholar
  89. Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, Hashimoto M, Ishibashi K, Oda K, Sakata M, Hamamoto M, Kobayashi S, Katayama Y, Ishii K (2011) Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson’s disease patients. PLoS One 6(2):e17338PubMedPubMedCentralCrossRefGoogle Scholar
  90. Nair A, Veronese M, Xu X, Curtis C, Turkheimer F, Howard R, Reeves S (2016) Test-retest analysis of a non-invasive method of quantifying [11C]-PBR28 binding in Alzheimer’s disease. EJNMMI Res 6(1):72PubMedPubMedCentralCrossRefGoogle Scholar
  91. Ohnishi A, Senda M, Yamane T, Sasaki M, Mikami T, Nishio T, Ikari Y, Nishida H, Shukuri M, Takashima T, Mawatari A, Doya H, Watanabe Y, Onoe H (2014) Human whole-body biodistribution and dosimetry of a new PET tracer, [11C]ketoprofen methyl ester, for imagings of neuroinflammation. Nucl Med Biol 41(7):594–599PubMedCrossRefGoogle Scholar
  92. Ohnishi A, Senda M, Yamane T, Mikami T, Nishida H, Nishio T, Akamatsu G, Ikari Y, Kimoto S, Aita K, Sasaki M, Shinkawa H, Yamamoto Y, Shukuri M, Mawatari A, Doi H, Watanabe Y, Onoe H (2016) Exploratory human PET study of the effectiveness of 11C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer’s disease. Nucl Med Biol 43(7):438–444PubMedCrossRefGoogle Scholar
  93. Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, Walker Z, Kennedy A, Fox N, Rossor M, Brooks DJ (2009) Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 72(1):56–62PubMedPubMedCentralCrossRefGoogle Scholar
  94. Ory D, Celen S, Gijsbers R, Van Den Haute C, Postnov A, Koole M, Vandeputte C, Andrés JI, Alcazar J, De Angelis M, Langlois X, Bhattacharya A, Schmidt M, Letavic MA, Vanduffel W, Van Laere K, Verbruggen A, Debyser Z, Bormans G (2016) Preclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primates. J Nucl Med 57(9):1436–1441PubMedCrossRefGoogle Scholar
  95. Owen F, Poulter M, Waddington JL, Mashal RD, Crow TJ (1983) [3H]R05-4864 and [3H]flunitrazepam binding in kainate-lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type. Brain Res 278(1–2):373–375PubMedCrossRefGoogle Scholar
  96. Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, Gunn RN, Rabiner EA, Wilkins MR, Reynolds R, Matthews PM, Parker CA (2010) Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9):1608–1618PubMedPubMedCentralCrossRefGoogle Scholar
  97. Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, Innis RB, Pike VW, Reynolds R, Matthews PM, Parker CA (2011) Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 52(1):24–32PubMedCrossRefGoogle Scholar
  98. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (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
  99. Pasternak O, Kubicki M, Shenton ME (2016) In vivo imaging of neuroinflammation in schizophrenia. Schizophr Res 173(3):200–212PubMedCrossRefGoogle Scholar
  100. Perrone M, Moon BS, Park HS, Laquintana V, Jung JH, Cutrignelli A, Lopedota A, Franco M, Kim SE, Lee BC, Denora N (2016) A novel PET imaging probe for the detection and monitoring of translocator protein 18 kDa expression in pathological disorders. Sci Rep 6:20422PubMedPubMedCentralCrossRefGoogle Scholar
  101. Prokop S, Miller KR, Heppner FL (2013) Microglia actions in Alzheimer’s disease. Acta Neuropathol 126(4):461–477PubMedCrossRefGoogle Scholar
  102. Raffel J, Sridharan S, Nicholas R (2017) [11C]PBR-28 positron emission tomography in multiple sclerosis: neuroinflammation or otherwise? Ann Neurol 81(2):323–324PubMedCrossRefGoogle Scholar
