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

Abstract

Excessive activation of inflammatory signaling pathways seems to be a hallmark of epileptogenesis. Positron emission tomography (PET) allows in vivo detection of brain inflammation with spatial information and opportunities for longitudinal follow-up scanning protocols.Here, we assessed whether molecular imaging of the 18 kDa translocator protein (TSPO) can serve as a biomarker for the development of epilepsy. Therefore, brain uptake of [18F]GE-180, a highly selective radioligand of TSPO, was investigated in a longitudinal PET study in a chronic rat model of temporal lobe epilepsy. Analyses revealed that the influence of the epileptogenic insult on [18F]GE-180 brain uptake was most pronounced in the earlier phase of epileptogenesis. Differences were evident in various brain regions during earlier phases of epileptogenesis with [18F]GE-180 standardized uptake value enhanced by 2.1 to 2.7fold. In contrast, brain regions exhibiting differences seemed to be more restricted with less pronounced increases of tracer uptake by 1.8–2.5fold four weeks following status epilepticus and by 1.5–1.8fold in the chronic phase. Based on correlation analysis, we were able to identify regions with a predictive value showing a correlation with seizure development. These regions include the amygdala as well as a cluster of brain areas. This cluster comprises parts of different brain regions, e.g. the hippocampus, parietal cortex, thalamus, and somatosensory cortex.In conclusion, the data provide evidence that [18F]GE-180 PET brain imaging can serve as a biomarker of epileptogenesis. The identification of brain regions with predictive value might facilitate the development of preventive concepts as well as the early assessment of the interventional success. Future studies are necessary to further confirm the predictivity of the approach.

[18F]GE180 positron emission tomographic imaging indicates a potential double‐hit insult in the intrahippocampal kainate mouse model of temporal lobe epilepsy

“…4 As serial imaging with dedicated small animal PET scanners has become an available technique also for laboratory rodents, 3,5 TSPO PET represents a noninvasive and quantitative tool with high translational potential. In line with recent studies using different rat epilepsy models and TSPO tracers, [6][7][8] we recently elucidated the detailed spatiotemporal profile of microglial activation during epileptogenesis in the widely used pilocarpine rat model of temporal lobe epilepsy by longitudinal TSPO PET imaging with the ligand [ 11 C] PK11195 and complementary in vitro techniques. 9 Furthermore, a recent paper demonstrates the predictive potential of TSPO PET at epilepsy onset in a rat model of temporal lobe epilepsy.…”

Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers

“…All four targets have shown alterations during epileptogenesis with apparently different time profiles. TSPO expression has previously been investigated in this 11,13 and other animal models of epileptogenesis, [19][20][21][22]35 and is known to be upregulated during epileptogenesis as shown by immunohistological staining of activated microglia. 18 They reported a global decrease of mGluR5 expression in the acute phase after SE that was maintained in hippocampus and amygdala in the subacute and chronic phases.…”

Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein

“…14 Binding was correlated with ac tivated microglia, cell loss, and seizures. 19 A small number of human imaging studies support the hypothesis that epilepsy is associated with increased TSPO binding, suggesting the presence of inflammation. 15 In the lithium-pilocarpine status epilepticus model, increased TSPO binding was seen with ([11C]PK11195 PET, correlated with microglial and astroglial activation as well as neuronal loss.…”