Epileptic activity in Alzheimer's disease: causes and clinical relevance

Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

[1]  B. Cretin,et al.  Epileptic Prodromal Alzheimer's Disease, a Retrospective Study of 13 New Cases: Expanding the Spectrum of Alzheimer's Disease to an Epileptic Variant? , 2016, Journal of Alzheimer's disease : JAD.

[2]  N. Krogan,et al.  Critical Role of Acetylation in Tau-Mediated Neurodegeneration and Cognitive Deficits , 2015, Nature Medicine.

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

[4]  A. Vortmeyer,et al.  Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons , 2012, Nature Neuroscience.

[5]  Kai Zhang,et al.  Tau Reduction Prevents Aβ-Induced Defects in Axonal Transport , 2010, Science.

[6]  Lief E. Fenno,et al.  Chronic optogenetic activation augments Aβ pathology in a mouse model of Alzheimer disease , 2022 .

[7]  S. Younkin,et al.  Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse and Drosophila Genetic Models of Epilepsy , 2013, The Journal of Neuroscience.

[8]  E. Mandelkow,et al.  Amyloid‐β oligomers induce synaptic damage via Tau‐dependent microtubule severing by TTLL6 and spastin , 2013, The EMBO journal.

[9]  Shagufta Ahmad,et al.  Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids , 2005, Epilepsy Research.

[10]  L. Willmore,et al.  Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection , 2007, Brain Research.

[11]  Shaomin Li,et al.  Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance , 2016, Neurobiology of Disease.

[12]  Zeina N Chemali,et al.  Clinical and Neurophysiologic Characteristics of Unprovoked Seizures in Patients Diagnosed With Dementia. , 2015, The Journal of neuropsychiatry and clinical neurosciences.

[13]  Shaomin Li,et al.  Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake , 2009, Neuron.

[14]  T. Golde,et al.  Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease , 2014, The Journal of Neuroscience.

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

[16]  Hwamee Oh,et al.  Frontotemporal Network Connectivity during Memory Encoding Is Increased with Aging and Disrupted by Beta-Amyloid , 2013, The Journal of Neuroscience.

[17]  Maria Thom,et al.  Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study. , 2011, Brain : a journal of neurology.

[18]  Nick C Fox,et al.  Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. , 2016, Brain : a journal of neurology.

[19]  Chia-Hsiung Cheng,et al.  Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: A meta-analysis , 2011, Epilepsy Research.

[20]  A Hofman,et al.  Clinical features and mortality in patients with early-onset Alzheimer's disease. , 1996, European neurology.

[21]  E. Marsh,et al.  Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer's disease , 2016, Neurobiology of Aging.

[22]  K Patterson,et al.  Focal cortical presentations of Alzheimer's disease. , 2007, Brain : a journal of neurology.

[23]  S. Rothman,et al.  Levetiracetam has a time- and stimulation-dependent effect on synaptic transmission , 2009, Seizure.

[24]  L. Hugonot-Diener,et al.  Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial , 2011, Alzheimer's Research & Therapy.

[25]  D. Neary,et al.  TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype , 2011, Acta Neuropathologica.

[26]  J. Hodges,et al.  The syndrome of transient epileptic amnesia , 2007, Annals of neurology.

[27]  Jukka Peltola,et al.  Immediate effects of deep brain stimulation of anterior thalamic nuclei on executive functions and emotion-attention interaction in humans , 2014, Journal of clinical and experimental neuropsychology.

[28]  C. Jack,et al.  Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. , 2011, Archives of general psychiatry.

[29]  Q. Gong,et al.  Altered functional connectivity in default mode network in absence epilepsy: A resting‐state fMRI study , 2011, Human brain mapping.

[30]  J. McLaurin,et al.  Hippocampal GABAergic neurons are susceptible to amyloid-β toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model. , 2012, Journal of Alzheimer's disease : JAD.

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

[32]  V. Prasher,et al.  Onset of seizures as a poor indicator of longevity in people with down syndrome and dementia , 1993 .

[33]  Yadong Huang,et al.  Apolipoprotein E4 Causes Age- and Tau-Dependent Impairment of GABAergic Interneurons, Leading to Learning and Memory Deficits in Mice , 2010, The Journal of Neuroscience.