  103. Ramanan VK, Risacher SL, Nho K, Kim S, Shen L, McDonald BC, Yoder KK, Hutchins GD, West JD, Tallman EF, Gao S, Foroud TM, Farlow MR, De Jager PL, Bennett DA, Aisen PS, Petersen RC, Jack CR Jr, Toga AW, Green RC, Jagust WJ, Weiner MW, Saykin AJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2015) GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP. Brain 138(Pt 10):3076–3088PubMedPubMedCentralCrossRefGoogle Scholar
  104. Rissanen E, Virta JR, Paavilainen T, Tuisku J, Helin S, Luoto P, Parkkola R, Rinne JO, Airas L (2013) Adenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX brain PET study. J Cereb Blood Flow Metab 33(9):1394–1401PubMedPubMedCentralCrossRefGoogle Scholar
  105. Rizzo G, Veronese M, Tonietto M, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A (2014) Kinetic modeling without accounting for the vascular component impairs the quantification of [11C]PBR28 brain PET data. J Cereb Blood Flow Metab 34(6):1060–1069PubMedPubMedCentralCrossRefGoogle Scholar
  106. Rodriguez-Vieitez E, Carter SF, Chiotis K, Saint-Aubert L, Leuzy A, Schöll M, Almkvist O, Wall A, Långström B, Nordberg A (2016a) Comparison of early-phase 11C-deuterium-l-deprenyl and 11C-Pittsburgh compound B PET for assessing brain perfusion in Alzheimer disease. J Nucl Med 57(7):1071–1077PubMedCrossRefGoogle Scholar
  107. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Schöll M, Chiotis K, Thordardottir S, Graff C, Wall A, Långström B, Nordberg A (2016b) Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139(Pt 3):922–936PubMedPubMedCentralCrossRefGoogle Scholar
  108. Roncaroli F, Su Z, Herholz K, Gerhard A, Turkheimer FE (2016) TSPO expression in brain tumours: is TSPO a target for brain tumour imaging? Clin Transl Imaging 4:145–156PubMedPubMedCentralCrossRefGoogle Scholar
  109. Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S, Mizrahi R (2011) Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab 31(8):1807–1816PubMedPubMedCentralCrossRefGoogle Scholar
  110. Santillo AF, Gambini JP, Lannfelt L, Långström B, Ulla-Marja L, Kilander L, Engler H (2011) In vivo imaging of astrocytosis in Alzheimer’s disease: an 11C-l-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging 38(12):2202–2208PubMedCrossRefGoogle Scholar
  111. Schöll M, Carter SF, Westman E, Rodriguez-Vieitez E, Almkvist O, Thordardottir S, Wall A, Graff C, Långström B, Nordberg A (2015) Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography. Sci Rep 5:16404PubMedPubMedCentralCrossRefGoogle Scholar
  112. Schuitemaker A, van Berckel BN, Kropholler MA, Kloet RW, Jonker C, Scheltens P, Lammertsma AA, Boellaard R (2007) Evaluation of methods for generating parametric (R-[11C]PK11195 binding images. J Cereb Blood Flow Metab 27(9):1603–1615PubMedCrossRefGoogle Scholar
  113. Schuitemaker A, van der Doef TF, Boellaard R, van der Flier WM, Yaqub M, Windhorst AD, Barkhof F, Jonker C, Kloet RW, Lammertsma AA, Scheltens P, van Berckel BN (2012) Microglial activation in healthy aging. Neurobiol Aging 33(6):1067–1072PubMedCrossRefGoogle Scholar
  114. Schuitemaker A, Kropholler MA, Boellaard R, van der Flier WM, Kloet RW, van der Doef TF, Knol DL, Windhorst AD, Luurtsema G, Barkhof F, Jonker C, Lammertsma AA, Scheltens P, van Berckel BN (2013) Microglial activation in Alzheimer’s disease: an (R)-[11C]PK11195 positron emission tomography study. Neurobiol Aging 34(1):128–136PubMedCrossRefGoogle Scholar
  115. Schwartz M, Deczkowska A (2016) Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37(10):668–679PubMedCrossRefGoogle Scholar
  116. Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL, Rekkas PV, Houle S, Meyer JH (2015) Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72(3):268–275PubMedPubMedCentralCrossRefGoogle Scholar
