CoChat
Sign Up
Cited by 173Neuroinflammation and Neurodegeneration MechanismsPharmacological Receptor Mechanisms and EffectsMedical Imaging Techniques and Applications

TSPO in diverse CNS pathologies and psychiatric disease: a critical review and a way forward

Open access
Guilarte, Tomás R.·2019·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2018.09.003PMC PMC6348013
Open this paper in CoChat — free account

Abstract

The use of Translocator Protein 18 kDa (TSPO) as a clinical neuroimaging biomarker of brain injury and neuroinflammation has increased exponentially in the last decade. There has been a furious pace in the development of new radiotracers for TSPO positron emission tomography (PET) imaging and its use has now been extensively described in many neurological and mental disorders. This fast pace of research and the ever-increasing number of new laboratories entering the field often times lack an appreciation of the historical perspective of the field and introduce dogmatic, but unproven facts, related to the underlying neurobiology of the TSPO response to brain injury and neuroinflammation. Paradoxically, while in neurodegenerative disorders and in all types of CNS pathologies brain TSPO levels increase, a new observation in psychiatric disorders such as schizophrenia is decreased brain levels of TSPO measured by PET. The neurobiological bases for this new finding is currently not known, but rigorous experimental design using multiple experimental approaches and careful interpretation of results is critically important to provide the methodological and/or biological underpinnings to this new observation. This review provides a perspective of the early history of validating TSPO as a biomarker of brain injury and neuroinflammation and a critical analysis of controversial topics in the literature related to the cellular sources of the TSPO response. The latter is important in order to provide the correct interpretation of PET studies in neurodegenerative and psychiatric disorders. Furthermore, this review proposes some yet to be explored explanations to new findings in psychiatric disorders and new approaches to quantitatively assess the glial sources of the TSPO response in order to move the field forward.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.pharmthera.2018.09.003

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Increased TSPO expression has been commonly attributed to activated microglia/macrophages and there is often an implication that the activation is pro-inflammatory.

    “Increased TSPO expression also has been commonly attributed to activated microglia/macrophages and there is often an implication that the activation is pro-inflammatory (Guilarte, 2019).”

    From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Guilarte, 2019

    In “TSPO-PET literature indicating TSPO as an exclusive microglia biomarker” (page unavailable), the review says many studies attribute the TSPO signal to microglia or infiltrating macrophages, supporting the first part of the claim. The passages describe TSPO as a proposed biomarker of neuroinflammation, but do not establish the further claim that the activation is often implied to be pro-inflammatory. The review also cautions that astrocytes can contribute to the signal. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • TSPO is a marker of inflammation commonly attributed to microglial activation in neuroinflammatory and neurodegenerative diseases.

    “TSPO is a marker of inflammation commonly attributed to microglial activation in neuroinflammatory and neurodegenerative diseases (Guilarte, 2019).”

    From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Guilarte, 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 146