[34]  Keith A. Johnson,et al.  Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. , 2015, Brain : a journal of neurology.

[35]  Jeffrey Noebels,et al.  A perfect storm: Converging paths of epilepsy and Alzheimer’s dementia intersect in the hippocampal formation , 2011, Epilepsia.

[36]  R. S. Williams,et al.  A prospective study of Alzheimer disease in Down syndrome. , 1989, Archives of neurology.

[37]  S. Maeda,et al.  Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice , 2016, EMBO reports.

[38]  Edward O. Mann,et al.  Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model , 2012, Cell.

[39]  S. A. Hussaini,et al.  Neuronal activity enhances tau propagation and tau pathology in vivo , 2016, Nature Neuroscience.

[40]  J. Ziburkus,et al.  Inhibitory Neuron and Hippocampal Circuit Dysfunction in an Aged Mouse Model of Alzheimer's Disease , 2013, PloS one.

[41]  L. Mucke,et al.  Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks , 2010, Nature Neuroscience.

[42]  H. Kim,et al.  Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease , 2014, Scientific Reports.

[43]  L. Hirsch,et al.  A Randomized, Double‐Blind, Placebo‐Controlled Trial of Donepezil to Improve Memory in Epilepsy , 2007, Epilepsia.

[44]  M. Gillard,et al.  Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. , 2011, European journal of pharmacology.

[45]  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.

[46]  R. Mayeux,et al.  Cumulative risks of developing extrapyramidal signs, psychosis, or myoclonus in the course of Alzheimer's disease. , 1991, Archives of neurology.

[47]  D. Y. Lee,et al.  Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. , 2015, JAMA.

[48]  A. Pariente,et al.  Benzodiazepine use and risk of Alzheimer’s disease: case-control study , 2014, BMJ : British Medical Journal.

[49]  C. Rowe,et al.  Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study , 2013, The Lancet Neurology.

[50]  Jürgen Götz,et al.  Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models , 2010, Cell.

[51]  Laurie A. Miller,et al.  Senile plaques in temporal lobe epilepsy , 1994, Acta Neuropathologica.

[52]  Dietmar R. Thal,et al.  Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years , 2011, Journal of neuropathology and experimental neurology.

[53]  S. Ferreira,et al.  Taurine prevents the neurotoxicity of β‐amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[54]  L. Volicer,et al.  Effect of seizures on progression of dementia of the Alzheimer type. , 1995, Dementia.

[55]  Daniel Friedman,et al.  Seizures and Epilepsy in Alzheimer's Disease , 2012, CNS neuroscience & therapeutics.

[56]  Vinh Q Nguyen,et al.  Down syndrome and dementia: seizures and cognitive decline. , 2012, Journal of Alzheimer's disease : JAD.

[57]  You-Qiang Song,et al.  A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. , 2016, Journal of the Formosan Medical Association = Taiwan yi zhi.

[58]  W. Löscher,et al.  High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats , 1990, Naunyn-Schmiedeberg's Archives of Pharmacology.

[59]  P. Calabresi,et al.  Levetiracetam monotherapy in Alzheimer patients with late‐onset seizures: a prospective observational study , 2007, European journal of neurology.

[60]  Keith A. Johnson,et al.  Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia , 2009, Neuron.

[61]  S. Tekin,et al.  Antiglutamatergic therapy in Alzheimer's disease – effects of lamotrigine , 1998, Journal of Neural Transmission.

[62]  A. Palmeri,et al.  Picomolar Amyloid-β Positively Modulates Synaptic Plasticity and Memory in Hippocampus , 2008, The Journal of Neuroscience.

[63]  D. Hoffman,et al.  Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease , 2015, The Journal of Neuroscience.

[64]  S. Strittmatter,et al.  Fyn inhibition rescues established memory and synapse loss in Alzheimer mice , 2015, Annals of neurology.

[65]  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.

[66]  Arturo Alvarez-Buylla,et al.  Inhibitory Interneuron Progenitor Transplantation Restores Normal Learning and Memory in ApoE4 Knock-In Mice without or with Aβ Accumulation , 2014, The Journal of Neuroscience.

