Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease

Vossel, Keith A.; Beagle, Alexander J.; Rabinovici, Gil D.; Shu, Huidy; Lee, Suzee E.; Naasan, Georges; Hegde, Manu; Cornes, Susannah; Henry, Maya L.; Nelson, Alexandra; Seeley, William W.; Geschwind, Michael D.; Gorno‐Tempini, Maria Luisa; Shih, Tina; Kirsch, Heidi E.; Garcia, Paul A.; Miller, Bruce L.; Mucke, Lennart

doi:10.1001/jamaneurol.2013.136

Cited by 607 publications

(670 citation statements)

References 48 publications

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“…Higher levels of tau may also be responsible for the increased AD risk associated with a more common single nucleotide polymorphism in MAPT 58. Increased tau levels also predict the development of epilepsy, which is more frequent in patients with mild cognitive impairment (MCI) or AD than in control populations and may be associated with an earlier cognitive decline in AD 45, 48, 59.…”

Section: Discussionmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Discussionmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…Our interpretation that this biochemical alteration also reflects aberrant network excitability in humans is supported by the clinical evidence of aberrant network excitability we found in our chart review. Notably, it is likely that calbindin depletion in the hippocampus is a more sensitive indicator of aberrant network excitability then routine scalp EEG, which can easily miss intermittent epileptiform events and is notoriously insensitive to epileptic activity in deeper brain regions such as the hippocampus 50, 51…”

Section: Discussionmentioning

confidence: 99%

“…In patients with early AD and a seizure disorder, a substantial proportion of the seizure activity was nonconvulsive and could have easily been missed on routine exams 51. This caveat may also apply to DLB.…”

Section: Discussionmentioning

confidence: 99%

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Morris

Sanchez

Verret

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

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“…28,29 Early alterations of network activity in AD Long unrecognized in the clinical care of AD patients, in particular at early stages of the disease, epileptiform activity is now receiving increasing attention, as it appears to play an important role in AD pathogenesis and progression. 30,31 AD is associated with an enhanced risk of seizures, and patients displaying (subclinical) epileptiform activity or overt seizures show earlier onset of cognitive decline and faster transition into severe dementia. 32 Pharmacological suppression of aberrant network activity in AD should therefore offer more than symptomatic treatment as it is thought to interfere with a mechanism that contributes to and propels cognitive decline.…”

Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease

Cited by 607 publications

References 48 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

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