Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study

DiFrancesco, Jacopo C.; Tremolizzo, Lucio; Polonia, Valeria; Giussani, Giorgia; Bianchi, Elisa; Franchi, Carlotta; Nobili, Alessandro; Appollonio, Ildebrando; Beghi, Ettore; Ferrarese, Carlo

doi:10.3233/jad-170392

Cited by 67 publications

(53 citation statements)

References 44 publications

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“…During epileptogenesis, a wide spectrum of potentially pro‐epileptogenic neurodegenerative changes is seen in limbic structures including mossy fiber sprouting; neuronal reorganization‐synaptic remodeling; neurogenesis; blood‐brain barrier disruption, γ‐aminobutyric acid (GABA) receptor, and GABAergic neurons changes; alterations in peptide and brain‐derived neurotrophic factor (BDNF) expression; neuroinflammation; changes in ion channels; alterations in axonal transport, amyloid‐β peptide, tau, and PP2A pathology; and other cellular and functional changes . These neuropathological changes are not specific of epilepsy; however, they are similar to those of neurodegenerative disorders such as Alzheimer's disease, even when there is no clear history of epilepsy . Neurodegeneration is a progressive process that evolves during acquired epileptogenesis; however, some studies suggest that the neurodegeneration may not directly result in the epileptogenesis, but it may induce other processes that do .…”

Section: Neurodegenerative Mechanisms Relevant To Acquired Epilepsiesmentioning

confidence: 99%

Neurodegenerative pathways as targets for acquired epilepsy therapy development

2020

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There is a growing body of clinical and experimental evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult may share common etiological mechanisms. Acquired epilepsy commonly develops as a comorbid condition in patients with neurodegenerative diseases such as Alzheimer's disease, although it is likely much under diagnosed in practice. Progressive neurodegeneration has also been described after traumatic brain injury, stroke, and other forms of brain insults. Moreover, recent evidence has shown that acquired epilepsy is often a progressive disorder that is associated with the development of drug resistance, cognitive decline, and worsening of other neuropsychiatric comorbidities. Therefore, new pharmacological therapies that target neurobiological pathways that underpin neurodegenerative diseases have potential to have both an anti-epileptogenic and diseasemodifying effect on the seizures in patients with acquired epilepsy, and also mitigate the progressive neurocognitive and neuropsychiatric comorbidities. Here, we review the neurodegenerative pathways that are plausible targets for the development of novel therapies that could prevent the development or modify the progression of acquired epilepsy, and the supporting published experimental and clinical evidence. K E Y W O R D SAMPA, amyloid-β, glutamate, mTOR, neuroinflammation, tau

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Section: Neurodegenerative Mechanisms Relevant To Acquired Epilepsiesmentioning

confidence: 99%

Neurodegenerative pathways as targets for acquired epilepsy therapy development

2020

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“…Substantial evidence shows that loss of GABAergic tone leads to seizures [97]. 10–22% of AD patients exhibit seizures [98–100], as do hAPP FAD mice [101], and the onset of these seizures precedes cognitive decline [102]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

Najm

Jones

Huang

2019

Mol Neurodegeneration

122

113

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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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“…Furthermore, dementia due to AD and other etiologies are estimated to account for 10-20% of LOE (5). However, despite the bulk of the literature focused on dementia as startling cause of epilepsy in elderly (6)(7)(8)(9) as well as on cognitive performance in young onset epilepsy (10)(11)(12)(13), little is known on cognition among people with LOE (4). Indeed, only isolated reports are available, yet they do not providing the prevalence and characterization of cognitive impairment in people who have received a LOE diagnosis (4,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Late-Onset Epilepsy With Unknown Etiology: A Pilot Study on Neuropsychological Profile, Cerebrospinal Fluid Biomarkers, and Quantitative EEG Characteristics

et al. 2020

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Introduction: Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls. Methods: Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed. Results: Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients (p < 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93-10.58, p = 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8-12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources. Nardi Cesarini et al. LOEU: Cognitive, CSF, qEEG Profile Discussion: MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables.

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Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study

Cited by 67 publications

References 44 publications

Neurodegenerative pathways as targets for acquired epilepsy therapy development

Neurodegenerative pathways as targets for acquired epilepsy therapy development

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

Late-Onset Epilepsy With Unknown Etiology: A Pilot Study on Neuropsychological Profile, Cerebrospinal Fluid Biomarkers, and Quantitative EEG Characteristics

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