  1. Abourbeh G, Theze B, Maroy R, Dubois A, Brulon V, Fontyn Y, Dolle F, Tavitian B, Boisgard R (2012) Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [18F]-DPA-714. J Neurosci 32, 5728– 5736. 22539835 PMC6703630
  2. Anholt RRH, Pedersen PL, De Suoza EB, Snyder SH (1986) The peripheral-type benzodiazepine receptor-localization to the mitochondrial outer membrane. J Biol Chem 261, 576– 583. 3001071
  3. Arlicot N, Katsifis A, Garreau L, Mattner F, Vergote J, Duval S, Bodard S, Guilloteau D, Chalon S (2008) Evaluation of CLINDE as potent translocator protein (18 kDa) SPECT radiotracer reflecting the degree of neuroinflammation in a rat model of microglial activation. Eur J Nucl Med Mol Imaging 35, 2203– 2211. 18536913
  4. Arlicot N, Tronel C, Bodard S, Garreau L, de la Crompe B, Vandevelde I, Guilloteau D, Antier D, Chalon S (2014) Translocator protein (18 kDa) mapping with [125I]-CLINDE in the quinolinic acid rat model of excitotoxicity: a longitudinal comparison with microglial activation, astrogliosis, and neuronal death. Mol Imag 13, 1– 11. 24622813
  5. Baestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterized by high-affinity [3H]-diazepam binding. Proc Nat Acad Sci 74, 3805– 3809. 20632 PMC431738
  6. Banati RB, Myers R, Kreutzberg GW (1997) PK (‘peripheral benzodiazepine’) – binding sites in the CNS indicate early and discrete brain lesions: microautoradiography detection of [3H]-PK11195 binding to activated microglia. J Neurocytol 26, 77– 82. 9181482
  7. Banati RB, Goerres GW, Myers R, Gunn RN, Turkheimer FE, Kreutzberg GW, Brooks DJ, Jones T, Duncan JS (1999) [11C]-R-PK11195 positron emission tomography imaging of activated microglia in Rasmussen’s encephalitis. Neurology 53, 2199– 2203. 10599809
  8. 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 measure of disease activity. Brain 123, 2321– 2337. 11050032
  9. Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, Dubroeucq MC, Gueremy C, LeFleur G, (1983) Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]-PK11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem 41, 1744– 1750. 6315880
  10. Benavides J, Fage D, Carter C, Scatton B (1987) Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage. Brain Res 421, 167– 172. 2891401
  11. Benavides J, Cornu P, Dennis T, Dubois A, Hauw JJ, MacKenzie ET, Sazdovitch V, Scatton B (1988) Imaging of human brain lesions with an omega 3 site radioligand. Ann Neurol 24, 708– 712. 2849920
  12. Benlloch JM, Gonzalez AJ, Pani R, Preziosi E, Jackson C, Murphy J, Barbera J, Correcher C, Aussenhofer S, Gareis D, Visvikis D, Bert J, Langstrom B, Farde L, Toth M, haggkvist J, Caixeta FV, Kullander K, Somial-Schweiger I, Schwaiger M (2018) The MINDVIEW project: First results. Eur Psych 50, 21– 27. 29398564
  13. Ben-Scachar D (2002) Mitochondria dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem 83, 1241– 1251. 12472879
  14. Biesmans S, Acton PD, Cotto C, Langlois X, Ver Donck L, Bouwknecht JA, Aelvoet S-A, Hellings N, Meert TF, Nuydens R (2015) Effect of stress and peripheral immune activation on astrocyte activation in transgenic bioluminescent Gfap-luc mice. GLIA 63, 11261137. 25690758
  15. Brackhan M, Bascunana P, Postema JM, Ross TL, Bengel FM, Bankstahl M, Bankstahl JP (2016) Serial quantitative TSPO-targeted PET reveals peak microglia activation up to 2 weeks after an epileptogenic brain insult. J Nucl Med 57, 1302– 1308. 27056616
  16. Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26, 4930– 4939. 16672668 PMC1963412
  17. Cagnin A, Myers R, Gunn RN, Lawrence AD, Stevens T, Kreutzberg GW, Jones T, Banati RB (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, 2014– 2027. 11571219
  18. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE (2001) In vivo measurement of activated microglia in dementia. THE LANCET 358, 461– 467. 11513911
  19. Chen MK, Baidoo K, Verina T, Guilarte TR (2004) Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain 127, 1379– 1392. 15069023
  20. Chen MK, Guilarte TR (2006) Imaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination. Toxicol Sci 91, 532– 539. 16554315
  21. Chen MK, Guilarte TR (2008) Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Therap 118, 1– 17. 18374421 PMC2453598
  22. Coliste K, Plaven-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, Amini N, Aeinehband S, Karolinska Schizophrenia Project (KaSP)., Erhardt S, Halidin C, Flyckt L, Farde L, Cervenka S (2017) Lower levels of the glial marker TSPO in drug-naïve first-episode psychosis patients as measured using PET and [11C]PBR28. Mol Psych 22, 850856. 28194003
