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

Mol Imaging Biol. 2018 Dec;20(6):952-962. doi: 10.1007/s11307-018-1201-3.

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.

Keywords: LPS; Microglia activation; Neuroinflammation; PET/MRI; SPECT/CT; Systemic infection; [125I]CLINME; [125I]iomazenil; [18F]FDG; [99mTc]HMPAO.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Disease Models, Animal
  • Fluorodeoxyglucose F18 / pharmacokinetics
  • Glucose / metabolism
  • Iodine Radioisotopes / pharmacokinetics
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred C57BL
  • Multimodal Imaging / methods
  • Neuroimaging / methods*
  • Nuclear Medicine / methods
  • Positron-Emission Tomography / methods
  • Radioactive Tracers*
  • Radionuclide Imaging / methods*
  • Sepsis-Associated Encephalopathy / chemically induced
  • Sepsis-Associated Encephalopathy / diagnosis*
  • Sepsis-Associated Encephalopathy / metabolism
  • Sepsis-Associated Encephalopathy / pathology
  • Technetium Tc 99m Exametazime / pharmacokinetics
  • Tomography, Emission-Computed, Single-Photon / methods

Substances

  • Iodine Radioisotopes
  • Lipopolysaccharides
  • Radioactive Tracers
  • Fluorodeoxyglucose F18
  • Technetium Tc 99m Exametazime
  • Iodine-125
  • Glucose