More Evidence That Epilepsy Drug Calms Neurons and Boosts Memory

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

Comments

  1. This is a fantastic paper, as it illustrates the translation from rodent electrophysiological experiments into a randomized clinical study toward a novel, promising approach for the treatment of age-related memory disorders, including Alzheimer´s disease (AD). Moreover, the paper draws our attention to the critical role of neuronal hyperactivity for the earliest symptoms of AD (see Busche and Konnerth, 2015). 

    The study contains several very important results: (a) hippocampal networks are hyperactive in patients with amnestic mild cognitive impairment (aMCI), many of whom have early AD; (b) this hyperactivity is directly related to poor performance in a specific memory task; (c) the well-established anti-epileptic drug levetiracetam, at a dose that was more than four times lower than commonly used for the treatment of epilepsy, rescues hippocampal hyperactivity; (d) the restoration of normal activity in the hippocampus leads to improved performance in that memory task (yet not on standard neuropsychological testing).

    Previous work has nicely demonstrated that CA3 hippocampal neurons become abnormally hyperactive in aging-impaired rats (Wilson et al., 2005). This excessive activity results in a failure of the neurons to encode new information rapidly. Hyperactivity of hippocampal neurons has also been shown in memory-impaired mouse models of AD (Busche et al., 2012; Siskova et al., 2014). Several studies in humans with aMCI and even presymptomatic AD have demonstrated that hippocampus hyperactivity is also apparent in macroscopic fMRI signals (O'Brien et al., 2010; Yassa et al., 2010). The direct link between hyperactivity and memory impairment has prompted further studies in animal models and humans to assess whether activity-dampening drugs like levetiracetam could be beneficial (Koh et al., 2010; Bakker et al., 2012; Sanchez et al., 2012).

    By putting all these pieces of information together, the present paper strongly demonstrates that hippocampus hyperactivity is a quantitative diagnostic marker of memory impairment in early AD that responds to a treatment with a low dose of the anti-epileptic drug levetiracetam.

    A surprising and unexpected finding from the present study is that the entorhinal cortex is hypoactive in aMCI, and levetiracetam normalized the activity status of that region. 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. This may also help explain why the higher dose of levetiracetam did not rescue hippocampal hyperactivity. Moreover, this finding indicates that both hyper- and hypoactivity play a role in AD and that their specific contributions to the disease pathophysiology, and their underlying causes, are still largely unknown. Finally, it would be interesting to see whether the low dose of levetiracetam has any effect on epileptiform activity that can be associated with early AD (Vossel et al., 2013). 

     

    References:

    Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. 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.

    Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. Epub 2012 May 16 PubMed.

    Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. PubMed.

    O'Brien JL, O'Keefe KM, Laviolette PS, Deluca AN, Blacker D, Dickerson BC, Sperling RA. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 2010 Jun 15;74(24):1969-76. PubMed.

    Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.

    Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13 PubMed.

    Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013 Sep 1;70(9):1158-66. PubMed.

    Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci. 2005 Jul 20;25(29):6877-86. 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.

    View all comments by Marc Aurel Busche

  2. This new study by Dr. Gallagher and colleagues provides valuable data in multiple groups of MCI patients to support the hypothesis that a) abnormalities of neural network function are important contributors to memory deficits in MCI; b) targeting these physiologic/functional abnormalities with specific treatments can ameliorate memory deficits; c) such treatment provides benefits by normalizing hippocampal function. These results, in conjunction with a series of other findings in the field (including Bakker et al.’s prior findings, and those by Lennart Mucke and colleagues), make a strong case for the need for further studies of physiologic neural network-level abnormalities in AD and related disorders, and also for the targeting of these abnormalities for novel approaches to treatment.

    View all comments by Brad Dickerson

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References

News Citations

  1. Research Brief: Hippocampal Hyperactivity Tied to Early MCI Atrophy
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?
  3. Epilepsy Drug Calms the Hippocampus, Aids Memory
  4. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
  5. Aβ, Neural Activity Linked to DNA Damage

Paper Citations

  1. 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.
  2. 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.
  3. Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci. 2011 Oct;34(10):515-25. PubMed.
  4. 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.

Further Reading

Papers

  1. Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009 Apr;66(4):435-40. Epub 2009 Feb 9 PubMed.

Primary Papers

  1. 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.

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