  23. Conway EL, Gundlach AL, Craven JA (1998) Temporal changes in glial fibrillary acidic protein messenger RNA and [3H]-PK11195 binding in relation to imidazoline-I2-receptor and α2-adrenoceptor binding to the hippocampus following transient global forebrain ischaemia in the rat. Neurosci 82, 805– 817. 9483537
  24. Coughlin JM, Wang Y, Ma S, Yue C, Kim PK, Adams AV, Roosa HV, Gage KL, Stathis M, Rais R, Rojas C, McGlothan JL, Watkins CC, Sacktor N, Guilarte TR, Zhou Y, Sawa A, Slusher BS, Caffo B, Kassiou M, Endres CJ, Pomper MG (2014) Regional distribution of translocator protein using [11C]-DPA-713 PET in individuals infected with HIV. J Neurovirol 20, 219– 232. 24567030 PMC4078660
  25. Coughlin JM, Wang Y, Munro CA, Ma S, Yue C, Chen MS, Airan R, Kim PK, Adams AV, Garcia C, Higgs C, Sair HI, Sawa A, Smith G, Lyketsos CG, Caffo B, Kassiou M, Guilarte TR, Pomper MG (2015) Neuroinflammation and brain atrophy in former NFL players: an in vivo multimodal imaging pilot study. Neurobiol Dis 74, 58– 65. 25447235 PMC4411636
  26. Coughlin JM, Wang Y, Minn I, Bienko N, Ambinder EB, Xu. X, Peters ME, Dougherty JW, Vranesic M, Koo SM, Ahn HH, Lee M, Cottrell C, Sair HI, Sawa A, Munro CA, Nowinski CJ, Dannals RF, Lyketsos CG, Kassiou M, Smith G, Caffo B, Mori S, Guilarte TR, Pomper MG (2017) Imaging of glial cell activation and white matter integrity in brains of active and recently retired National Football League players. JAMA Neurol 74, 67– 74. 27893897 PMC5504689
  27. 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. 12752399
  28. De Picker LJ, Morrens M, Chance SA, Boche D (2017) Microglia and brain plasticity in acute psychosis and schizophrenia illness course: a meta-review. Frontiers Psych 8, article 238. PMC5696326 29201010
  29. Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, Rinne J, Solin O, Haaparanta-Solin M, Jones PA, Trigg W, Anthony DC, Airas L (2014) Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med 55, 466– 472. 24516258
  30. Diorio D, Welner SA, Butterworth RF,, Meaney MJ, Suranyi-Cadotte BE (1991) Peripheral benzodiazepine binding sites in Alzheimer’s disease frontal cortex and temporal cortex. Neurobiol. Aging 12, 255– 258. 1652108
  31. Doble A, Malgouris C, Daniel M, Daniel N, Imbault F, Basbaum A, Uzan A, Gueremy C, LeFur G (1987) Labelling of peripheral-type benzodiazepine binding sites in human brain using [3H]-PK11195: anatomical and subcellular distribution. Brain Res Bull 18, 49– 61. 3030512
  32. Dolle F, Luus C, Reynolds A, Kassiuo M (2009) Radiolabelled molecules for imaging the translocator protein (18 kDa) using positron emission tomography. Curr Med Chem 16, 2899– 2923. 19689272
  33. Domene A, Cavanagh C, Page G, Bodard S, Klein C, Delarasse C, Chalon S, Krantic S (2016) Expression of phenotypic astrocyte marker is increased in a transgenic mouse model of Alzheimer’s disease versus age-matched controls: a presymptomatic stage study. Int J Alzheimers Dis 2016: 5696241. 27672476 PMC5031839
  34. Doorduin J, de Vries EF, Dierck RA, Klein HC (2008) PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des 14, 3297– 3315. 19075709
  35. 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. 2835123
  36. Frick LR, Williams K, Pittenger C (2013) Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013: 608654. 23690824 PMC3652125
  37. Garrido MJ, Valle M, Calvo R, Troconiz IF (1999) Altered plasma and brain disposition and pharmacodynamics of methadone in abstinent rats. J Pharm Exp Ther 288, 179– 187. 9862769
  38. Gavish M, Weizman A, Karo L, Tyano S, Tanne Z (1986) Decreased peripheral benzodiazepine binding sites in platelets of neuroleptic-treated schizophrenics. Eur J Pharmacol 121, 275– 279. 2870930
  39. Gehlert DR, Yamamura HI, Wamsley JK (1985) Autoradiographic localization of “peripheral-type” benzodiazepine binding sites in the rat brain, heart, and kidney. Naunyn Schmiedebergs Arch Pharmacol 328, 454– 460. 2986017
  40. Gehlert DR, Stephenson DT, Schober DA, Rash K, Clemens JA (1997) Increased expression of peripheral benzodiazepine receptors in the facial nucleus following motor neuron axotomy. Neurochem Int 31, 705– 713. 9364456
  41. 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]-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 61, 686– 689. 12963764
  42. Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ (2004) In vivo imaging of microglial activation with [11C]-PK11195 PET in corticobasal degeneration. Mov Dis 19, 1221– 1226. 15390000
