Evaluation of Brain Nuclear Medicine Imaging Tracers in a Murine Model of Sepsis-Associated Encephalopathy

Dávid Szöllősi, Nikolett Hegedűs, Dániel S. Veres, Ildikó Futó, Ildikó Horváth, Noémi Kovács, Bernadett Martinecz, Ádám Dénes, Daniel Seifert, Ralf Bergmann, Ondřej Lebeda, Zoltán Varga, Zoltán Kaleta, Krisztián Szigeti, Domokos Máthé

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Abstract

Purpose: The purpose of this study was to evaluate a set of widely used nuclear medicine imaging agents as possible methods to study the early effects of systemic inflammation on the living brain in a mouse model of sepsis-associated encephalopathy (SAE). The lipopolysaccharide (LPS)-induced murine systemic inflammation model was selected as a model of SAE. Procedures: C57BL/6 mice were used. A multimodal imaging protocol was carried out on each animal 4 h following the intravenous administration of LPS using the following tracers: [99mTc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hydroxyiminobutan-2-yl]azanide ([99mTc]HMPAO) and ethyl-7-[125I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([125I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[125I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl-acetamide ([125I]CLINME). Radiotracer uptakes were measured in different brain regions and correlated. Microglia activity was also assessed using immunohistochemistry. Brain glutathione levels were measured to investigate oxidative stress. Results: Significantly reduced perfusion values and significantly enhanced [18F]FDG and [125I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [125I]iomazenil uptake was measured in the LPS-treated group’s hippocampus and cerebellum. In this group, both [18F]FDG and [125I]iomazenil uptake showed highly negative correlation to perfusion measured with ([99mTc]HMPAO uptake in all brain regions. No significant differences were detected in brain glutathione levels between the groups. The CD45 and P2Y12 double-labeling immunohistochemistry showed widespread microglia activation in the LPS-treated group. Conclusions: Our results suggest that [125I]CLINME and [99mTc]HMPAO SPECT can be used to detect microglia activation and brain hypoperfusion, respectively, in the early phase (4 h post injection) of systemic inflammation. We suspect that the enhancement of [18F]FDG and [125I]iomazenil uptake in the LPS-treated group does not necessarily reflect neural hypermetabolism and the lack of neuronal damage. They are most likely caused by processes emerging during neuroinflammation, e.g., microglia activation and/or immune cell infiltration.

Original languageEnglish (US)
Pages (from-to)952-962
Number of pages11
JournalMolecular Imaging and Biology
Volume20
Issue number6
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
Acknowledgements. This work was funded in part by INMiND (HEALTH.2011.2.2.1-2 No.278850) of FP7 and by VKSZ-14-1-2005-0151. We thank Mediso Ltd. for technical background of NanoSPECT/CT Plus and nanoScan PET/MRI. K Szigeti was supported by the Janos Bolyai Research Fellowship program of the Hungarian Academy of Science.

Keywords

  • LPS
  • Microglia activation
  • Neuroinflammation
  • PET/MRI
  • SPECT/CT
  • Systemic infection
  • [F]FDG
  • [I]CLINME
  • [I]iomazenil
  • [Tc]HMPAO

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