title: Non-invasive PET imaging of brain inflammation at disease onset predicts spontaneous recurrent seizures and reflects comorbidities.
abstract: Brain inflammation is an important factor in the conversion of a healthy brain into an epileptic one, a phenomenon known as epileptogenesis, offering a new entry point for prognostic tools. The development of anti-epileptogenic therapies to treat before or at disease onset is hampered by our inability to predict the severity of the disease outcome. In a rat model of temporal lobe epilepsy we aimed to assess whether in vivo non-invasive imaging of brain inflammation at disease onset was predictive of spontaneous recurrent seizures (SRS) frequency and severity of depression-like and sensorimotor-related comorbidities. To this end, translocator protein, a biomarker of inflammation, was imaged by means of positron emission tomography (PET) 2 and 4weeks post-status epilepticus using [18F]-PBR111. Translocator protein was highly upregulated 2weeks post-status epilepticus in limbic structures (up to 2.1-fold increase compared to controls in temporal lobe, P<0.001), whereas 4weeks post-status epilepticus, upregulation decreased (up to 1.6-fold increase compared to controls in temporal lobe, P<0.01) and was only apparent in a subset of these regions. Animals were monitored with video-electroencephalography during all stages of disease (acute, latent - first seizures appearing around 2weeks post-status epilepticus - and chronic phases), for a total of 12weeks, in order to determine SRS frequency for each subject (range 0.00-0.83SRS/day). We found that regional PET uptake at 2 and 4weeks post-status epilepticus correlated with the severity of depression-like and sensorimotor-related comorbidities during chronic epilepsy (P<0.05 for each test). Regional PET imaging did not correlate with SRS frequency, however, by applying a multivariate data-driven modeling approach based on translocator protein PET imaging at 2weeks post-status epilepticus, we accurately predicted the frequency of SRS (R=0.92; R2=0.86; P<0.0001) at the onset of epilepsy. This study not only demonstrates non-invasive imaging of translocator protein as a prognostic biomarker to ascertain SRS frequency, but also shows its capability to reflect the severity of depression-like and sensorimotor-related comorbidities. Our results are an encouraging step towards the development of anti-epileptogenic treatments by providing early quantitative assessment of SRS frequency and severity of comorbidities with high clinical relevance.
authors.affiliation: University of Antwerp, Department of Translational Neurosciences, Wilrijk, Belgium.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bertoglio
authors.affiliation: University of Antwerp, Molecular Imaging Center Antwerp, Wilrijk, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Verhaeghe
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Santermans
authors.affiliation: University of Antwerp, Department of Translational Neurosciences, Wilrijk, Belgium.
authors.forename: Halima
authors.initials: H
authors.lastname: Amhaoul
authors.affiliation: University of Antwerp, Bio-Imaging Lab, Wilrijk, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jonckers
authors.affiliation: University of Antwerp, Molecular Imaging Center Antwerp, Wilrijk, Belgium; Antwerp University Hospital, Department of Nuclear Medicine, Edegem, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.affiliation: University of Antwerp, Bio-Imaging Lab, Wilrijk, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van Der Linden
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium; Centre for Health Economics Research and Modelling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Niel
authors.initials: N
authors.lastname: Hens
authors.affiliation: University of Antwerp, Molecular Imaging Center Antwerp, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.affiliation: University of Antwerp, Department of Translational Neurosciences, Wilrijk, Belgium. Electronic address: Stefanie.dedeurwaerdere@hotmail.com.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D018450:Disease Progression; D004569:Electroencephalography; D004660:Encephalitis / Q000000981:diagnostic imaging*; D008297:Male; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012640:Seizures / Q000000981:diagnostic imaging*; D013226:Status Epilepticus / Q000000981:diagnostic imaging*
keywords: Biomarker; Comorbidity; Epileptogenesis; PET; Spontaneous recurrent seizures; Translocator protein