[67]  N. Muhlert,et al.  Accelerated forgetting of real-life events in Transient Epileptic Amnesia , 2010, Neuropsychologia.

[68]  J. Trojanowski,et al.  Clinicopathological correlations in corticobasal degeneration , 2011, Annals of neurology.

[69]  Keith A. Vossel,et al.  Tau reduction prevents A-induced axonal transport deficits by blocking activation of GSK 3 , 2015 .

[70]  L. Mucke,et al.  Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease , 2011, The Journal of Neuroscience.

[71]  R. Gallassi.  Epileptic Amnesic Syndrome: An Update and Further Considerations , 2006, Epilepsia.

[72]  Karen M Rodrigue,et al.  Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. , 2015, JAMA.

[73]  R. Petersen,et al.  Recurrent seizures in patients with dementia: Frequency, seizure types, and treatment outcome , 2009, Epilepsy & Behavior.

[74]  Y. Smith,et al.  Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet , 2006, Annals of neurology.

[75]  Korey Kam,et al.  Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology , 2016, Scientific Reports.

[76]  D. Bredesen,et al.  Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain , 2011, Neurobiology of Aging.

[77]  Kewei Chen,et al.  A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease , 2015, Alzheimer's Research & Therapy.

[78]  Bradley T. Hyman,et al.  The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease , 2014, Neuron.

[79]  Jason E Gestwicki,et al.  Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden , 2010, Molecular Neurodegeneration.

[80]  G. Holmes,et al.  Hippocampal interictal epileptiform activity disrupts cognition in humans , 2013, Neurology.

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

[82]  C. Jack,et al.  Chronic divalproex sodium use and brain atrophy in Alzheimer disease , 2011, Neurology.

[83]  T. Losey,et al.  Seizures and dementia in the elderly: Nationwide Inpatient Sample 1999–2008 , 2014, Epilepsy & Behavior.

[84]  Julie Harris,et al.  Reversing EphB2 depletion rescues cognitive functions in Alzheimer model , 2011, Nature.

[85]  D. Holtzman,et al.  Antisense Reduction of Tau in Adult Mice Protects against Seizures , 2013, The Journal of Neuroscience.

[86]  J. Tsiouris,et al.  Adverse effects of phenytoin given for late-onset seizures in adults with Down syndrome , 2002, Neurology.

[87]  B. Uthman,et al.  New onset geriatric epilepsy , 2005, Neurology.

[88]  A. Cukiert,et al.  Seizure outcome after hippocampal deep brain stimulation in a prospective cohort of patients with refractory temporal lobe epilepsy , 2014, Seizure.

[89]  W. Hauser,et al.  Seizures and myoclonus in patients with Alzheimer's disease , 1986, Neurology.

[90]  E. Mandelkow,et al.  The Tau/A152T mutation, a risk factor for frontotemporal‐spectrum disorders, leads to NR2B receptor‐mediated excitotoxicity , 2016, EMBO reports.

[91]  Sylvain Rheims,et al.  Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy , 2009, The Journal of Neuroscience.

[92]  M. Romero-Acebal,et al.  Calretinin interneurons are early targets of extracellular amyloid-beta pathology in PS1/AbetaPP Alzheimer mice hippocampus. , 2010, Journal of Alzheimer's disease : JAD.

[93]  A. Hofman,et al.  Risk of dementia in patients with Parkinson's disease, epilepsy, and severe head trauma: a register-based follow-up study. , 1995, American journal of epidemiology.

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

[95]  Shao Li,et al.  Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice , 2014, Neurobiology of Aging.

[96]  James T. Becker,et al.  A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity , 2015, NeuroImage: Clinical.

[97]  H. Tanila,et al.  Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels , 2011, Epilepsy Research.

[98]  L. Costantini,et al.  Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial , 2009, Nutrition & metabolism.

[99]  Susanne Schoch,et al.  Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease , 2014, Neuron.

[100]  G. Landreth,et al.  Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy , 2014, Neurobiology of Aging.

[101]  M. Pangalos,et al.  Sodium Channel Cleavage Is Associated with Aberrant Neuronal Activity and Cognitive Deficits in a Mouse Model of Alzheimer's Disease , 2013, The Journal of Neuroscience.

[102]  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.