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.
Bibliographical noteFunding Information:
This research was supported by the European Union’s Seventh Framework Program (FP7/2007-2013, grant agreement 602102, EPITARGET) to A.F., the Israel Science Foundation (717/15) (to A.F.), the Binational Israel-USA Science Foundation (to D.K. and A.F.), a Bakar Foundation Fellowship and the Archer Foundation Award (to D.K.), NSF GRFP fellowships (to V.V.S. and A.R.F.), and the Canadian Institute of Health Research (CIHR 366355) (to A.F.).
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