  43. Gerhard A, Schwarz J, Myers R, Ise R, Banati RB (2005) Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. NeuroImage 24, 591– 595. 15627603
  44. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ (2006a) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21, 404– 412. 16182554
  45. Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ (2006b) In vivo imaging of microglia activation with [11C](R)-PK11195 PET in Progressive Supranuclear Palsy. Mov Dis 21, 89– 93. 16108021
  46. Ghadery C, Koshimori Y, Coakeley S, Harris M, Rusjan P, Kim J, Houle S, Strafella AP (2017) Microglia activation in Parkinson’s disease using [18F]-FEPPA. J Neuroinflammation 14, 8. 28086916 PMC5234135
  47. Goodman M, Luby ED, Froham CE, Gottlieb JS (1961) Orosomucoid in schizophrenia. Nature 192, 370– 371. 13900323
  48. Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkB signaling, MAPK, and Jak1/Stat1 pathways. GLIA, 59 242– 255. 21125645
  49. 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, 2207– 2210. 8523106
  50. Guilarte TR, Kuhlmann AC, O’Callaghan JP, Micelli RC (1995) Enhanced expression of peripheral benzodiazepine receptors in the trimethyltin-exposed rat brain: a biomarker of neurotoxicity. Neurotoxicol 16, 441– 450. 8584276
  51. Guilarte TR, Nihei MK, McGlothan JL, Howard AS (2003) Methamphetamine-induced deficits of brain monoaminergic markers: distal axotomy or neuronal plasticity. Neurosci 122, 499– 513. 14614914
  52. Gut P, Zweckstetter M, Banati RB (2015) Lost in translocation: the functions of the 18-kD translocator protein. Trends Endocrinol Metabol 26, 349– 356. PMC5654500 26026242
  53. Holladay JW, Dewey MJ, Yoo SD (1998) Pharmacokinetics and antidepressant activity of fluoxetine in transgenic mice with elevated serum alpha1-acid glycoproteins levels. Drug Metabol Dispos 26, 20– 24. 9443847
  54. Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, McArthur JC, Pomper MG (2005) Imaging glial cell activation with [11C]-R-PK1119 in patients with AIDS. J Neurovirol 11, 346– 355. 16162478
  55. Hannestad J, DellaGioia N, Gallezot J-D, Lim K, Nabulsi N, Esterlis I, Pittman B, Lee J-Y, O’Connor KC, Pelletier D, Carson RE (2013) The neuoinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression. Brain Beh Immun 33, 131– 138. PMC3899398 23850810
  56. Hannestad J, Gallezot JD, Schafbauer T, Lim K, Kloczynski T, Morris ED, Carson RE, Ding YS, Cosgrove KP (2012) Endotoxin-induced systemic inflammation activates microglia: [11C]-PBR28 positron emission tomography in nonhuman primates. NeuroImage 63, 232– 239. 22776451 PMC3699786
  57. Hardwick MJ, Chen M-K, Baidoo K, Pomper MG, Guilarte TR (2005) In vivo imaging of peripheral benzodiazepine receptors in mouse lungs: a biomarker of inflammation. Mol Imaging 4, 432– 438. 16285905
  58. Harhausen D, Sudmann V, Khojasteh U, Muller J, Zille M, Graham K, Thiele A, Dyrks T, Dirnagl U, Wunder A (2013) Specific imaging of inflammation with the 18 kDa translocator protein ligand DPA-714 in animal models of epilepsy and stroke. PLOS One 8, e69529. 23936336 PMC3732268
  59. Henkel K, Karitzky J, Schmid M, Mader I, Glatting G, Unger JW, Neumaier B, Ludolph AC, Reske SN, Landwehrmeyer GB (2004) Imaging activated microglia with PET and [11C]-PK11195 in corticobasal degeneration. Mov Dis 19, 817– 821. 15254941
  60. Hillmer AT, Holden D, Fowles K, Nabulsi N, West BL, Carson RE, Cosgrove KP (2017a) Microglia depletion and activation: a [11C]-PBR28 PET study in nonhuman primates. EJNMMI Res 7, 59. 28741281 PMC5524658
  61. Hillmer AT, Sandiego CM, Hannestad J, Angarita GA, Kumar A, McGovern EM, Huang Y, O’Connor KC, Carson RE, O’Malley SS, Cosgrove KP (2017b) In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry 22, 1759– 1766. 28242869 PMC5573660
  62. Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, Gerhard A, Talbot PS (2017) Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psych 83, 61– 69. 28939116
  63. Iaccarino L, Moresco RM, Presotto L, Bugiani O, Iannaccone G, Tagliavini F, Perani D (2017) An in vivo [11C](R)-PK11195 PET and in vitro pathology study of microglia activation in Creutzfeldt-Jakob disease. Mol Neurobiol 55, 2856– 2868. 28455699
  64. Iaccarino L, Presotto L, Bettinardi V, Gianolli L, Roiter I, Capellari S, Parchi P, Cortelli P, Perani D (2018) An in vivo 11C-PK PET study of microglia activation in Fatal Familial Insomnia. Ann Clin Transl Neurol 5, 11– 18. 29376088 PMC5771322
