scholarly journals Temporal Lobe Epilepsy and Alzheimer’s Disease: From Preclinical to Clinical Evidence of a Strong Association

2021 ◽  
pp. 1-19
Author(s):  
Mario Tombini ◽  
Giovanni Assenza ◽  
Lorenzo Ricci ◽  
Jacopo Lanzone ◽  
Marilisa Boscarino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Detrimental Effect ◽  
Clinical Evidence ◽  
Epileptiform Activity ◽  
Strong Association ◽  
Amyloid Β ◽  
Neurodegenerative Process

Increasing evidence coming from both experimental and humans’ studies strongly suggest the existence of a link between epilepsy, in particular temporal lobe epilepsy (TLE), and Alzheimer’s disease (AD). Patients with mild cognitive impairment and AD are more prone to have seizures, and seizures seem to facilitate amyloid-β and tau deposits, thus promoting neurodegenerative processes. Consistent with this view, long-lasting drug-resistant TLE and AD have been shown to share several pathological and neuroimaging features. Even if studies addressing prevalence of interictal and subclinical epileptiform activity in these patients are not yet conclusive, their findings raise the possibility that epileptiform activity might negatively impact memory and hasten cognitive decline, either directly or by association with unrecognized silent seizures. In addition, data about detrimental effect of network hyperexcitability in temporal regions in the premorbid and early stages ofADopen up newtherapeutic opportunities for antiseizure medications and/or antiepileptic strategies that might complement or enhance existing therapies, and potentially modify disease progression. Here we provide a review of evidence linking epileptiform activity, network hyperexcitability, and AD, and their role promoting and accelerating neurodegenerative process. Finally, the effects of antiseizure medications on cognition and their optimal administration in patients with AD are summarized.

scholarly journals Alzheimer-like amyloid and tau alterations associated with cognitive deficit in temporal lobe epilepsy

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 191-209 ◽  
Author(s):  
Sarah Gourmaud ◽  
Haochang Shou ◽  
David J Irwin ◽  
Kimberly Sansalone ◽  
Leah M Jacobs ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Temporal Lobe Epilepsy ◽  
Amyloid Precursor Protein ◽  
Temporal Lobe ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Drug Resistant ◽  
Stress Kinases

Abstract Temporal lobe epilepsy represents a major cause of drug-resistant epilepsy. Cognitive impairment is a frequent comorbidity, but the mechanisms are not fully elucidated. We hypothesized that the cognitive impairment in drug-resistant temporal lobe epilepsy could be due to perturbations of amyloid and tau signalling pathways related to activation of stress kinases, similar to those observed in Alzheimer’s disease. We examined these pathways, as well as amyloid-β and tau pathologies in the hippocampus and temporal lobe cortex of drug-resistant temporal lobe epilepsy patients who underwent temporal lobe resection (n = 19), in comparison with age- and region-matched samples from neurologically normal autopsy cases (n = 22). Post-mortem temporal cortex samples from Alzheimer’s disease patients (n = 9) were used as positive controls to validate many of the neurodegeneration-related antibodies. Western blot and immunohistochemical analysis of tissue from temporal lobe epilepsy cases revealed increased phosphorylation of full-length amyloid precursor protein and its associated neurotoxic cleavage product amyloid-β*56. Pathological phosphorylation of two distinct tau species was also increased in both regions, but increases in amyloid-β1-42 peptide, the main component of amyloid plaques, were restricted to the hippocampus. Furthermore, several major stress kinases involved in the development of Alzheimer’s disease pathology were significantly activated in temporal lobe epilepsy brain samples, including the c-Jun N-terminal kinase and the protein kinase R-like endoplasmic reticulum kinase. In temporal lobe epilepsy cases, hippocampal levels of phosphorylated amyloid precursor protein, its pro-amyloidogenic processing enzyme beta-site amyloid precursor protein cleaving enzyme 1, and both total and hyperphosphorylated tau expression, correlated with impaired preoperative executive function. Our study suggests that neurodegenerative and stress-related processes common to those observed in Alzheimer’s disease may contribute to cognitive impairment in drug-resistant temporal lobe epilepsy. In particular, we identified several stress pathways that may represent potential novel therapeutic targets.

Characterizing the Resilience Effect of Neurodegeneration for the Mechanistic Pathway of Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Di Hu ◽  
Chuning Liu ◽  
Kai Xia ◽  
Amy Abramowitz ◽  
Guorong Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rapid Development ◽  
Demographic Data ◽  
Strong Association ◽  
Synergetic Effect ◽  
Amyloid Β ◽  
Angular Gyrus ◽  
Limited Attention ◽  
Brain Resilience