  117. Slavik R, Müller Herde A, Haider A, Krämer SD, Weber M, Schibli R, Ametamey SM, Mu L (2016) Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2. J Neurochem 138(6):874–886PubMedCrossRefGoogle Scholar
  118. Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD, Appling LL, Borneo J, Poon C, Ho T, Cai F, Steiner P, van der Brug MP, Modrusan Z, Kaminker JS, Hansen DV (2016) Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat Commun 7:11295PubMedPubMedCentralCrossRefGoogle Scholar
  119. Stefaniak J, O’Brien J (2016) Imaging of neuroinflammation in dementia: a review. J Neurol Neurosurg Psychiatry 87(1):21–28PubMedGoogle Scholar
  120. 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 15:5263–5274PubMedCrossRefGoogle Scholar
  121. Sturm S, Forsberg A, Nave S, Stenkrona P, Seneca N, Varrone A, Comley RA, Fazio P, Jamois C, Nakao R, Ejduk Z, Al-Tawil N, Akenine U, Halldin C, Andreasen N, Ricci B (2016) Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline. Eur J Nucl Med Mol Imaging. doi: 10.1007/s00259-016-3510-6 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Su Z, Herholz K, Gerhard A, Roncaroli F, Du Plessis D, Jackson A, Turkheimer F, Hinz R (2013) [11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging 40(9):1406–1419PubMedPubMedCentralCrossRefGoogle Scholar
  123. Su L, Blamire AM, Watson R, He J, Hayes L, O’Brien JT (2016a) Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer’s disease and dementia with Lewy bodies. Transl Psychiatry 6(8):e877PubMedPubMedCentralCrossRefGoogle Scholar
  124. Su L, Faluyi YO, Hong YT, Fryer TD, Mak E, Gabel S, Hayes L, Soteriades S, Williams GB, Arnold R, Passamonti L, Vázquez Rodríguez P, Surendranathan A, Bevan-Jones RW, Coles J, Aigbirhio F, Rowe JB, O’Brien JT (2016b) Neuroinflammatory and morphological changes in late-life depression: the NIMROD study. Br J Psychiatry 209(6):525–526PubMedPubMedCentralCrossRefGoogle Scholar
  125. Suridjan I, Rusjan PM, Voineskos AN, Selvanathan T, Setiawan E, Strafella AP, Wilson AA, Meyer JH, Houle S, Mizrahi R (2014) Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18 kDa (TSPO) radioligand, [18F]-FEPPA. Neuroimage 84:868–875PubMedCrossRefGoogle Scholar
  126. Suridjan I, Pollock BG, Verhoeff NP, Voineskos AN, Chow T, Rusjan PM, Lobaugh NJ, Houle S, Mulsant BH, Mizrahi R (2015) In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA. Mol Psychiatry 20(12):1579–1587PubMedCrossRefGoogle Scholar
  127. Takata K, Kato H, Shimosegawa E, Okuno T, Koda T, Sugimoto T, Mochizuki H, Hatazawa J, Nakatsuji Y (2014) 11C-acetate PET imaging in patients with multiple sclerosis. PLoS One 9(11):e111598PubMedPubMedCentralCrossRefGoogle Scholar
  128. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194PubMedCrossRefGoogle Scholar
  129. Tanzi RE (2015) TREM2 and risk of Alzheimer’s disease-friend or foe? N Engl J Med 372(26):2564–2565PubMedCrossRefGoogle Scholar
  130. Temel SG, Kahveci Z (2009) Cyclooxygenase-2 expression in astrocytes and microglia in human oligodendroglioma and astrocytoma. J Mol Histol 40(5–6):369–377PubMedCrossRefGoogle Scholar
  131. Terada T, Yokokura M, Yoshikawa E, Futatsubashi M, Kono S, Konishi T, Miyajima H, Hashizume T, Ouchi Y (2016) Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann Nucl Med 30(8):579–587PubMedCrossRefGoogle Scholar
  132. Territo PR, Meyer JA, Peters JS, Riley AA, McCarthy BP, Gao M, Wang M, Green MA, Zheng QH, Hutchins GD (2017) Characterization of [11C]-GSK1482160 for targeting the P2X7 receptor as a biomarker for neuroinflammation. J Nucl Med 58:458–465PubMedCrossRefGoogle Scholar