  65. Israel I, Ohsiek A, Al-Momani E, Albert-Weissenberger C, Stetter C, Menci S, Buck AK, Kleinschnitz C, Samnick S, Siren A-L (2016). Combined [18F]-DPA-713 micropositron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice. J Neuroinflammation 13, 140. 27266706 PMC4897946
  66. Iwamoto K, Bundo M, Kato T (2005) Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder of schizophrenia, as revealed by large-size DNA microarray analysis. Human Mol Genet 14, 241– 253. 15563509
  67. Janssen B, Vugts DJ, Funke U, Molenaar GT, Kruijer PS, van Berckel BNM, Lammertsma AA, Windhorst AD (2017) Imaging of neuroinflammation in Alzheimer’s disease, multiple sclerosis, and stroke: recent developments in positron emission tomography. Biochim Biophys Acta 1862, 425– 441. 26643549
  68. Javaid JI, Notorangelo MP, Pandey SC, Reddy PL, Pandey GN, Davis JM (1994) Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans. Biol Psych 36, 44– 50. 8080902
  69. Jeyakumar M, Butters TD, Dwek RA, Platt FM (2002) Glycosphingolipid lysosomal storage disease: therapy and pathogenesis. Neuropath Appl Neurobiol 28, 343– 357. 12366816
  70. Jolliet-Riant R, Boukef MF, Duche JC, Simon N, Tillement JP (1998) The genetic variant A of human alpha1-acid glycoprotein limits the blood to brain transfer of drugs it binds. Pharmacol Lett 62, 219– 226. 9570346
  71. Junck L, Olson JMM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, McKeever PE, Wieland DM, Kilbourn MR, Starosta-Rubenstien S, Mancini WR, Kuhl DE, Greenberg HS, Young AB (1989) PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol 26, 752– 758. 2557794
  72. Kanaan NM, Kordower JH, Collier TJ (2010) Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys. Neurobiol Aging 31, 937– 952. 18715678 PMC2872507
  73. Kannan S, Saadani-Makki F, Muzik O, Chakraborty P, Mangner TJ, Janisse J, Romero R, Chugani DC (2007) Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with [11C]-R-PK11195 and small-animal PET. J Nucl Med 48, 946– 954. 17504871
  74. Kim R, Healey KL, Sepulveda-Orengo MT, Reissner KJ (2017) Astrogial correlates of neuropsychiatric disease: from astrocytopathy to astrogliosis. Prog Neuropsychopharmacol Biol Psych pii: S0278–5846(17)30485–2. PMC5889368 28989099
  75. Knezevic D, Verhoeff NPL, Hafizi S, Strafella AP, Graff-Guerrero A, Rajji T, Pollock BG, Houle S, Rusjan PM, Mizhari R (2017) Imaging microglia activation and amyloid burden in amnestic mild cognitive impairment. J Cereb Blood Flow Metab 1: 271678X17741395. PMC6259323 29135331
  76. Krueger KE, Papadopoulos V (1990) Peripheral-type benzodiazepine receptors mediate translocationof cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem 265, 15015– 15022. 2168398
  77. Kuhlmann AC, Guilarte TR (1997) The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity. Brain Res 751, 281– 288. 9099816
  78. Kuhlmann AC, Guilarte TR (1999) Regional and temporal expression of the peripheral benzodiazepine receptor in MPTP neurotoxicity. Toxicol Sci 48, 107– 116. 10330690
  79. Kuhlmann AC, Guilarte TR (2000) Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem 74, 1694– 1704. 10737628
  80. Kurumaji A, Wakai T, Toru M (1997) Decreases in peripheral-type benzodiazepine receptors in postmortem brains of chronic schizophrenics. J Neural Transm 104, 1361– 1370. 9503282
  81. Lavisse S, Guillermier M, Herard A-S, Petit F, Delahaye M, Van Camp N, Haim LB, Lebon B, Remy P, Dolle F, Delzescaux T, Bonveto G, Hantraye P, Escartin C (2012) Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. Neurobiol Dis 32, 10809– 10818. PMC6621018 22875916
  82. Lavisse S, Inoue K, Jan C, Peyronneau MA, Petit F, Goutal S, Dauguet J, Guillermier M, Dolle F, Rhah-Vidal L, Van Camp N, Aron-Badin R, Remy P, Hantraye P (2015) [18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain. Eur J Nucl Med Mol Imaging 42, 478– 494. 25488184
  83. Lemus MB, Bayliss JA, Lockie SH, Santos VV, Reichenbach A, Stark R, Andrews ZB (2015) A sterological analysis of NPY, POMC, Orexin, GFAP astrocyte, and Iba1 microglial cell number and volume in diet-induced obese male mice. Endocrinol 156, 17011713. 25742051
  84. Levinson I, Levine S (1995) Negative correlation between Alpha-1-Acid-Glycoprotein plasma level and response to haloperidol in the acute treatment of schizophrenia. Biol Psych 38, 198200. 7578667
  85. Li H, Sagar AP, Keri S (2018) Translocator protein (18 kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. Prog Neuropsychpharm Biol Psych 83, 1– 7. 29269262