Background: With the rapid development of neurobiology and neuroimaging technologies, mounting evidence shows that Alzheimer’s disease (AD) is caused by the build-up of two abnormal proteins, amyloid-β plaques (A) and neurofibrillary tangles (T). Over time, these AD-related neuropathological burdens begin to spread throughout the brain, which results in the characteristic progression of symptoms in AD. Objective: Although tremendous efforts have been made to link biological indicators to the progression of AD, limited attention has been paid to investigate the multi-factorial role of socioeconomic status (SES) in the prevalence or incidence of AD. There is high demand to explore the synergetic effect of sex and SES factors in moderating the neurodegeneration process caused by the accumulation of A and T biomarkers. Methods: We carry out a meta-data analysis on the longitudinal neuroimaging data, clinical outcomes, genotypes, and demographic data in Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). Results: Our major findings include 1) education and occupation show resilience effects at the angular gyrus, superior parietal lobule, lateral occipital-temporal sulcus, and posterior transverse collateral sulcus where we found significant slowdown of neurodegeneration due to higher education level or more advanced occupation rank; 2) A and T biomarkers manifest different spatial patterns of brain resilience; 3) BDNF (brain-derived neurotrophic factor) single nucleotide polymorphism (SNP) rs10835211 shows strong association to the identified resilience effect; 4) the identified resilience effect is associated with the clinical manifestation in memory, learning, and organization performance. Conclusion: Several brain regions manifest resilience from SES to A and T biomarkers. BDNF SNPs have a potential association with the resilience effect from SES. In addition, cognitive measures of learning and memory demonstrate the resilience effect.

scholarly journals Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment

Brain ◽  
2020 ◽  
Author(s):  
Erik Kaestner ◽  
Anny Reyes ◽  
Austin Chen ◽  
Jun Rao ◽  
Anna Christina Macari ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Late Onset ◽  
Amnestic Mild Cognitive Impairment

Abstract Epilepsy incidence and prevalence peaks in older adults yet systematic studies of brain ageing and cognition in older adults with epilepsy remain limited. Here, we characterize patterns of cortical atrophy and cognitive impairment in 73 older adults with temporal lobe epilepsy (>55 years) and compare these patterns to those observed in 70 healthy controls and 79 patients with amnestic mild cognitive impairment, the prodromal stage of Alzheimer’s disease. Patients with temporal lobe epilepsy were recruited from four tertiary epilepsy surgical centres; amnestic mild cognitive impairment and control subjects were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Whole brain and region of interest analyses were conducted between patient groups and controls, as well as between temporal lobe epilepsy patients with early-onset (age of onset <50 years) and late-onset (>50 years) seizures. Older adults with temporal lobe epilepsy demonstrated a similar pattern and magnitude of medial temporal lobe atrophy to amnestic mild cognitive impairment. Region of interest analyses revealed pronounced medial temporal lobe thinning in both patient groups in bilateral entorhinal, temporal pole, and fusiform regions (all P < 0.05). Patients with temporal lobe epilepsy demonstrated thinner left entorhinal cortex compared to amnestic mild cognitive impairment (P = 0.02). Patients with late-onset temporal lobe epilepsy had a more consistent pattern of cortical thinning than patients with early-onset epilepsy, demonstrating decreased cortical thickness extending into the bilateral fusiform (both P < 0.01). Both temporal lobe epilepsy and amnestic mild cognitive impairment groups showed significant memory and language impairment relative to healthy control subjects. However, despite similar performances in language and memory encoding, patients with amnestic mild cognitive impairment demonstrated poorer delayed memory performances relative to both early and late-onset temporal lobe epilepsy. Medial temporal lobe atrophy and cognitive impairment overlap between older adults with temporal lobe epilepsy and amnestic mild cognitive impairment highlights the risks of growing old with epilepsy. Concerns regarding accelerated ageing and Alzheimer’s disease co-morbidity in older adults with temporal lobe epilepsy suggests an urgent need for translational research aimed at identifying common mechanisms and/or targeting symptoms shared across a broad neurological disease spectrum.

scholarly journals Voxel-based morphometry focusing on medial temporal lobe structures has a limited capability to detect amyloid β, an Alzheimer’s disease pathology

Aging ◽  
2020 ◽  
Vol 12 (19) ◽  
pp. 19701-19710
Author(s):  
Masashi Kameyama ◽  
Kenji Ishibashi ◽  
Jun Toyohara ◽  
Kei Wagatsuma ◽  
Yumi, Umeda-Kameyama ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Amyloid Β ◽  
Voxel Based Morphometry

scholarly journals Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Audrey Hector ◽  
Jonathan Brouillette
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Synaptic Activity ◽  
Early Stages ◽  
The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

scholarly journals Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

2017 ◽  
Vol 214 (11) ◽  
pp. 3151-3169 ◽  
Author(s):  
Axel Montagne ◽  
Zhen Zhao ◽  
Berislav V. Zlokovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Neurodegenerative Process ◽  
Blood Brain ◽  
Underlying Mechanisms

The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

scholarly journals Alternative ion channel splicing in mesial temporal lobe epilepsy and Alzheimer's disease

2007 ◽  
Vol 8 (3) ◽  
pp. R32 ◽  
Author(s):  
Erin L Heinzen ◽  
Woohyun Yoon ◽  
Michael E Weale ◽  
Arjune Sen ◽  
Nicholas W Wood ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe Epilepsy ◽  
Ion Channel ◽  
Temporal Lobe ◽  
Mesial Temporal Lobe Epilepsy ◽  
Mesial Temporal Lobe
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