Abstract
AbstractEarly-onset Alzheimer’s disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.
Funder
National Center for Advancing Translational Sciences
National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,General Medicine,Biochemistry
Reference134 articles.
1. Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y (2006) Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia 47(5):867–872. https://doi.org/10.1111/j.1528-1167.2006.00554.x
2. Scarmeas N, Honig LS, Choi H, Cantero J, Brandt J, Blacker D, Albert M, Amatniek JC, Marder K, Bell K, Hauser WA, Stern Y (2009) Seizures in Alzheimer disease: who, when, and how common? Arch Neurol 66(8):992–997. https://doi.org/10.1001/archneurol.2009.130
3. Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ (2017) Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease. Nat Med 23(6):678–680. https://doi.org/10.1038/nm.4330
4. Ackermann RF, Engel J Jr, Phelps ME (1986) Identification of seizure-mediating brain structures with the deoxyglucose method: studies of human epilepsy with positron emission tomography, and animal seizure models with contact autoradiography. Adv Neurol 44:921–934
5. Buckmaster PS, Dudek FE (1997) Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comp Neurol 385(3):385–404
Cited by
26 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献