title: Longitudinal assessment of blood-brain barrier leakage during epileptogenesis in rats. A quantitative MRI study.
abstract: The blood-brain barrier (BBB) plays an important role in the homeostasis of the brain. BBB dysfunction has been implicated in the pathophysiology of various neurological disorders, including epilepsy in which it may contribute to disease progression. Precise understanding of BBB dynamics during epileptogenesis may be of importance for the assessment of future therapies, including BBB leakage blocking-agents. Longitudinal changes in BBB integrity can be studied with in vivo magnetic resonance imaging (MRI) in combination with paramagnetic contrast agents. Although this approach has shown to be suitable to detect major BBB leakage during the acute phase in experimental epilepsy models, so far no studies have provided information on dynamics of the extent of BBB leakage towards later phases. Therefore a sensitive and quantitative approach was used in the present study, involving fast T1 mapping (dynamic approach) during a steady-state infusion of gadobutrol, as well as pre- and post-contrast T1-weighted MRI (post-pre approach). This was applied in an experimental epilepsy model in which previous MRI studies failed to detect BBB leakage during epileptogenesis. Adult male Sprague-Dawley rats were injected with kainic acid to induce status epilepticus (SE). MRI experiments were performed before SE (control) and during the acute (1 day) and chronic epileptic phases (6 weeks after SE). BBB leakage was quantified by fast T1 mapping (Look-Locker gradient echo MRI) with a time resolution of 48 s from 5 min before up to 45 min after 20 min step-down infusion of 0.2M gadobutrol. In addition, T1-weighted MRI was acquired before and 45 min after infusion. MRI data were compared to post-mortem microscopic analysis using the BBB tracer fluorescein. Our MRI data showed BBB leakage, which was evident at 1 day and 6 weeks after SE in the hippocampus, entorhinal cortex, amygdala and piriform cortex. These findings were confirmed by microscopic analysis of fluorescein leakage. Furthermore, our MRI data revealed non-uniform BBB leakage throughout epileptogenesis. This study demonstrates BBB leakage in specific brain regions during epileptogenesis, which can be quantified using MRI. Therefore, MRI may be a valuable tool for experimental or clinical studies to elucidate the role of the BBB in epileptogenesis.
authors: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands; Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands. Electronic address: e.a.vanvliet@uva.nl.
authors: E A
authors: EA
authors: van Vliet
authors: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pediatric Neurology, Rudolf Magnus Institute of Neuroscience, University medical Center Utrecht, Utrecht, The Netherlands.
authors: W M
authors: WM
authors: Otte
authors: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands; Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands.
authors: J A
authors: JA
authors: Gorter
authors: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: R M
authors: RM
authors: Dijkhuizen
authors: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands; Epilepsy Institute in The Netherlands Foundation (Stichting Epilepsie Instellingen Nederland, SEIN), Heemstede, The Netherlands.
authors: W J
authors: WJ
authors: Wadman
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology*; D003287:Contrast Media / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000150:complications* / Q000473:pathology*; D013997:Time Factors
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C090600:gadobutrol
keywords: BBB; Blood–brain barrier; FSC; Fluorescein; Gadolinium; KA; Magnetic resonance imaging; SE; Status epilepticus; Temporal lobe epilepsy; blood–brain barrier; fluorescein; kainic acid; status epilepticus