  133. Thériault P, ElAli A, Rivest S (2015) The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimers Res Ther 7(1):41PubMedPubMedCentralCrossRefGoogle Scholar
  134. Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A, Cobelli C, Brooks DJ, Turkheimer FE (2008) Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease. J Nucl Med 49(8):1249–1256PubMedCrossRefGoogle Scholar
  135. Toyohara J, Sakata M, Hatano K, Yanai S, Endo S, Ishibashi K, Wagatsuma K, Ishii K, Ishiwata K (2016) Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography. Ann Nucl Med 30(8):534–543PubMedCrossRefGoogle Scholar
  136. Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, Gerhard A, Hinz R, Tai YF, Brooks DJ (2007) Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med 48(1):158–167PubMedGoogle Scholar
  137. Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A, Veronese M (2015) The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans 43(4):586–592PubMedPubMedCentralCrossRefGoogle Scholar
  138. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15(3):601–609PubMedCrossRefGoogle Scholar
  139. van Dyck CH (2008) Imaging microglial activation in Alzheimer’s disease: what does it mean? Biol Psychiatry 64(10):833–834PubMedCrossRefGoogle Scholar
  140. Varrone A, Mattsson P, Forsberg A, Takano A, Nag S, Gulyás B, Borg J, Boellaard R, Al-Tawil N, Eriksdotter M, Zimmermann T, Schultze-Mosgau M, Thiele A, Hoffmann A, Lammertsma AA, Halldin C (2013) In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients. Eur J Nucl Med Mol Imaging 40(6):921–931PubMedCrossRefGoogle Scholar
  141. Varrone A, Oikonen V, Forsberg A, Joutsa J, Takano A, Solin O, Haaparanta-Solin M, Nag S, Nakao R, Al-Tawil N, Wells LA, Rabiner EA, Valencia R, Schultze-Mosgau M, Thiele A, Vollmer S, Dyrks T, Lehmann L, Heinrich T, Hoffmann A, Nordberg A, Halldin C, Rinne JO (2015) Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects. Eur J Nucl Med Mol Imaging 42(3):438–446PubMedCrossRefGoogle Scholar
  142. Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6):308–322PubMedPubMedCentralCrossRefGoogle Scholar
  143. Venneti S, Wang G, Nguyen J, Wiley CA (2008) The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J Neuropathol Exp Neurol 67(10):1001–1010PubMedPubMedCentralCrossRefGoogle Scholar
  144. Venneti S, Wiley CA, Kofler J (2009) Imaging microglial activation during neuroinflammation and Alzheimer’s disease. J Neuroimmune Pharmacol 4(2):227–243PubMedCrossRefGoogle Scholar
  145. Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, Achten E, Slegers G, Dierckx RA, Korf J (2003) Assessment of neuroinflammation and microglial activation in Alzheimer’s disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 50(1):39–47PubMedCrossRefGoogle Scholar
  146. Vivash L, O’Brien TJ (2016) Imaging microglial activation with TSPO PET: lighting up neurologic diseases? J Nucl Med 57(2):165–168PubMedCrossRefGoogle Scholar
  147. Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) Beta-amyloid (1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632PubMedCrossRefGoogle Scholar
  148. Weissman BA, Bolger GT, Isaac L, Paul SM, Skolnick P (1984) Characterization of the binding of [3H]Ro 5-4864, a convulsant benzodiazepine, to guinea pig brain. J Neurochem 42:969–975PubMedCrossRefGoogle Scholar
  149. Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, DeKosky ST, Mathis CA (2009) Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol 66(1):60–67PubMedPubMedCentralCrossRefGoogle Scholar
