Abstract
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Objectives: Neuroinflammation has been suggested to be a key patho-mechanism of epileptogenesis, i.e. the gradual process that leads to epilepsy. Our objective is to identify potential in vivo markers of brain inflammation in order to reveal insight into complex changes during experimental, insult-induced epileptogenesis.
Methods: To this aim, we performed longitudinal neuroimaging studies in the lithium-pilocarpine rat model. Female Sprague Dawley rats were scanned in baseline conditions and at various time points after status epilepticus (SE). We investigated glucose (18F-FDG) and amino acid (18F-FET) turnover, and microglia activation (11C-PK11195) by PET as well as blood-brain barrier (BBB) impairment by contrast-enhanced MRI. PET imaging was analyzed by kinetic modeling using 2-tissue compartment model (18F-FDG and 18F-FET) or simplified reference tissue model (11C-PK11195). For MRI, images were co-registered to a rat brain MRI template and normalized to pons using Pmod software. Furthermore, additional brains were histologically evaluated for neurodegeneration, as well as microglia and astroglia activation.
Results: 18F-FDG SUV showed up-regulation in the first 24 h after SE (by max. 57%, p<0.0001) while 18F-FET volume of distribution was slightly reduced at 48 h days after SE (-29%, p=0.033). Hypometabolism was found for both in the chronic phase of epilepsy. MRI revealed increased BBB permeability 48 h after SE (by max. 124%, p<0.0001), mainly in epileptogenesis-associated brain regions like hippocampus, piriform cortex, thalamus, or amygdala. Compared to baseline, 11C-PK11195 binding potential increased at 48 h after SE and peaked between 7 and 14 days after SE depending on the brain region (by max. 88%, p<0.0001) which was also reflected by histology. In regions where BBB impairment was detected, neuroinflammation was maintained at 14 days after SE, whereas it was almost back to baseline in non-epileptogenic regions.
Conclusion: After generalized alterations in the acute phase directly after SE, alterations are mainly restricted to temporal regions suggested to be involved in epileptogenesis as amygdala, piriform cortex and hippocampus. BBB opening seems to be an early change preceding microglia activation. Glucose and amino acid turnover evaluation reveal important insight into epileptogenic brain changes, but seem not to reveal additional information about epileptogenesis-associated brain inflammation. Research Support: This study was funded by the European Union Seventh’s Framework Programme under grant agreement no. 602102 (EPITARGET).