Imaging Blood-Brain Barrier Dysfunction as a Biomarker for Epileptogenesis

Brain. 2017 Jun 1;140(6):1692-1705. doi: 10.1093/brain/awx073.

Abstract

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Keywords: biomarker; blood–brain barrier; epilepsy; magnetic resonance imaging.

MeSH terms

  • Anesthesia, Inhalation
  • Anesthetics, Inhalation / administration & dosage
  • Anesthetics, Inhalation / pharmacology*
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Biomarkers
  • Blood-Brain Barrier / diagnostic imaging*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiopathology*
  • Disease Models, Animal
  • Electrocorticography
  • Isoflurane / administration & dosage
  • Isoflurane / pharmacology*
  • Losartan / administration & dosage
  • Losartan / pharmacology*
  • Magnetic Resonance Imaging / methods*
  • Male
  • Prospective Studies
  • Rats
  • Rats, Sprague-Dawley
  • Status Epilepticus / diagnostic imaging*
  • Status Epilepticus / drug therapy
  • Status Epilepticus / physiopathology*

Substances

  • Anesthetics, Inhalation
  • Angiotensin II Type 1 Receptor Blockers
  • Biomarkers
  • Isoflurane
  • Losartan