18 F]FDG hypometabolism precedes cognitive impairment in rats recovered from severe systemic inflammation.

Abstract

Individuals who survive a severe systemic inflammatory episode are at higher risk to develop cognitive impairment. In this context, neuroinflammation has been considered a key player in Alzheimer's disease (AD). However, the mechanisms behind inflammation-driven cognitive impairment/neurodegeneration are not elucidated. Here, we aimed at investigating the long-term consequences of a severe systemic inflammatory episode on brain energy metabolism. We hypothesized that brain energetic metabolism does not completely recover from a systemic inflammatory episode, which could act as a trigger for neurodegeneration. Wistar rats (90 days old) were submitted to cecal ligation and perforation surgery (CLP; a model of sepsis) and short-term memory was assessed 30 and 120 days later through the object recognition test. Brain glucose metabolism was evaluated in vivo via micro-PET [18 F]FDG. Whole brain [18 F]FDG hypometabolism was observed in sepsis group after 30-days recovery period (sham SUVr = 1.37 ± 0.09; sepsis SUVr = 1.27 ± 0.15). Percentage of change and t-statistical maps revealed a peak of ∼17% in the hippocampal area (peak t = 3.17). When brain regions were analyzed, a significant [18 F]FDG hypometabolism was detected in the hippocampus and striatum of sepsis-induced rats. The evaluation of [18 F]FDG metabolism in rats 120 days after CLP demonstrated a persistent brain hypometabolism (sham SUVr = 1.34 ± 0.10; sepsis SUVr = 1.19 ± 0.14). Regional analysis evidenced a significant decrease in [18 F]FDG uptake in the hippocampus, frontal and temporoparietal cortices, hypothalamus and cerebellum. Voxelwise analysis did not find differences between sepsis groups 30- and 120-days post-CLP. Despite the brain hypometabolism being observed 30-days after induction of systemic inflammation, no cognitive deficit was evident at this point. An impairment in short-term memory was observed 120-days post-CLP. These results demonstrate that an episode of severe systemic inflammation causes long-term brain metabolic disturbances and cognitive impairment. Interestingly, [18 F]FDG hypometabolism can be detected earlier than behavioral alterations, suggesting a link between peripheral inflammation and cognitive decline/neurodegeneration.