Abstract
Purpose
Expression of the translocator protein (TSPO) is upregulated in activated macrophages/microglia and is considered to be a marker of neuroinflammation. We investigated the novel TSPO ligand [18F]GE-180 in patients with relapsing–remitting multiple sclerosis (RRMS) to determine the feasibility of [18F]GE-180 PET imaging in RRMS patients and to assess its ability to detect active inflammatory lesions in comparison with the current gold standard, contrast-enhanced magnetic resonance imaging (MRI).
Methods
Nineteen RRMS patients were prospectively included in this study. All patients underwent TSPO genotyping and were classified as high-affinity, medium-affinity or low-affinity binders (HAB/MAB/LAB). PET scans were performed after administration of 189 ± 12 MBq [18F]GE-180, and 60–90 min summation images were used for visual analysis and assessment of standardized uptake values (SUV). The frontal nonaffected cortex served as a pseudoreference region (PRR) for evaluation of SUV ratios (SUVR). PET data were correlated with MRI signal abnormalities, i.e. T2 hyperintensity or contrast enhancement (CE). When available, previous MRI data were used to follow the temporal evolution of individual lesions.
Results
Focal lesions were identified as hot spots by visual inspection. Such lesions were detected in 17 of the 19 patients and overall 89 [18F]GE-180-positive lesions were found. TSPO genotyping revealed 11 patients with HAB status, 5 with MAB status and 3 with LAB status. There were no associations between underlying binding status (HAB, MAB and LAB) and the signal intensity in either lesions (SUVR 1.87 ± 0.43, 1.95 ± 0.48 and 1.86 ± 0.80, respectively; p = 0.280) or the PRR (SUV 0.36 ± 0.03, 0.40 ± 0.06 and 0.37 ± 0.03, respectively; p = 0.990). Of the 89 [18F]GE-180-positive lesions, 70 showed CE on MRI, while the remainder presented as T2 lesions without CE. SUVR were significantly higher in lesions with CE than in those without (2.00 ± 0.53 vs. 1.60 ± 0.15; p = 0.001). Notably, of 19 [18F]GE-180-positive lesions without CE, 8 previously showed CE, indicating that [18F]GE-180 imaging may be able to detect lesional activity that is sustained beyond the blood–brain barrier breakdown.
Conclusion
[18F]GE-180 PET can detect areas of focal macrophage/microglia activation in patients with RRMS in lesions with and without CE on MRI. Therefore, [18F]GE-180 PET imaging is a sensitive and quantitative approach to the detection of active MS lesions. It may provide information beyond contrast-enhanced MRI and is readily applicable to all patients. [18F]GE-180 PET imaging is therefore a promising new tool for the assessment of focal inflammatory activity in MS.
Similar content being viewed by others
References
Halper J, Harris C. Nursing practice in multiple sclerosis: a core curriculum. New York: Springer; 2016.
Kobelt G. Costs and quality of life for patients with multiple sclerosis in Belgium. Eur J Health Econ. 2006;7(2):24–33.
Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol. 2014;122:15–58.
Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–8.
Filippi M, Rocca MA, Barkhof F, Brück W, Chen JT, Comi G, et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012;11(4):349–60.
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–86.
Filippi M, Rocca MA, Ciccarelli O, De Stefano N, Evangelou N, Kappos L, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016;15(3):292–303.
Colasanti A, Guo Q, Muhlert N, Giannetti P, Onega M, Newbould RD, et al. In vivo assessment of brain white matter inflammation in multiple sclerosis with (18)F-PBR111 PET. J Nucl Med. 2014;55(7):1112–8.
Ching ASC, Kuhnast B, Damont A, Roeda D, Tavitian B, Dollé F. Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases. Insights Imaging. 2012;3(1):111–9.
Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BN, Lammertsma AA. Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies. J Cereb Blood Flow Metab. 2006;26(11):1431–41.
Wadsworth H, Jones PA, Chau WF, Durrant C, Fouladi N, Passmore J, et al. [18F]GE-180: a novel fluorine-18 labelled PET tracer for imaging translocator protein 18 kDa (TSPO). Bioorg Med Chem Lett. 2012;22(3):1308–13.
Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, et al. 18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015;42(3):503–11.
Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 2014;55(3):466–72.
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.
Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med. 2011;52(1):24–32.
Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P, et al. 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. 2010;49(4):2924–32.
Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32(1):1–5.
Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN. Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. Neuroimage. 2012;60(2):902–10.
