Silent Seizures and Memory Loss in Alzheimer's Disease

Editorial

08 March 2021

Editorial: Silent Seizures and Memory Loss in Alzheimer's Disease

Keith Vossel

and

Elissaios Karageorgiou

4,389 views

4 citations

Editors

Keith Vossel

University of California

Elissaios Karageorgiou

University of West Attica

Impact

Original Research

19 June 2020

Ablating Tau Reduces Hyperexcitability and Moderates Electroencephalographic Slowing in Transgenic Mice Expressing A53T Human α-Synuclein

Samuel T. Peters

, 4 more and

Keith Vossel

Abnormal sleep patterns in A53T mice are not dependent on tau. (A) During the active (dark) phase, all mice were awake for most of the 10-h cycle across age groups. One-way ANOVA determined that there are genotypic differences in time spent awake at 3–4 months. Tukey post hoc test demonstrated that A53T/mTau−/− mice spent more time awake in the active phase than nontransgenic (NTG) mice. No differences were found in other genotype or ages. 3–4 months: F(3, 35) = 4.642, p = 0.0078; 6–7 months: F(3, 30) = 0.6481, p = 0.5903; 9–10 months: F(3, 31) = 1.840, p = 0.1604. (B) Correspondingly, A53T/mTau−/− mice had decreased NREM sleep in the active phase relative to NTG in the 3–4 month group. One-way ANOVA, 3–4 months: F(3, 35) = 4.889, p = 0.0061; 6–7 months: F(3, 30) = 0.7059, p = 0.556; 9–10 months: F(3, 31) = 1.81, p = 0.1659. (C) The time spent in REM sleep during the active phase was low across all genotypes, and no significant differences were noted in any age group. 3–4 months: F(3, 35) = 2.254, p = 0.0993; 6–7 months: F(3, 30) = 0.9996, p = 0.4065; 9–10 months: F(3, 31) = 1.841, p = 0.1603. (D,E) Mice generally spent more time sleeping in the quiescent (light) phase than the active phase. (D) Across age groups, genotype significantly impacted time spent awake in the quiescent phase [3–4 months: F(3, 35) = 13.11, p < 0.0001; 6–7 months: F(3, 30) = 17.78, p < 0.0001; 9–10 months: F(3, 31) = 20.57, p < 0.0001]. After Tukey adjustment, A53T and A53T/mTau−/− mice spent significantly more time awake than did controls, and A53T/mTau−/− were awake for significantly more time on average than A53T at 6–7 months. (E) NREM sleep time in the quiescent phase was significantly impacted by the genotype factor in all age groups, and transgenic mice both with and without endogenous tau spent less time in NREM sleep than NTG or mTau−/− mice during the light phase [3–4 months: F(3, 35) = 12.03, p < 0.0001; 6–7 months: F(3, 30) = 15.93, p < 0.0001; 9–10 months: F(3, 31) = 18.89, p < 0.0001]. However, A53T/mTau−/− mice accumulated less NREM sleep than A53T mice in the 6–7 month group. (F) ANOVA warranted further analysis of REM deficits in A53T mice at 3–4 months of age [F(3, 35) = 3.245, p = 0.0334]. However, there were no significant differences after post hoc correction for multiple comparisons. The impact of genotype on REM deficits during the quiescent phase was evident in the older groups [6–7 months: F(3, 30) = 20.49, p < 0.0001; 9–10 months: F(3, 31) = 12.44, p < 0.0001]. All significant main effects in ANOVA were followed with the Tukey test. 3–4 months: nNTG = 10, nmTau−/− = 10, nA53T = 10, nA53T/mTau−/− = 9; 6–7 months: nNTG=8, nmTau−/− = 8, nA53T = 9, nA53T/mTau−/− = 9; 9–10 months: nNTG = 10, nmTau−/− = 11, nA53T = 7, nA53T/mTau−/− = 7. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Bars represent means ± SEM.

