Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.

Importance Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD). Objective 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. Interventions 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. Results 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. Trial Registration ClinicalTrials.gov Identifier: NCT02002819.

[1]  G. Csukly,et al.  Subclinical epileptiform activity accelerates the progression of Alzheimer’s disease: A long-term EEG study , 2021, Clinical Neurophysiology.

[2]  M. Albert,et al.  Dementia in late-onset epilepsy , 2020, Neurology.

[3]  Alice D. Lam,et al.  Association of epileptiform abnormalities and seizures in Alzheimer disease , 2020, Neurology.

[4]  A. Danek,et al.  Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course , 2020, Journal of Neurology.

[5]  K. Vossel,et al.  Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline , 2020, Science Translational Medicine.

[6]  W. Henley,et al.  A Longitudinal Study of Epileptic Seizures in Alzheimer's Disease , 2019, Front. Neurol..

[7]  S. Lipton,et al.  Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls , 2019, eLife.

[8]  Alice D. Lam,et al.  New Approaches to Studying Silent Mesial Temporal Lobe Seizures in Alzheimer's Disease , 2019, Front. Neurol..

[9]  Dan J Stein,et al.  Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 , 2019, The Lancet Neurology.

[10]  G. S. Stephens,et al.  ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease. , 2017, Cell reports.

[11]  K. Vossel,et al.  Epileptic activity in Alzheimer's disease: causes and clinical relevance , 2017, The Lancet Neurology.

[12]  Alice D. Lam,et al.  Silent Hippocampal Seizures and Spikes Identified by Foramen Ovale Electrodes in Alzheimer’s Disease , 2017, Nature Medicine.

[13]  Heidi E Kirsch,et al.  Incidence and impact of subclinical epileptiform activity in Alzheimer's disease , 2016, Annals of neurology.

[14]  S. Strittmatter,et al.  Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model , 2015, Alzheimer's Research & Therapy.

[15]  Caroline L. Speck,et al.  Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance , 2015, NeuroImage: Clinical.

[16]  Hong-Guang Xie,et al.  Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice , 2013, CNS neuroscience & therapeutics.

[17]  Howard J. Rosen,et al.  NIH EXAMINER: Conceptualization and Development of an Executive Function Battery , 2013, Journal of the International Neuropsychological Society.

[18]  Heidi E Kirsch,et al.  Seizures and epileptiform activity in the early stages of Alzheimer disease. , 2013, JAMA neurology.

[19]  Keith A. Vossel,et al.  Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model , 2012, Proceedings of the National Academy of Sciences.

[20]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[21]  W. M. van der Flier,et al.  Prevalence and Clinical Significance of Epileptiform EEG Discharges in a Large Memory Clinic Cohort , 2010, Dementia and Geriatric Cognitive Disorders.

[22]  E. Cumbo,et al.  Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease , 2010, Epilepsy & Behavior.

[23]  Yaakov Stern,et al.  Incidence and Predictors of Seizures in Patients with Alzheimer's Disease , 2006, Epilepsia.

[24]  I G McKeith,et al.  The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. , 2000, The British journal of psychiatry : the journal of mental science.

[25]  M. Mega,et al.  The Neuropsychiatric Inventory , 1994, Neurology.

[26]  J. Morris The Clinical Dementia Rating (CDR) , 1993, Neurology.

[27]  K. Davis,et al.  A new rating scale for Alzheimer's disease. , 1984, The American journal of psychiatry.

[28]  S. Folstein,et al.  “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician , 1975 .

[29]  G. Csukly,et al.  Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. , 2018, Journal of Alzheimer's disease : JAD.

[30]  K. Vossel,et al.  Relative Incidence of Seizures and Myoclonus in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia. , 2017, Journal of Alzheimer's disease : JAD.

[31]  Emiliano Santarnecchi,et al.  Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[32]  T. Ichida,et al.  World Medical Association declaration of Helsinki , 2008, Gastroenterologia Japonica.

[33]  M. Mendez,et al.  Seizures in Elderly Patients with Dementia , 2003, Drugs & aging.

[34]  M. Sano,et al.  An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease , 1997, Alzheimer disease and associated disorders.

[35]  S H Ferris,et al.  Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. , 1997, Alzheimer disease and associated disorders.