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

Dan Z Milikovsky1, Jonathan Ofer1, Vladimir V Senatorov Jr2,3,4, Aaron R Friedman3, Ofer Prager1, Liron Sheintuch1, Netta Elazari1, Ronel Veksler1, Daniel Zelig1, Itai Weissberg1, Guy Bar-Klein5, Evyatar Swissa1, Erez Hanael6, Gal Ben-Arie7, Osnat Schefenbauer1, Lyna Kamintsky8, Rotem Saar-Ashkenazy1,9, Ilan Shelef7, Merav H Shamir6, Ilan Goldberg10, Amir Glik11,12,13, Felix Benninger11,13, Daniela Kaufer2,3, Alon Friedman14,8

  1. Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
  2. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
  3. Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  4. Berkeley Stem Cell Center, University of California, Berkeley, Berkeley, CA 94720, USA.
  5. Howard Hughes Medical Institute and the Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  6. Koret School of Veterinary Medicine, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
  7. Department of Medical Imaging, Soroka University Medical Center, Beer-Sheva 84105, Israel.
  8. Department of Medical Neuroscience, Dalhousie University, Halifax, NS B3H4R2, Canada.
  9. Faculty of Social Work, Ashkelon Academic College, Ashkelon 78211, Israel.
  10. Department of Neurology, Wolfson Medical Center, Holon 58100, Israel.
  11. Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 49100, Israel.
  12. Cognitive Neurology Clinic, Rabin Medical Center, Beilinson Hospital, Petach Tikva 49100, Israel.
  13. Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
  14. Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. alon.friedman@dal.ca.

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.

Presented By Dan Milikovsky

Neuroscience, MedicineNicholas Liao2019-12 (Dec)