  86. Liu B, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Holton P, Reiser V, Jones PA, Trigg W, Di Carli MF, Lemere CA (2015) In vivo detection of age- and disease-related increases in neuroinflammation by 18F-GE180 TSPO microPET imaging in wildtype and Alzheimer’s transgenic mice. J Neurosci 35, 15716– 15730. 26609163 PMC6705465
  87. 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 α1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker. Nucl Med Biol 30, 199– 206. 12623120
  88. Loth MK, Choi J, McGlothan JL, Pletnikov MV, Pomper MG, Guilarte TR (2016) TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology. Neurobiol Dis 85, 174– 186. 26545928 PMC4688219
  89. Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, Zhang M-R, Suzuki K, Suhara T (2007) Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res 1157, 100– 111. 17540348
  90. Mahuran DF (1999) Biochemical consequences of mutations causing the GM2 gangliosidosis. Biochem Biophys Acta 1455, 105– 138. 10571007
  91. Mankowski JL, Queen SE, Tarwater PJ, Adams RJ, Guilarte TR (2003) Elevated peripheral benzodiazepine receptor expression in simian immunodeficiency virus encephalitis. J Neurovirol 9, 94– 100. 12587072
  92. Maragos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (1982) Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]-Ro5–4864. Mol Pharmacol 22, 26– 32. 6289073
  93. Masgrau R, Guaza C, Ransohoff RM, Galea E (2017) Should we stop saying “glial” and “neuroinflammation”. Trends Mol Med 23, 485– 500. 28499701
  94. Mattner F, Linares Bandin D, Staykova M, Berghofer P, Claude Gregoire M, Ballantyne P, Quinlivan M, Fordham S, Pham T, Willenborg DO, Katsifis A (2011) Evaluation of [123I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation. Eur J Nucl Med Mol Imaging 38, 1516– 1528. 21484375
  95. McNeela AM, Bernick C, Hines RM, Hines DJ (2017) TSPO regulation in reactive gliotic diseases. J Neuro Res 96, 978– 988. 29315754
  96. Miller TR, Wetter JB, Jarvis MF, Bitner RS (2013) Spinal microglia activation in rat models of neuropathic osteoarthritic pain: an autoradiographic study using [3H]-PK11195. Eur J Pain 17, 692– 703. 23070996
  97. Mirzaei N, Pham Tang S, Ashworth S, Coello C, Plisson C, Passchier J, Selvaraj V, Tyacke RJ, Nutt DJ, Sastre M (2016) In vivo imaging of microglia activation by positron emission tomography with [11C]-PBR28 in the 5XFAD model of Alzheimer’s disease. GLIA, 64, 993– 1006. 26959396
  98. Miyazawa N, Diksic M, Yamamoto Y (1995) Chronological study of peripheral benzodiazepine binding sites in the rat stab wounds using [3H]-PK11195 as a marker of gliosis. Acta Neurochir (Wien) 137, 207– 216. 8789663
  99. Morohaku K, Pelton SH, Daugherty DJ, Butler WR, Deng W, Selvaraj V (2014) Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinol 155, 89– 97. PMC3868810 24174323
  100. Myers R, Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JE (1991) Macrophage and astrocyte populations in relation to [3H]-PK11195 binding in the cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab 11, 314– 322. 1997503
  101. Nguyen D-L, Wimberley C, Truillet C, Jego B, Caille F, Pottier G, Boisgard R, Buvat I, Bouilleret V (2018) Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: toward identification of optimal treatment windows. Epilepsia 59, 1234– 1244. 29672844
  102. Notter T, Coughlin JM, Sawa A, Meyer U (2017) Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Mol Psych 23, 36– 47. 29203847
  103. Notter T, Coughlin JM, Gschwind T, Weber-Stadlbauer U, Wang Y, Kassiou M, Vernon AC, Benke D, Pomper MG, Sawa A, Meyer U (2018) Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. Mol Psych 23, 323– 334. 28093569
  104. Ory D, Planas A, Dresselaers T, Gsell W, Postnov A, Celen S, Casteels C, Himmelreich U, Debyser Z, Van Laere K, Verbruggen A, Bormans G (2015) PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide. Nucl Med Biol 42, 753– 761. 26220690
  105. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27, 402– 409. 16822554
  106. Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB (2000) Thalamic microglial activation in ischemic stroke detected in vivo by [11C]-R-PK11195. Neurology 55, 1052– 1054. 11061271
  107. Patel J, Marangos PJ (1982) Differential effects of GABA on peripheral and central type benzodiazepine binding sites in brain. Neurosci Lett 30, 157– 160. 6287365