Wickstrøm T, Clarke A, Gausemel I, Horn E, Jørgensen K, Khan I, et al. The development of an automated and GMP compliant FASTlab™ synthesis of [18F] GE-180; a radiotracer for imaging translocator protein (TSPO). J Labelled Comp Radiopharm. 2014;57(1):42–8.
Fan Z, Calsolaro V, Atkinson RA, Femminella GD, Waldman A, Buckley C, et al. Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein. J Nucl Med. 2016;57(11):1753–9.
Vomacka L, Albert NL, Lindner S, Unterrainer M, Mahler C, Brendel M, et al. TSPO imaging using the novel PET ligand [18F]GE-180: quantification approaches in patients with multiple sclerosis. EJNMMI Res. 2017;7(1):89.
Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19(4):224–47.
Drever L, Robinson DM, McEwan A, Roa W. A local contrast based approach to threshold segmentation for PET target volume delineation. Med Phys. 2006;33(6):1583–94.
Brendel M, Probst F, Jaworska A, Overhoff F, Korzhova V, Albert NL, et al. Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple-tracer PET study. J Nucl Med. 2016;57(6):954–60.
Feeney C, Scott G, Raffel J, Roberts S, Coello C, Jolly A, et al. Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain. Eur J Nucl Med Mol Imaging. 2016;43(12):2201–10.
Takano A, Piehl F, Hillert J, Varrone A, Nag S, Gulyas B, et al. In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI Res. 2013;3(1):30.
Oh U, Fujita M, Ikonomidou VN, Evangelou IE, Matsuura E, Harberts E, et al. Translocator protein PET imaging for glial activation in multiple sclerosis. J Neuroimmune Pharmacol. 2011;6(3):354–61.
Ratchford JN, Endres CJ, Hammoud DA, Pomper MG, Shiee N, McGready J, et al. Decreased microglial activation in MS patients treated with glatiramer acetate. J Neurol. 2012;259(6):1199–205.
Banati R, Newcombe J, Gunn R, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Brain. 2000;123(11):2321–37.
Giannetti P, Politis M, Su P, Turkheimer F, Malik O, Keihaninejad S, et al. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study. Neurobiol Dis. 2014;65:203–10.
Owen DR, Howell OW, Tang S-P, Wells LA, Bennacef I, Bergstrom M, et al. Two binding sites for [3H] PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab. 2010;30(9):1608–18.
Debruyne J, Versijpt J, Van Laere K, De Vos F, Keppens J, Strijckmans K, et al. PET visualization of microglia in multiple sclerosis patients using [11C] PK11195. Eur J Neurol. 2003;10(3):257–64.
Albert NL, Unterrainer M, Fleischmann D, Lindner S, Vettermann F, Brunegraf A, et al. TSPO PET for glioma imaging using the novel ligand 18F-GE-180: first results in patients with glioblastoma. Eur J Nucl Med Mol Imaging. 2017;44(13):2230–8.
Russmann V, Brendel M, Mille E, Helm-Vicidomini A, Beck R, Günther L, et al. Identification of brain regions predicting epileptogenesis by serial [18F] GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy. Neuroimage Clin. 2017;15:35–44.
Zwergal A, Günther L, Brendel M, Beck R, Lindner S, Xiong G, et al. In vivo imaging of glial activation after unilateral labyrinthectomy in the rat: a [18F]GE180-PET study. Front Neurol. 2017;8:665.
Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 2009;35(3):306–28.
Acknowledgments
We thank Professor C. Wetzel for support regarding polymorphism genotyping. Additionally, we thank W. Trigg, C. Buckley and GE-Healthcare for support regarding tracer production.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None.
Ethical approval
The prospective study was authorized by the local Ethics Committee (IRB no. 48-15) and the German Radiation Protection Committee in accordance with the ICH Guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki.
Informed consent
All patients gave written consent to participate in the study. Some of the study population were previously evaluated and reported by Vomacka et al. [21].
Electronic supplementary material
ESM 1
(DOCX 2470 kb)
Rights and permissions
About this article
Cite this article
Unterrainer, M., Mahler, C., Vomacka, L. et al. TSPO PET with [18F]GE-180 sensitively detects focal neuroinflammation in patients with relapsing–remitting multiple sclerosis. Eur J Nucl Med Mol Imaging 45, 1423–1431 (2018). https://doi.org/10.1007/s00259-018-3974-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-018-3974-7