Abnormal brain activity characteristic of patients with Alzheimer’s disease (AD) can be “normalized” with a single intravenous infusion of high-dose levetiracetam (LEV) (multiple brands), although treatment has no effect on cognitive function, new research shows.
“The failure of amyloid therapies in Alzheimer’s disease has opened up interest in other avenues to try and treat this disease,” Daniel Press, MD, Berenson-Allen Center for Noninvasive Brain Stimulation at the Beth Deaconess Medical Center in Boston, Massachusetts, told.
“We saw essentially normalization of abnormalities on patients’ electroencephalographic [EEG] profiles with a single acute dose of the medication. You never know which avenue is going to be the one that leads to something successful, but results are definitely encouraging,” he added.
The study was published online June 23 in the Journal of Alzheimer’s Disease.
Normalized EEGs
Seven patients with mild AD completed the feasibility study. Mild AD was defined as a patient’s having a score of 20 to 29 on the Mini–Mental Status Examination.
“All the included participants received standard treatment with acetylcholinesterase inhibitors,” the investigators write.
Although 12 participants were originally enrolled in the study, three did not complete the protocol because of experiencing claustrophobia while undergoing MRI, and one patient refused to undergo cognitive testing.
Participants received either a low-dose or a high-dose bolus of intravenous levetiracetam (2.5 mg/kg or 7.5 mg/kg, respectively) or placebo in a double-blind, within-subject protocol. EEGs were taken at rest and before and after patients received the antiseizure medication.
To quantify brain activity and to identify where it was taking place, patients subsequently underwent MRI to measure blood flow to various regions in the brain.
Study participants underwent cognitive testing to assess frontal executive function, declarative memory, and overall cognitive performance.
Reporting only on EEG changes, Dr Press and colleagues note that only high-dose levetiracetam had a beneficial effect on abnormalities in brain activity.
“In the current study, we found that administration of high-dose LEV led to a decrease in coherence in the delta band and increases in beta1, beta2, and beta3 bands,” the researchers write.
“This pattern of increases in coherence in higher frequency bands and decreases in lower frequency band represents normalization of EEG abnormalities typically seen in patients with AD,” they add.
Dr Press noted that there was no improvement in cognition after treatment.
“However, I think that’s largely because we gave levetiracetam as a single dose,” he said.
Dr Press and colleagues are currently planning a larger study to assess the effect on cognitive function using the same approach. In that study, levetiracetam will be given more frequently.
Therapeutic Potential
Commenting on the findings, Arnold Bakker, PhD, assistant professor of psychiatry and behavioral sciences, the Johns Hopkins University School of Medicine, Baltimore, Maryland, corroborated the study authors’ observations that abnormal brain activation, typically seen in patients with seizures, are also evident in AD patients.
“This abnormal activation is referred to as subclinical epileptiform activity, as these patients typically don’t have clinically evident seizures,” said Dr Bakker.
“But abnormal brain activation has been associated with cognitive deficits and thus provides a new potential approach to the treatment of cognitive impairment in Alzheimer’s disease,” he added.
Dr Bakker and colleagues have published several studies in which they evaluated the use of levetiracetam in patients with amnestic mild cognitive impairment.
Findings revealed that short-term treatment with low-dose levetiracetam successfully normalized abnormal activation in the hippocampus, Dr Bakker pointed out.
Furthermore, the same treatment improved memory function in patients with MCI.
“These results strongly support the idea that elevated activation plays an important role in the memory impairment observed in these patients and that targeting this condition with levetiracetam has therapeutic potential,” Dr Bakker said.
“The work by Dr Press further supports earlier reported findings that abnormal or subclinical epileptic activity can be observed in patients with Alzheimer’s disease. Given the failure of other treatment approaches to this disease, this is an important avenue to explore,” he added.
The study was supported by a grant from the Fidelity Biosciences Research Initiative and private donations. Neither Dr Press nor Dr Bakker have disclosed any relevant financial relationships.
J Alzheimers Dis. Published online June 23, 2017.
