What is the effect of 4 weeks of treatment with low-dose levetiracetam on cognitive function in patients with Alzheimer disease (AD)?
In this randomized clinical trial of 34 adults with AD, treatment with levetiracetam did not significantly modify cognitive function. However, the treatment did improve executive function and spatial memory among participants with AD who had seizures or subclinical epileptiform activity that was identified through extended neurophysiological recordings.
This study’s findings indicated that extended neurophysiological assessments are important to identify patients with AD who could benefit from antiseizure approaches and that levetiracetam treatment could improve cognitive symptoms in the estimated 60% of patients with AD who have seizures and subclinical epileptiform activity.
Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).
To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.
Design, Setting, and Participants
The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.
Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.
Main Outcomes and Measures
The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.
Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, −0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.
Conclusions and Relevance
In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.
ClinicalTrials.gov Identifier: NCT02002819
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: August 5, 2021.
Published Online: September 27, 2021. doi:10.1001/jamaneurol.2021.3310
Corresponding Author: Keith Vossel, MD, MSc, Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, 710 Westwood Plaza, RNRC C-224, Los Angeles, CA 90095 (email@example.com).
Author Contributions: Drs Vossel and Ranasinghe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Vossel, Ranasinghe, Mucke, Possin, Boxer, Miller, Nagarajan, Kirsch.
Acquisition, analysis, or interpretation of data: Vossel, Ranasinghe, Beagle, La, Ah Pook, Castro, Mizuiri, Honma, Venkateswaran, Koestler, Zhang, Mucke, Howell, Possin, Kramer, Boxer, Nagarajan, Kirsch.
Drafting of the manuscript: Vossel, Ranasinghe, La, Ah Pook, Howell, Kramer.
Critical revision of the manuscript for important intellectual content: Vossel, Ranasinghe, Beagle, Castro, Mizuiri, Honma, Venkateswaran, Koestler, Zhang, Mucke, Possin, Boxer, Miller, Nagarajan, Kirsch.
Statistical analysis: Vossel, Ranasinghe, Venkateswaran, Mucke, Possin, Nagarajan.
Obtained funding: Vossel, Mucke.
Administrative, technical, or material support: Vossel, Beagle, La, Castro, Mizuiri, Honma, Venkateswaran, Koestler, Zhang, Howell, Boxer, Miller, Nagarajan.
Supervision: Vossel, Ranasinghe, Boxer, Miller, Nagarajan.
Conflict of Interest Disclosures: Dr Vossel reported receiving grants from the Alzheimer’s Association and the National Institute on Aging, National Institutes of Health and donations from the Fineberg Foundation, the N. Bud and Beverly Grossman Foundation, and the S. D. Bechtel, Jr. Foundation during the conduct of the study. Dr Mucke reported receiving grants from the S. D. Bechtel, Jr. Foundation during the conduct of the study and research funding for an independent project from Cure Network Dolby Acceleration Partners; personal fees from Eisai and Takeda Pharmaceutical; and serving on the scientific advisory boards of Acumen, Alkahest, Arvinas, Biogen, and Dolby Family Ventures outside the submitted work. Dr Possin reported receiving grants from the Global Brain Health Institute, the National Institutes of Health, the Rainwater Charitable Foundation, and Quest Diagnostics during the conduct of the study and personal fees from ClearView Healthcare Partners and Vanguard outside the submitted work. Dr Boxer reported receiving grants from the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, the Association for Frontotemporal Degeneration, Biogen, the Bluefield Project to Cure Frontotemporal Dementia, Eisai, Eli Lilly and Company, the National Institutes of Health, the Rainwater Charitable Foundation, Regeneron Pharmaceuticals, and the State of California; personal fees from Alector, Applied Genetic Technologies, Arkuda Therapeutics, Arvinas, AZTherapies, GlaxoSmithKline, Humana, Lundbeck, Oligomerix, Roche, the Roissy Foundation, Stealth BioTherapeutics, Transposon Therapeutics, TrueBinding, UCB, and Wave Pharma; and nonfinancial support from Eli Lilly and Company and Novartis; and serving as a consultant for Applied Genetic Technologies, Alector, Arkuda Therapeutics, Arvinas, Asceneuron, AZTherapies, BioAge Labs, GlaxoSmithKline, Humana, Oligomerix, Ono Pharmaceutical, Roche, Samumed, Sangamo Therapeutics, Stealth BioTherapeutics, Third Rock Ventures, Transposon Therapeutics, and Wave Pharma outside the submitted work. Dr Miller reported receiving grants from the Bluefield Project to Cure Frontotemporal Dementia and royalties from the Cambridge University Press, Guilford Press, John Hopkins Press, and Oxford University Press; being the editor-in-chief of Neurocase and a section editor of Frontiers in Neurology; serving as a scientific advisor, consultant, or board member for the Bluefield Project to Cure Frontotemporal Dementia, Biogen, the Buck Institute for Research on Aging, the National Institute for Health Research Cambridge Biomedical Research Centre and its Biomedical Research Unit in Dementia, the John Douglas French Alzheimer’s Foundation, the Larry L. Hillblom Foundation, the Massachusetts General Hospital/Harvard Medical School Alzheimer’s Disease Research Center, the Rainwater Charitable Foundation, SafelyYou, the Stanford Alzheimer’s Disease Research Center, The University of Texas at Dallas Center for BrainHealth, and the University of Washington Alzheimer’s Disease Research Center outside the submitted work. Dr Nagarajan reported receiving grants from RICOH MEG outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by grant PCTRB-13-288476 from the Alzheimer’s Association made possible by Part the Cloud (Dr Vossel); grants K23 AG038357 (Dr Vossel), K08 AG058749 (Dr Ranasinghe), F32 AG050434 (Dr Ranasinghe), R01 NS100440 (Dr Nagarajan), RF1 AG062196 (Dr Nagarajan), R01 DC017696 (Dr Nagarajan), P50 AG023501 (Dr Miller), and P01 AG19724 (Dr Miller) from the National Institutes of Health; grant 2015-A-034-FEL from the Larry L. Hillblom Foundation (Dr Ranasinghe), and funding from the Fineberg Foundation (Dr Vossel), the N. Bud and Beverly Grossman Foundation (Dr Vossel), and the S. D. Bechtel, Jr. Foundation (Drs Vossel and Mucke).
Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the participants and study partners for their generous time and commitment to this study. Marcos Contreras, PharmD, of the University of California, San Francisco, Drug Product Services Laboratory, and Karen Muir, RPh, of Safeway Compounding Pharmacy created and maintained the blinded randomization scheme. Deborah Barnes, PhD, of the University of California, San Francisco, provided advice on study design. Kirsten Peterson, RPSGT, and Amy Pearson, RPSGT, of the University of Minnesota provided technical assistance with sleep and electroencephalography studies. Sarah Ellis, CCRC, and Deanna Dickens, MD, of United Hospital assisted with setting up the magnetoencephalography plus electroencephalography research studies. Robert Rissman, PhD, of the University of California, San Diego, performed cerebrospinal fluid analysis on 3 samples. Melissa Terpstra, PhD, of the University of Minnesota assisted with setting up the magnetic resonance imaging research protocol. Zuzan Cayci, MD, of the University of Minnesota read the results of amyloid positron emission tomography for 1 participant. None of these individuals received financial compensation for their contributions.
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