Epileptiform activity is a common occurrence in the brains of people with Alzheimer disease (AD), but the underlying mechanisms are poorly understood. A new study published in Science Translational Medicine identifies a possible EEG-based indicator of subclinical seizure activity in patients with AD and suggests a role for blood–brain barrier (BBB) dysfunction in AD-associated epilepsy.

A team led by Alon Friedman, who holds positions at Dalhousie University in Canada and Ben-Gurion University in Israel, examined EEG recordings from 39 individuals: 16 with AD, 12 with mild cognitive impairment and 11 age-matched controls. The recordings revealed a specific pattern of transient slow brain activity, termed paroxysmal slow wave events (PSWEs), that was more frequent in the patients with AD than in the other two groups. The number of PSWEs per minute correlated with the degree of cognitive impairment.

In the next stage of the study, the researchers turned their attention to patients with epilepsy. EEG recordings from these individuals revealed the presence of interictal PSWEs. Most importantly, dynamic contrast-enhanced MRI (DCE-MRI) showed that this activity colocalized with areas of BBB disruption. A similar spatial relationship between PSWEs and BBB dysfunction was identified in three animal models: aged mice, the 5×FAD mouse model of AD and a rat model of status epilepticus.

To investigate the causal link between BBB disruption and PSWEs, Friedman and colleagues performed unilateral intraventricular injections of serum albumin into the brains of young rats. This intervention, which mimicked the effects of breaching the BBB, was found to induce the development of PSWEs in the injected hemisphere.

On the basis of these multiple lines of evidence, the investigators propose a mechanism whereby BBB disruption in AD and other neurological disorders induces PSWEs, which provide an EEG signature of nonconvulsive seizure activity. As the team acknowledge, prospective trials that combine DCE-MRI scans with EEG recordings will be required to test this model.

the investigators propose a mechanism whereby BBB disruption in AD and other neurological disorders induces PSWEs

“We have described a new approach to quantify transient shifts in cortical network activity using a simple, clinically applicable approach,” concludes Friedman. “We further show that breaching the BBB is sufficient to introduce such changes in brain activity.”