Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction

Dan Z. Milikovsky, Jonathan Ofer, Vladimir V. Senatorov, Aaron R. Friedman, Ofer Prager, Liron Sheintuch, Netta Elazari, Ronel Veksler, Daniel Zelig, Itai Weissberg, Guy Bar-Klein, Evyatar Swissa, Erez Hanael, Gal Ben-Arie, Osnat Schefenbauer, Lyna Kamintsky, Rotem Saar-Ashkenazy, Ilan Shelef, Merav H. Shamir, Ilan GoldbergAmir Glik, Felix Benninger, Daniela Kaufer, Alon Friedman

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer’s disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus–induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Original languageEnglish
Article numbereaaw8954
JournalScience Translational Medicine
Volume11
Issue number521
DOIs
StatePublished - 4 Dec 2019

ASJC Scopus subject areas

  • Medicine (all)

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