  108. Plaven-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, Mizhari R, Pomper MG, Rusjan P, Veronese M, Wang Y, Cervenka S (2018) Positron Emission Tomography studies in the glial cell marker Translocator Protein in patients with psychosis: A meta-analysis using individual participant data. Biol Psych pii: S0006–3223, 3129831308. PMC7893597 29653835
  109. Politis M, Lahiri N, Niccolini F, Su P, Wu K, Giannetti P, Scahill RI, Turkheimer FE, Tabrizi SJ, Piccini P (2015) Increased central microglial activation associated with peripheral cytokine levels in premanisfest Huntington’s disease gene carriers. Neurobiol Dis 83, 115– 121. 26297319
  110. Rao VLR, Dogan A, Bowen KK, Dempsey RJ (2000) Traumatic brain injury leads to increased expression of peripheral benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol 161, 102– 114. 10683277
  111. Richards EM, Zanotti-Fregonara P, Fujita M, Newman L, Farmer C, Ballard ED, Machado-Vieja R, Yuan P, Niciu MJ, Lyoo CH, Henter ID, Salvadore G, Drevets WC, Kolb H, Innis RB, Zarate CA Jr. (2018) EJNNMI Res 8, 57. PMC6029989 29971587
  112. Ritsner M, Modai I, Gibel A, Leschneir S, Silver H, Tsinovoy G, Weizman A, Gavish M (2003) Decreased platelet peripheral-type benzodiazepine receptors in persistently violent schizophrenia patients. J Psych Res 37, 549– 556. 14563387
  113. Roberts RC (2017) Postmortem studies on mitochondria in schizophrenia. Schizophr Res 187, 17– 25. 28189530 PMC5550365
  114. Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, Llop J, Gomez V, Gispert JD, Millan O, Chamorro A, Planas AM (2007) Imaging brain inflammation with [11C]PK11195 by PET and induction of the peripheral-benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 27, 1975– 1986. 17457364
  115. Sango K, Yamanaka S Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL (1995) Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic and phenotype and ganglioside metabolism. Nat Genet 11, 170– 176. 7550345
  116. Schain M, Kreisl WC (2017) Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep 17, 25. 28283959
  117. Schoemaker H, Morelli M, Deshmukh P, Yamamura HI (1982) [3H]-Ro5–4864 benzodiazepine binding in the kainate lesioned striatum and Huntington’s disease basal ganglia. Brain Res 248, 396– 401. 6291702
  118. Selvaraj V, Stocco DM (2015) The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metabol 26, 341– 348. PMC7171652 25801473
  119. Selvaraj V, Tu LN (2016) Current status and future perspectives: TSPO in steroid neuroendocrinology. J. Endocrinol 231, R1– R30. 27422254
  120. Sérrière S, Tauber C, Vercouille J, Mothes C, Pruckner C, Guilloteau D, Kassiou M, Domene A, Garreau L, Page G, Chalon A (2015) Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study. Neurobiol Aging 36, 1639– 1652. 25680265
  121. Setiawan E, Wilson AA, Mizhari 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 Psych 72, 268– 275. PMC4836849 25629589
  122. Setiawan E, Attwells S, Wilson AA, Mizhari R, Rusjan PM, Miler L, Xu C, Sharma S, Kish S, Houle S, Meyer JH (2018) Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psych 5, 339– 347. 29496589
  123. Somerville SM, Conley RR, Roberts RC (2012) Striatal mitochondria in subjects with chronic undifferentiated vs. chronic paranoid schizophrenia. Synapse 66, 29– 41. 21905126
  124. Starosta-Rubenstein S, Ciliax BJ, Penney JB, McKeever P, Young AB (1987) Imaging of a glioma using peripheral benzodiazepine receptor ligands. Proc Nat Acad Sci 84, 891– 895. 3027710 PMC304322
  125. Stephenson DT, Schober DA, Smaistig 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– 5274. 7623150 PMC6577872
  126. Suranyi-Cadotte B, Lafaille F, Dongier M, Dumas M, Quirion R (1988) Decreased density of peripheral benzodiazepine binding sites on platelets of currently drinking, but not abstinent alcoholics. Neuropharmacol 27, 443– 445. 2843780
  127. Tai YF, Pavese N, Gerhardt A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (2007) Imaging microglial activation in Huntington’s disease. Brain Res Bull 72, 148– 151. 17352938
  128. Telford JE, Bones J, McManus C, Saldova C, Manning G, Doherty M, Leweke FM, Rothermundt M, Guest PC, Rahmoune H, Bahn S, Rudd PM (2012) Antipsychotic treatment of acute paranoid schizophrenia patients with olanzapine results in altered glycosyltion of serum glycoproteins. J Proteome Res 11, 3743– 3752. 22594947
  129. 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, 1249– 1256. 18632810
  130. Toyama H, Hatano K, Suzuki H, Ichise M, Momosaki S, Kudo G, Ito F, Kato T, Yamaguchi H, Katada K, Sawada M, Ito K (2008) In vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand: [11C]-PK11195 and animal PET following ethanol injury in rat striatum. Ann. Nucl Med 22, 417– 424. 18600420