  150. Wimberley C, Lavisse S, Peyronneau M-A, Stute S, Reilhac A, Brulon V, Comtat C, Leroy C, Remy P, Stankoff B, Buvat I, Bottlaender M (2016) Impact of vascular trapping of 18F-DPA-714 on binding parameter estimates in the healthy human. In: NeuroReceptorMapping meeting, O-021Google Scholar
  151. Yaqub M, van Berckel BN, Schuitemaker A, Hinz R, Turkheimer FE, Tomasi G, Lammertsma AA, Boellaard R (2012) Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies. J Cereb Blood Flow Metab 32(8):1600–1608PubMedPubMedCentralCrossRefGoogle Scholar
  152. Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, Nozaki S, Fujimura Y, Koeda M, Asada T, Suhara T (2008) Increased binding of peripheral benzodiazepine receptor in Alzheimer’s disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry 64(10):835–841PubMedCrossRefGoogle Scholar
  153. Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, Nozaki S, Takahashi S, Mizukami K, Asada T, Suhara T (2012) Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [11C]DAA1106. Psychiatry Res 203(1):67–74PubMedCrossRefGoogle Scholar
  154. Yoder KK, Nho K, Risacher SL, Kim S, Shen L, Saykin AJ (2013) Influence of TSPO genotype on 11C-PBR28 standardized uptake values. J Nucl Med 54(8):1320–1322PubMedPubMedCentralCrossRefGoogle Scholar
  155. Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, Wakuda T, Sugihara G, Takebayashi K, Suda S, Iwata Y, Ueki T, Tsuchiya KJ, Suzuki K, Nakamura K, Ouchi Y (2011) In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 38(2):343–351PubMedCrossRefGoogle Scholar
  156. Yokokura M, Terada T, Bunai T, Nakaizumi K, Takebayashi K, Iwata Y, Yoshikawa E, Futatsubashi M, Suzuki K, Mori N, Ouchi Y (2017) Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195. J Cereb Blood Flow Metab 37:877–889PubMedCrossRefGoogle Scholar
  157. Zahr NM, Mayer D, Rohlfing T, Sullivan EV, Pfefferbaum A (2014) Imaging neuroinflammation? A perspective from MR spectroscopy. Brain Pathol 24(6):654–664PubMedPubMedCentralCrossRefGoogle Scholar
  158. Zeineh MM, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK (2015) Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging 36(9):2483–2500PubMedPubMedCentralCrossRefGoogle Scholar
  159. Zhang J (2015) Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging. J Neuroinflammation 12:108PubMedPubMedCentralCrossRefGoogle Scholar
  160. Zhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC (2012) NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage 61(4):1000–1016PubMedCrossRefGoogle Scholar
  161. Zimmer ER, Leuzy A, Benedet AL, Breitner J, Gauthier S, Rosa-Neto P (2014) Tracking neuroinflammation in Alzheimer’s disease: the role of positron emission tomography imaging. J Neuroinflammation 11:120PubMedPubMedCentralCrossRefGoogle Scholar
  162. Zürcher NR, Loggia ML, Lawson R, Chonde DB, Izquierdo-Garcia D, Yasek JE, Akeju O, Catana C, Rosen BR, Cudkowicz ME, Hooker JM, Atassi N (2015) Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [11C]-PBR28. Neuroimage Clin 7:409–414PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Julien Lagarde
    • 1
  • Marie Sarazin
    • 1
  • Michel Bottlaender
    • 2
    • 3
  1. 1.Unit of Neurology of Memory and Language, Centre de Psychiatrie et NeurosciencesINSERM UMR S894, Centre Hospitalier Sainte-Anne and Université Paris DescartesParisFrance
  2. 2.UNIACT, NeuroSpin, Institut d’Imagerie Biomédicale, Direction de la Recherche Fondamentale, Commissariat à l’Energie AtomiqueGif-sur-YvetteFrance
  3. 3.Laboratoire Imagerie Moléculaire in Vivo, UMR 1023, Service Hospitalier Frédéric Joliot, Institut d’Imagerie Biomédicale, Direction de la Recherche FondamentaleCommissariat à l’Energie AtomiqueOrsayFrance

Personalised recommendations