WASHINGTON, DC — Researchers have identified epileptiform abnormalities in patients with late-onset Alzheimer’s disease (AD).
A previous study suggested that people with early-onset AD have subclinical epileptiform activity, and researchers wondered whether this is the case with late-onset AD, which is more common, lead study author, Alice D. Lam, MD, PhD, instructor in neurology, Massachusetts General Hospital, Boston, told Medscape Medical News.
“So the question is, over the age of 65 or so, do you still see that same increase in hyper-excitability, the same subclinical epileptiform discharges?”
This could be important as the population ages. In addition, recent evidence suggests that the incidence of epilepsy is increasing among older people.
The findings were presented here at the American Epilepsy Society (AES) 71st Annual Meeting 2017.
Alzheimer’s Biomarker?
The study included 19 participants: 8 cognitively normal control persons (mean age, 71 years), 7 with amnestic mild cognitive impairment (aMCI) (mean age, 74 years), and 4 with mild AD dementia (mean age, 74 years).
Dr Lam noted that the dementia diagnosis was based on clinical evidence and consensus opinion, not on biomarkers of, for example, amyloid or tau.
None of the participants had been diagnosed with epilepsy or had risk factors for epilepsy.
Participants underwent scalp electroencephalography (EEG), and the recordings were analyzed by a board-certified clinical neurophysiologist for epileptiform discharges and other abnormalities. The assessor was blinded to the participants’ cognitive status.
About 45% of the patients with aMCI and AD had subclinical epileptiform discharges. This included 3 of the 7 patients with aMCI and 2 of the 4 with AD. None of the controls had such discharges.
“We know that some AD patients have epilepsy and you might expect to see spikes in these patients, but you would not necessarily have expected to see spikes in patients in the study who weren’t diagnosed with epilepsy,” said Dr Lam.
It’s not clear why some patients with AD have this spike while others don’t, she said. “We’re still at the stages of trying to figure out how prevalent the problem is.”
A “big question” now is whether these spikes are a sort of biomarker of more aggressive AD and whether reducing these discharges will improve the course of AD, said Dr Lam.
“Where this research needs to go next is to try to figure out if this is something that’s driving the process or not. If we can treat the discharges and see improvements in rates of cognitive decline or something along those lines, that would give us a lot better hope that this is sort of a modifiable contributor.”
Memory Disruptor?
Most of the spiking activity observed in the study occurred during sleep, Dr Lam noted.
“That’s really important because a lot of memories are consolidated during sleep; so it’s an intriguing possibility that this spiking behavior can disrupt memory consolidation,” she said.
The epileptiform discharges were in the left temporal region in 2 patients, were in the right temporal region in 1 patient, and were multifocal (left temporal, right temporal, and bi-frontal) in 2 patients.
Focal slowing was seen in four patients and diffuse slowing was seen in three patients with aMCI or mild AD.
There has been a “divide” between experts in the Alzheimer’s field and those in the epilepsy field, noted Dr Lam. Neurologists treating patients in memory clinics “don’t see these clinical seizures,” so they “don’t think it’s something necessarily driving the process” involved in cognition, she said.
But the phenomenon is increasingly being uncovered. In a study published earlier this year, Dr Lam and colleagues inserted electrodes to look directly at mesial temporal lobe activity in patients with AD. “We found silent seizures that no one suspected were happening, as well as a lot of spiking activity.”
In addition to the mesial temporal lobe, epileptiform discharges likely come from the hippocampus. These two areas represent “the anatomical convergence of AD and epilepsy,” said Dr Lam.
Tip of the Iceberg
There is “almost certainly an underestimation” of the extent of spikes in older patients, said Dr Lam. “This is sort of the tip of iceberg. It’s what we see on the surface.”
Currently, in patients suspected of having AD, clinicians look for a reversible cause of worsening cognition. Patients might, for example, undergo brain imaging to rule out a tumor.
Dr Lam believes that using EEG to look for abnormal electrical activity in the brain will become “common practice” as part of that hunt for causes of cognitive decline.
Does accumulation of tau or amyloid proteins have anything to do with these spikes in epileptiform activity? It’s possible, said Dr Lam. She noted that hyperexcitability can release tau from neurons.
Dr Lam’s work is part of a growing body of research in this area. Lennart Mucke, MD, director, Gladstone Institute of Neurological Disease, Joseph B. Martin Distinguished Professor of Neuroscience, and professor of neurology, University of California, San Francisco, is also pursuing this field.
Dr Mucke, who wasn’t involved in the study, said it’s “an informative extension” of his and his colleagues’ previous investigation into an older group of patients with late-onset AD.
“It confirms that nonconvulsive epileptic activity is much more common in this disorder than is widely appreciated.”
The research is also a reminder that detecting epileptic activity in patients with AD requires “sensitive methods” that are “ideally applied during sleep,” said Dr Mucke.
“I predict that equally well designed studies in larger groups of patients will further solidify these conclusions in the future.”
Studying epilepsy in older patients is becoming increasingly important as the incidence of epilepsy increases in this age group. During a lecture at the AES meeting, Colin Josephson, MD, assistant professor, neurology, University of Calgary, Alberta, Canada, cited a recent “landmark” population-based study in Finland showing that the incidence of epilepsy in the elderly increased fourfold in 40 years. Over the same period, the incidence in other age groups did not increase.
It’s not clear, said Dr Josephson, whether the increase in the elderly occurred because people are living longer and so develop comorbid conditions that lead to epilepsy, or if it’s just that clinicians are getting better at detecting epilepsy in older patients.
The investigators and Dr Josephson have disclosed no relevant financial relationships.
American Epilepsy Society (AES) 71st Annual Meeting 2017. Abstract 3.084. Presented December 4, 2017. Dr Josephson’s lecture was presented December 3, 2017.
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