  131. Tu LN, Morohaku K, Manna PR, Pelton SH, Butler WR, Stocco DM, Selvaraj V (2014) Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem 289, 27444– 27454. 24936060 PMC4183784
  132. Tu LN, Zhao AH, Stocco DM, Selvaraj V (2015) PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). Endocrinol 156, 1033– 1039. PMC4330312 25535830
  133. Van Kesteren CFMG, Gemmels H, Witte LD, Hoi EM, van Gool AR, Flakai PG, Kahn RS, Sommer IEC (2017) Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psych 7, e1075. PMC5404615 28350400
  134. Venneti s., Lopresti BJ, Wang G, Bissel SJ, Mathis CA, Meltzer CC, Boada F, Capuano S III, Kress GJ, Davis DK, Ruszkiewicz SR, Reynolds IJ, Murphey-Corb M, Trichel AM, Wisniewski SR, Wiley CA (2004) PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS. J Clin Invest 113, 981– 989. 15057304 PMC379322
  135. Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (Tanslocator Protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 80, 308– 322. 17156911 PMC1849976
  136. Venneti S, Wagner AK, Wang G, Slagel SL, Chen X, Lopresti BJ, Mathis CA, Wiley CA (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, 118– 127. 17658516 PMC2042945
  137. 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 Neuropath Exp Neurol 67, 1001– 1010. 18800007 PMC2669281
  138. Veronese M, Marques TR, Bloomfield PS, Rizzo G, Singh N, Jones D, Agushi E, Mosses D, Bertoldo A, Howes O, Roncaroli F, Turkheimer FE (2017) Kinetic modelling of [11C]PBR28 for translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis. J Cer Blood Flow Met 38, 1227– 1242. PMC6434448 28580888
  139. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, Antel JP (1997) PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res 50, 345353. 9373043
  140. Wang Y, Yue X, Kiesewetter DO, Niu G, Teng G, Chen X (2014) PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA714. Eur J Nucl Med Mol Imaging 41, 1440– 1449. 24615467 PMC4055510
  141. Weizman R, Tanne Z, Karp L, Tyano., Gavish M (1986) Peripheral-type benzodiazepine-binding sites in platelets of schizophrenics with and without tardive dyskinesia. Life Sci 39, 549– 555. 3016444
  142. Wierzba-Bobrowicz T, Lewandowska E, Kosno-Knusewska E, Lechowicz W, Pasennik E, Schmidt-Sidor B (2004) Degeneration of microglial cells in frontal cortex and temporal lobes of chronic schizophrenics. Folia Neuropathol 42, 157– 165. 15535034
  143. Williams RM, Hampton T, Pearce RKB, Hirsch SR, Ansorge O, Thom M, Maier M (2013) Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. Eur Arch Psych Clin Neurosci 263, 41– 52. 22660922
  144. Wodarz N, Rothenhofer C, Fischer R, Stober G, Kiehl B, Jungkunz G, Riederer P, Klein HE (1998) Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenia patients. Psych Res 81, 363– 369. 9925187
  145. Yankam Njiwa J, Costes N, Bouillot C, Bouvard S, Fieux S, Becker G, Levigoureux E, Kocevar G, Stamile C, Langlois JB, Bolbos R, Bonnet C, Bezin L, Zimmer L, Hammers A (2016) Quantitative longitudinal imaging of activated microglia as a marker of inflammation in the pilocarpine rat model of epilepsy using [11C]-(R)-PK11195 PET and MRI. J Cereb Blood Flow Metab 37, 1251– 1263. 27381824 PMC5414902
  146. Young EC, Patel A, Meyers BS, Kakuma T, Alexopoulos GS (1999) Alpha1-acid glycoprotein, age, and sex in mood disorders. Am J Geriatr Psych 7, 331– 334. 10521166

Cited by

Sorted by citations

Authors
Guilarte, T. R.
Affiliations
Florida International University (US)
Corresponding author
Guilarte, Tomás R.
ORCID
Guilarte, Tomás R.
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2019-02
Volume
194
Pages
44-58
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2018.09.003
PMC
PMC6348013
OpenAlex
W2890625851
Cited by
173
References
16
Citations by year
2026: 4 · 2025: 18 · 2024: 27 · 2023: 19 · 2022: 21 · 2021: 29 · 2020: 34 · 2019: 18 · 2018: 3
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Environmental Health Sciences (ES007062-19)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
translocator protein (TSPO), TSPO PET imaging, neuroinflammation, brain injury, neurodegenerative diseases, mental illness, schizophrenia, neuroimaging biomarkers
MeSH terms
Animals, Mental Disorders, Brain, Central Nervous System Diseases, Humans, Neuroglia, Receptors, GABA-A, Biomarkers, Receptors, GABA

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review