A randomized, double‐blind, placebo‐controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults

Schoenberg, Mike R.; Rum, Ruba; Osborn, Katie E.; Werz, Mary Ann

doi:10.1111/epi.13849

Cited by 28 publications

(15 citation statements)

References 28 publications

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“…Our data suggest that a detrimental consequence of aberrantly activating quiescent NSCs is the premature exhaustion of a finite NSC pool. Treatment with antiepileptic drugs effectively controls seizures and restores the dynamics of neurogenesis, but is not necessarily optimal for long-term use due to possible adverse effects (Eddy et al, 2011; Schoenberg et al, 2017). Thus, therapeutic strategies to enhance neurogenesis may hold great promise for the treatment of cognitive and/or mood disorders, but care must be taken to stimulate the right cell types to increase neurogenic output but not deplete the NSC pool.…”

Section: Discussionmentioning

confidence: 99%

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Iascone

Petrof

et al. 2019

Cell Reports

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SUMMARY Adult hippocampal neurogenesis has been reported to be decreased, increased, or not changed in Alzheimer’s disease (AD) patients and related transgenic mouse models. These disparate findings may relate to differences in disease stage, or the presence of seizures, which are associated with AD and can stimulate neurogenesis. In this study, we investigate a transgenic mouse model of AD that exhibits seizures similarly to AD patients and find that neurogenesis is increased in early stages of disease, as spontaneous seizures became evident, but is decreased below control levels as seizures recur. Treatment with the antiseizure drug levetiracetam restores neurogenesis and improves performance in a neurogenesis-associated spatial discrimination task. Our results suggest that seizures stimulate, and later accelerate the depletion of, the hippocampal neural stem cell pool. These results have implications for AD as well as any disorder accompanied by recurrent seizures, such as epilepsy.

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Section: Discussionmentioning

confidence: 99%

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Iascone

Petrof

et al. 2019

Cell Reports

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“…Levetiracetam, an anti-epileptic drug, successfully reverses hyperexcitability and learning and memory deficits in an hAPP FAD mouse model of AD [103, 104] and in aged mice [105–107]. Cognitively normal elderly, amnestic mild cognitive impairment (MCI), and AD patients all show cognitive improvement following chronic levetiracetam administration [108–110]. Thus, GABAergic dysfunction contributes to network-wide deficits in AD, which may in turn harm cognition.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

Najm

Jones

Huang

2019

Mol Neurodegeneration

120

126

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Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4’s detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

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“…Levetiracetam is currently the drug of first choice, and lacosamide has also shown its therapeutic benefits as add-on therapy early after its introduction into epilepsy therapy. Both drugs are well tolerated by patients and demonstrate low adverse effects and an absence of a significant impact on cognition and memory ( 44 – 47 ). From electrophysiological perspective, these observations are supported by our experimental study, which demonstrates the absence of any suppressive effect of these drugs on the SWR generation.…”

Section: Discussionmentioning

confidence: 99%

Lacosamide and Levetiracetam Have No Effect on Sharp-Wave Ripple Rate

et al. 2017

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Pathological high-frequency oscillations are a novel marker used to improve the delineation of epileptogenic tissue and, hence, the outcome of epilepsy surgery. Their practical clinical utilization is curtailed by the inability to discriminate them from physiological oscillations due to frequency overlap. Although it is well documented that pathological HFOs are suppressed by antiepileptic drugs (AEDs), the effect of AEDs on normal HFOs is not well known. In this experimental study, we have explored whether physiological HFOs (sharp-wave ripples) of hippocampal origin respond to AED treatment. The results show that application of a single dose of levetiracetam or lacosamide does not reduce the rate of sharp-wave ripples. In addition, it seems that these new generation drugs do not negatively affect the cellular and network mechanisms involved in sharp-wave ripple generation, which may provide a plausible explanation for the absence of significant negative effects on cognitive functions of these drugs, particularly on memory.

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A randomized, double‐blind, placebo‐controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults

Abstract: LEV was well tolerated in this elderly population in terms of cognition, mood, and balance. When anticonvulsant medication is indicated for older adults, LEV has pharmacokinetic advantages, and these data indicate no adverse impact on cognition or balance.

Cited by 28 publications

References 28 publications

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

Lacosamide and Levetiracetam Have No Effect on Sharp-Wave Ripple Rate

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