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

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Science Translational Medicine  04 Dec 2019:
Vol. 11, Issue 521, eaaw8954
DOI: 10.1126/scitranslmed.aaw8954

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Breaking barriers in aging and disease

The blood-brain barrier (BBB) regulates the communication between the vasculature and the brain. Aging and neurological disorders have been associated with BBB defects. Now, Milikovsky et al. and Senatorov et al. studied the consequences of BBB impairments in aging and disease. Milikovsky et al. found that in patients with epilepsy or Alzheimer’s disease, as well as in aging mice, BBB impairments were spatially associated with transient electroencephalographic abnormalities. Senatorov et al. extended the study at the molecular level, showing that BBB breakdown triggered transforming growth factor–β (TGFβ) signaling in astrocytes and cognitive impairments in aging rodents. Similar abnormalities were also found in brain tissue from aging individuals. TGFβ inhibition in aged mice reversed the pathological phenotype.


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.

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