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

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: [ ^99m Tc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hydroxyiminobutan-2-yl]azanide ([ ^99m Tc]HMPAO) and ethyl-7-[ ¹²⁵ I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([ ¹²⁵ I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[ ¹⁸ F]fluoro-D-glucose ([ ¹⁸ F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[ ¹²⁵ I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl-acetamide ([ ¹²⁵ I]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 [ ¹⁸ F]FDG and [ ¹²⁵ I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [ ¹²⁵ I]iomazenil uptake was measured in the LPS-treated group's hippocampus and cerebellum. In this group, both [ ¹⁸ F]FDG and [ ¹²⁵ I]iomazenil uptake showed highly negative correlation to perfusion measured with ([ ^99m Tc]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 [ ¹²⁵ I]CLINME and [ ^99m Tc]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 [ ¹⁸ F]FDG and [ ¹²⁵ I]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.