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Alterations in metabolism during epileptogenesis may be a therapy target. Recently, an increase in amino acid transport into the brain was proposed to play a role in epileptogenesis. We aimed to characterize alterations of substrate utilization during epileptogenesis and in chronic epilepsy. The lithium-pilocarpine post status epilepticus (SE) rat model was used. We performed longitudinal O-(2-[(18)F]fluoroethyl)-l-tyrosine ( 18 F-FET) and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) and calculated 18 F-FET volume of distribution (V t ) and 18 F-FDG uptake. Correlation analyses were performed with translocator protein-PET defined neuroinflammation from previously acquired data. We found reduced 18 F-FET V t at 48 h after SE (amygdala: -30.2%, p  = 0.014), whereas 18 F-FDG showed increased glucose uptake 4 and 24 h after SE (hippocampus: + 43.6% and +42.5%, respectively; p  < 0.001) returning to baseline levels thereafter. In chronic epileptic animals, we found a reduction in 18 F-FET and 18 F-FDG in the hippocampus. No correlation was found for 18 F-FET or 18 F-FDG to microglial activation at seven days post SE. Whereas metabolic alterations do not reflect higher metabolism associated to activated microglia, they might be partially driven by chronic neuronal loss. However, both metabolisms diverge during early epileptogenesis, pointing to amino acid turnover as a possible biomarker and/or therapeutic target for epileptogenesis.

Insult-associated blood-brain barrier leakage is strongly suggested to be a key step during epileptogenesis. In this study, we used three non-invasive translational imaging modalities, i.e. positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging, to evaluate BBB leakage after an epileptogenic brain insult. Sprague-Dawley rats were scanned during early epileptogenesis initiated by status epilepticus. Positron emission tomography and single photon emission computed tomography scans were performed using the novel tracer [ 68 Ga]DTPA or [ 99m Tc]DTPA, respectively. Magnetic resonance imaging included T2 and post-contrast T1 sequence after infusion of Gd-DTPA, gadobutrol, or Gd-albumin. All modalities revealed increased blood-brain barrier permeability 48 h post status epilepticus, mainly in epileptogenesis-associated brain regions like hippocampus, piriform cortex, thalamus, or amygdala. In hippocampus, Gd-DTPA-enhanced T1 magnetic resonance imaging signal was increased by 199%, [ 68 Ga]DTPA positron emission tomography by 37%, and [ 99m Tc]DTPA single photon emission computed tomography by 56%. Imaging results were substantiated by histological detection of albumin extravasation. Comparison with quantitative positron emission tomography and single photon emission computed tomography shows that magnetic resonance imaging sequences successfully amplify the signal from a moderate amount of extravasated DTPA molecules, enabling sensitive detection of blood-brain barrier disturbance in epileptogenesis. Imaging of the disturbed blood-brain barrier will give further pathophysiologic insights, will help to stratify anti-epileptogenic treatment targeting blood-brain barrier integrity, and may serve as a prognostic biomarker.