Leaky Blood–Brain Barrier: A Double Whammy for the Brain

Abstract

Blood–Brain Barrier Dysfunction in Aging Induces Hyperactivation of TGFβ Signaling and Chronic Yet Reversible Neural Dysfunction Senatorov VV Jr, Friedman AR, Milikovsky DZ, et al. Sci Transl Med. 2019;11(521):eaaw8283. doi:10.1126/scitranslmed.aaw8283. A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer 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 3 rodent models with BBB pathology: aged mice, young 5× 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 naive 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.