Data-driven modeling of brain inflammation predicts spontaneous seizures and abnormal behavior in a model of temporal lobe epilepsy
Abstract number :
1.085
Submission category :
1. Translational Research: 1E. Biomarkers
Year :
2016
Submission ID :
194058
Source :
www.aesnet.org
Presentation date :
12/3/2016 12:00:00 AM
Published date :
Nov 21, 2016, 18:00 PM
Authors :
Stefanie Dedeurwaerdere, University of Antwerp; Daniele Bertoglio, University of Antwerp; Eva Santermans, Hasselt University; Halima Amhaoul, University of Antwerp; Elisabeth Jonckers, university of Antwerp; Leonie Wyffels, University Hospital Antwerp; Da
Rationale: Acquired epilepsy occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult. About 50% of adults with epilepsy have at least one comorbid medical disorder (e.g. anxiety or depression), resulting in a devastating impact on the patients' every-day life. For this reason, there is an urgent need for the development of biomarkers targeting mechanisms important in disease ontogenesis to help with the early detection and treatment of epilepsy and its comorbidities. Brain inflammation is a key factor in the pathology of various types of epilepsy, including temporal lobe epilepsy (TLE). Translocator protein (TSPO), a hallmark of brain inflammation, is upregulated during disease ontogenesis. The aim of this study was to determine whether TSPO Positron Emission Tomography (PET) imaging during epileptogenesis could predict spontaneous seizures and abnormal behavior in the kainic acid-induced status epilepticus (KASE) model of temporal lobe epilepsy. Methods: PET imaging of neuroinflammation with TSPO ligand 18F-PBR111 and T2 MRI scans were acquired 2 and 4 w after Status Epilepticus (SE) (epileptogenesis) in 6 control and 15 KASE rats. Detection of SRS was performed by means of video-EEG recordings for 12 w after SE. Abnormal behavior was evaluated via the whisker nuisance task (WNT) 9 and 11 weeks post-SE, a sucrose preference test (SPT) and the forced swim test (FST) 12 weeks post-SE (chronic epilepsy). Additionally, based on the 2 weeks post-SE 18F-PBR111 uptake in 10 different Volumes of Interest (VOIs), principal component analysis (PCA) was performed to differentiate patterns of uptake across the animals as well as partial least squares (PLS) regression to construct a predictive model of SRS frequency. Results: 18F-PBR111 PET binding in the individual VOIs 2 w post-SE was highly increased in KASE rats compared to control animals in limbic structures, whereas at 4 w post-SE 18F-PBR111 PET binding was only significantly increased in a subset of brain regions in KASE animals. Volumetric MRI analysis showed significant reduction of hippocampal volume in KASE rats 2 weeks post-SE (p< 0.05), while 4 w post-SE also enlargement of ventricles was detected (p< 0.05). KASE rats exhibited abnormal behavior during WNT 9 w post-SE (p< 0.01) and 11 w post-SE (p = 0.048). KASE rats exhibited a reduced immobility time (p< 0.01) and they presented lower sucrose preference (anhedonia) during the SPT (p< 0.01). PCA was able to discriminate animals according to the severity of the disease, while using PLS regression a model was constructed which was able to predict the SRS frequency each animal will experience (R2 = 0.86). Finally, strong correlations were found between 18F-PBR111 uptake in relevant regions during epileptogenesis and behavioral tests during chronic epilepsy. Conclusions: Our findings provide a direct link between brain neuroinflammation during epileptogenesis, the development of SRS and comorbidities during chronic epilepsy. TSPO PET imaging can predict SRS frequency and severity of comorbidities in the KASE model of acquired epilepsy. This approach could have a key role in the identification of subjects to include in anti-epileptogenic preclinical trials and might lead to further understanding of the processes mediating the development of these disorders. Funding: BOF, FWO and Q.E.M.F.
Translational Research