Abnormal intraneuronal accumulation of the presynaptic protein α-synuclein (α-syn) is implicated in the etiology of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Recent work revealed that mice expressing human α-syn with the alanine-53-threonine (A53T) mutation have a similar phenotype to the human condition, exhibiting long-term potentiation deficits, learning and memory deficits, and inhibitory hippocampal remodeling, all of which were reversed by genetic ablation of microtubule-associated protein tau. Significantly, memory deficits were associated with histological signs of network hyperactivity/seizures. Electrophysiological abnormalities are often seen in parkinsonian dementias. Baseline electroencephalogram (EEG) slowing is used as a supportive diagnostic feature in DLB and PDD, and patients with these diseases may exhibit indicators of broad network dysfunction such as sleep dysregulation, myoclonus, and seizures. Given the translational significance, we examined whether human A53T α-syn expressing mice exhibit endogenous-tau-dependent EEG abnormalities, as measured with epidural electrodes over the frontal and parietal cortices. Using template-based waveform sorting, we determined that A53T mice have significantly high numbers of epileptiform events as early as 3–4 months of age and throughout life, and this effect is markedly attenuated in the absence of tau. Epileptic myoclonus occurred in half of A53T mice and was markedly reduced by tau ablation. In spectral analysis, tau ablation partially reduced EEG slowing in 6–7 month transgenic mice. We found abnormal sleeping patterns in transgenic mice that were more pronounced in older groups, but did not find evidence that this was influenced by tau genotype. Together, these data support the notion that tau facilitates A53T α-syn-induced hyperexcitability that both precedes and coincides with associated synaptic, cognitive, and behavioral effects. Tau also contributes to some aspects of EEG slowing in A53T mice. Importantly, our work supports tau-based approaches as an effective early intervention in α-synucleinopathies to treat aberrant network activity.

5,406 views

26 citations

Regional normalized eLORETA solutions (mean across subjects, log-10 transformed) of cortical sources of rsEEG rhythms relative to a statistical ANOVA interaction among the factors Group (Nold, N= 30; noADMCI-EEA using the rsEEG epochs without EEA, N = 13; noADMCI-EEA using the rsEEG epochs with EEA, N = 13), Band (delta, theta, alpha, beta, and gamma), and ROI (central, frontal, parietal, occipital, and temporal). This ANOVA design used the regional normalized eLORETA solutions as a dependent variable. Legend: the rectangles indicate the cortical regions and frequency bands in which the eLORETA solutions statistically presented a significant eLORETA pattern noADMCI-EEA using the rsEEG epochs without EEA ≠ noADMCI-EEA using the rsEEG epochs with EEA (p < 0.05 corrected = p < 0.002).

Original Research

23 October 2020

Abnormalities of Cortical Sources of Resting State Delta Electroencephalographic Rhythms Are Related to Epileptiform Activity in Patients With Amnesic Mild Cognitive Impairment Not Due to Alzheimer's Disease

Claudio Babiloni

, 14 more and

Claudio Del Percio

3,214 views

9 citations

Original Research

15 April 2020

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

Elena Nardi Cesarini

, 13 more and

Cinzia Costa

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.

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.

6,797 views

32 citations

Original Research

04 December 2019

A Longitudinal Study of Epileptic Seizures in Alzheimer's Disease

John Baker

, 2 more and

Adam Zeman

The prevalence of epileptic seizures is increased in patients in the clinical stages of Alzheimer's disease (AD) when compared to age-matched cognitively normal populations. In previously reported work from the Presentation of Epileptic Seizures in Dementia (PrESIDe) study, we identified a clinical suspicion of epilepsy in between 12.75 and 28.43% of patients with AD recruited from a memory clinic. EEGs were not performed in this study. Patients with epilepsy performed similarly to patients without epilepsy on cognitive testing at the time of recruitment but were more impaired on two measures of everyday functioning [Cambridge Behavioral Inventory—Revised and Clinical Dementia Rating (CBI-R and CDR)]. On repeated testing in this 12-month follow-up study, patients in whom a suspicion of epilepsy was identified performed significantly worse on cognitive function testing (p = 0.028) in addition to maintaining a difference on the informant questionnaires (CBI-R p < 0.001, CDR p = 0.020). These findings suggest that seizures in this population could be a marker of a more rapid decline and worse prognosis.

5,663 views

40 citations