Levetiracetam calmed hyperactive neurons and improved memory in people with mild cognitive impairment. Those were the conclusions from a Phase 2 clinical trial that treated volunteers with three doses of the anticonvulsant. The study, published February 21 in Neuroimage: Clinical, confirmed and extended positive results from a smaller pilot study, though the highest dose was ineffective. The researchers, led by Michela Gallagher at Johns Hopkins University in Baltimore, are gearing up for a multicenter Phase 3 trial.
Hyperactive neurons in the hippocampus in people with MCI may sound alarm bells that AD is impending (see Dickerson et al., 2005; Busche and Konnerth, 2015). While some researchers have proposed that this heightened activity may compensate for declining cognition, there are studies that suggest that the overzealous firing harms neurons, triggering neurodegeneration and hippocampal atrophy (see Dec 2011 news). Anti-epileptic drugs dampened seizure activity and improved cognition in mouse models of AD (see Sep 2007 news). Gallagher and colleagues found they had similar effects in people. In 2012, she ran a small clinical study with one of these drugs, levetiracetam. According to functional magnetic resonance imaging (fMRI) measurements taken while 17 participants performed a memory task, 125mg twice daily over two weeks reduced hippocampal hyperactivity in people with amnestic MCI (aMCI). It also improved their performance on that memory task (see May 2012 news).
Hyper Hippocampus. In this computerized model of a seizure, hippocampal neurons kick into overdrive. A similar phenomenon may impair memory and damage cells in people with mild cognitive impairment. [Image courtesy of Ivan Soltesz, Flickr Creative Commons.]
For the Phase 2 trial, first author Arnold Bakker and colleagues added a lower (62.5mg) and a higher (250mg) dose to the regimen to find the sweet spot. Fifty-four people with aMCI and 17 cognitively normal controls participated in the study. The primary outcome measure was a decrease in hippocampal hyperactivity, with secondary measures including changes in memory function. Those with aMCI were split evenly among the three dose groups, and randomized to receive the drug or placebo twice daily for two weeks before assessment of neural activity and memory. After a four-week wash-out period, those who were given the drug in the first round were given placebo for two weeks, and vice versa, followed by another assessment. This allowed the researchers to compare the way all the volunteers performed with and without the drug.
To measure both neural activity and hippocampal memory function, the volunteers underwent fMRI while they were tested on pattern separation—the ability to distinguish one memory from a different, yet similar, one (see Yassa and Stark, 2011). Volunteers looked at hundreds of images, and classified each as “new,” “old,” or “similar,” to one they had already seen. People with MCI are known to misidentify similar images as old ones (see Yassa et al., 2010). That happened during this study as well: People with MCI made more such errors than healthy controls. However, treatment with 62.5mg or 125mg of levetiracetam restored their performance to normal levels. Functional MRI measurements taken during the task revealed that while people with MCI had a hyperactive hippocampus compared with controls, low doses of the drug quieted this aberrant activity to near-normal levels, an effect that was only statistically significant at the 125mg dose. Interestingly, treatment with 250mg of levetiracetam neither restored memory nor reduced hyperactivity.
In addition to looking at hyperactivity in the hippocampus, the researchers scrutinized its next-door neighbor, the entorhinal cortex (EC). The EC both receives and delivers signals to the hippocampus, and is one of the first areas affected by amyloid pathology in AD. As opposed to the hippocampus, the entorhinal cortex displayed less activity in people with aMCI than in normal controls. Treatment with 62.5mg and 125mg of levetiracetam raised EC activity on par with controls. Again, treatment with 250mg of the drug had no effect.
How did levetiracetam dial up EC activity, while turning down overactivity in the hippocampus? Gallagher said the researchers can’t know for sure, but added that it seems the drug only turns down neurons with abnormally high activity, rather than shutting down all neurons equally. Marc Aurel Busche at the Technical University of Munich also found this puzzling. “This effect is hard to understand and highlights the need for further studies to elucidate the precise mechanisms of action of levetiracetam in the context of AD,” he told Alzforum (see full comment below). Gallagher pointed out that while axons emanating from the EC deliver signals to the hippocampus, the signals run the other way as well, and overactive hippocampus could somehow affect the EC.
Researchers were unsure what to make of the ineffectiveness of the highest dose of levetiracetam. However, the findings are in keeping with those of animal studies, in which the drug also proved ineffective at a higher dose. Dosages for people with epilepsy are around 15 times higher than the effective doses in this aMCI study.
Lennart Mucke of the University of California, San Francisco, who was not involved in the study, commented that the focused approaches employed in Gallagher’s two clinical studies form a solid foundation from which to move forward with a larger Phase 3 trial. Previous work in his lab implicated hyperactivity as a cause of synaptic deficits and neuronal DNA damage in an AD mouse model, and treatment with levetiracetam prevented these abnormalities (see Aug 2012 news and Mar 2013 news). On that basis, he proposed that the drug could potentially have disease-modifying effects—those that slow the neurodegenerative process, rather than just treat symptoms.
“People tend to cleanly differentiate between symptomatic versus disease-modifying therapeutics, but I think we are beginning to realize that the distinction can be muddy,” Mucke said. “There is a real chance that levetiracetam may be sitting on the border of having both symptomatic and disease-modifying effects.”
Gallagher plans to test that very hypothesis in a Phase 3 trial, which will be conducted by AgeneBio, the Baltimore company she founded. “When we target overactivity, will it slow progression? To answer this question, we need to do a long study. There’s really no surrogate for it,” she said.
The trial will test levetiracetam in people with MCI due to Alzheimer's disease. The researchers aim to have 250 amyloid-PET-positive people complete each arm of the study. Participants will take the drug (or placebo) once daily for two years, and will be screened for hippocampal atrophy and performance on the pattern-separation test and other standard cognitive and neuropsychiatric tests. Task-related fMRI will not be conducted in the larger trial, Gallagher said, as it would be difficult to standardize the procedure among many centers. Gallagher emphasized that the purpose of the trial will be to test levetiracetam’s effect on disease progression.—Jessica Shugart
- Research Brief: Hippocampal Hyperactivity Tied to Early MCI Atrophy
- Do "Silent" Seizures Cause Network Dysfunction in AD?
- Epilepsy Drug Calms the Hippocampus, Aids Memory
- Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
- Aβ, Neural Activity Linked to DNA Damage
- Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, Bertram L, Mullin K, Tanzi RE, Blacker D, Albert MS, Sperling RA. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005 Aug 9;65(3):404-11. PubMed.
- Busche MA, Konnerth A. Neuronal hyperactivity--A key defect in Alzheimer's disease?. Bioessays. 2015 Jun;37(6):624-32. Epub 2015 Mar 14 PubMed.
- Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci. 2011 Oct;34(10):515-25. PubMed.
- Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242-52. PubMed.
- Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009 Apr;66(4):435-40. Epub 2009 Feb 9 PubMed.
- Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688-98. Epub 2015 Feb 21 PubMed.