Seizures as an early symptom of autosomal dominant Alzheimer's disease

Vöglein, Jonathan; Noachtar, Soheyl; McDade, Eric; Ka, Quaid; Salloway, Stephen; Ghetti, Bernardino; Noble, James M.; Berman, Sarah B.; Chhatwal, Jasmeer P.; Mori, Hiroshi; Fox, Nick C.; Allegri, Ricardo; Masters, Colin L.; Ringman, JM; Rossor, Martin N.; Schofield, PR; Sperling, Reisa A.; Jucker, Mathias; Laske, Christoph; Paumier, Katrina L.; Morris, John C.; Bateman, Randall J.; Xiong, Chengjie; Danek, Adrian

doi:10.1016/j.neurobiolaging.2018.11.022

Cited by 34 publications

(26 citation statements)

References 25 publications

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“…The large-scale loss of inhibition due to interneuron degeneration would be expected to impair excitation:inhibition balance, leading to epilepsy. This is consistent with the high incidence of seizures observed in monogenic AD (4,5,(21)(22)(23)(24), with five of the AD patients studied here manifesting seizures and/or myoclonus, and with the hypothesis that seizures may occur before widespread neurodegeneration and even before clinical symptoms of dementia (25).…”

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confidence: 90%

Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution

Marinaro

Haneklaus

Zhang

et al. 2020

Preprint

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Cell and molecular biology analyses of sporadic Alzheimer's disease brain are confounded by clinical variability, ageing and genetic heterogeneity. Therefore, we used single-nucleus RNA sequencing to characterize cell composition and gene expression in the cerebral cortex in early-onset, monogenic Alzheimer's disease. Constructing a cellular atlas of frontal cortex from 8 monogenic AD individuals and 8 matched controls, provided insights into which neurons degenerate in AD and responses of different cell types to AD at the cellular and systems level. Such responses are a combination of positively adaptive and deleterious changes, including large-scale changes in synaptic transmission and marked metabolic reprogramming in neurons. The nature and scale of the transcriptional changes in AD emphasizes the global impact of the disease across all brain cell types.

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supporting

confidence: 90%

Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution

Marinaro

Haneklaus

Zhang

et al. 2020

Preprint

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“…This is particularly remarkable as we stipulated the diagnosis of AD dementia at a subsequent visit for the classification of the predementia stages to improve diagnostic accuracy. This finding is at odds with an increased seizure prevalence in the pre-symptomatic phase of autosomal dominant Alzheimer's disease (ADAD) [7]. A potential explanation could be that pathology in sporadic AD has to reach a higher threshold to increase seizure risk than in ADAD due to a higher susceptibility of the younger ADAD population for seizures.…”

Section: Discussionmentioning

confidence: 99%

“…An association between Alzheimer's disease and seizures was reported in several studies with figures for seizure prevalence in AD from 0.5% up to 64% [4,5]. In autosomal dominant AD, that can be considered as a model disease of the sporadic form without age-associated comorbidities, there is an increased likelihood for the occurrence of seizures [2,6], even very early in the disease course when cognitive impairment is absent [7]. A causal connection between AD and seizure pathophysiology is suggested by a number of mouse models for AD, which frequently show epileptiform activity on EEG and overt seizures [8].…”

Section: Introductionmentioning

confidence: 98%

Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course

et al. 2020

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Background Seizures are an important comorbidity in Alzheimer’s disease (AD). Conflicting results regarding clinical parameters associated with seizures in AD were previously reported. Data on seizure recurrence risk, a crucial parameter for treatment decisions, are lacking. Methods National Alzheimer’s Coordinating Center data were analyzed. Seizure prevalence in AD and an association with disease duration were investigated. Associations of seizures with age of AD onset and with cognitive and functional performance, and seizure recurrence risk were studied. Results 20,745 individuals were investigated. In AD dementia, seizure recurrence risk was 70.4% within 7.5 months. Seizure history was associated with an earlier age of onset of cognitive symptoms (seizures vs. no seizures: 64.7 vs. 70.4 years; p < 0.0001) and worse cognitive and functional performance (mean MMSE score: 16.6 vs. 19.6; mean CDR-sum of boxes score: 9.3 vs. 6.8; p < 0.0001; adjusted for disease duration and age). Seizure prevalence increased with duration of AD dementia (standardized OR = 1.55, 95% CI = 1.39–1.73, p < 0.0001), rising from 1.51% at 4.8 years to 5.43% at 11 years disease duration. Seizures were more frequent in AD dementia compared to normal controls (active seizures: 1.51% vs. 0.35%, p < 0.0001, OR = 4.34, 95% CI = 3.01–6.27; seizure history: 3.14% vs. 1.57%, p < 0.0001, OR = 2.03, 95% CI = 1.67–2.46). Conclusion Seizures in AD dementia feature an exceptionally high recurrence risk and are associated with a poor course of cognitive symptoms. AD patients are at an increased risk for seizures, particularly in later disease stages. Our findings emphasize a need for seizure history assessment in AD, inform individual therapeutic decisions and underline the necessity of systematic treatment studies of AD-associated epilepsy.

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“…Seizures are abnormal neuronal discharges that can happen after brain storks and neurodegenerative diseases such as Alzheimer's disease. 16,17 In animal works, one of the widely used compounds to induce seizure is PTZ. 18 In a similar manner with previous studies, 6 in our study injection of PTZ was associated with the development of seizure attacks in mice.…”

Section: Discussionmentioning

confidence: 99%

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

et al. 2019

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IntroductionEpileptic seizures are considered as a sever abnormal activity of neurons in specific areas of brain such as temporal lobe. 1 This abnormal activity of neurons can be followed by brain oxidative stress and disturbance of cognitive behaviors when they take place repeatedly. 2 In the epileptic seizure models, antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase have been also shown to protect the brain of rats against oxidative damage. 3 In large number of animal studies, pentylenetetrazole (PTZ) has been repeatedly administered for induction an epilepsy model. 1 It has been ducumented that PTZstimulated seizures was accompanied with motor activity impairment, learning and memory dysfunction, axiety and increased level of hippocampal inflammatory cytokines in rats. 4 In addition, seizures followed by PTZ administration have been propounded as an important cause of oxidative status imbalance in some brain areas including hippocampus. 5 For example, PTZ infusion associated with the sever stimulation of N-Methyl-Daspartate (NMDA) receptors has been shown to elevate the level of free radicals such as nitric oxide (NO) and peroxynitrite in the brain of rats. 6 On the other hand, the antioxidant properties of angiotensin-converting enzyme (ACE) inhibitors have been accepted. 7 Captopril as a known ACE inhibitor scavenges free radicals in various tissues. 8 Captopril has been demonstrated to reinforce enzymatic and nonenzymatic defense in different tissues. 9 Scientific evidence has indicated that captopril and valsartan (a specific AT1 receptor inhibitor) attenuate A B S T R A C TBackground: Frequent seizure is followed by overproduction of free radicals and brain oxidative stress. Renin angiotensin system (RAS) has some effects on central nervous system. We designed this research to challenge the effect of captopril as an angiotensin converting enzyme (ACE) inhibitor against brain oxidative stress in pentylenetetrazole (PTZ) -induced seizures in mice. Methods: The groups were including (1) Control (saline); (2) PTZ (100 mg/kg, i.p.), (3-5) PTZ-captopril (Capto) that received three doses of Capto 10, 50 and 100 mg/kg 30 min before PTZ injection. Latency time in the onset minimal clonic seizures (MCS) and generalized tonic-clonic seizures (GTCS) were recorded. The level of malondialdehyde (MDA) and total thiol, as well as superoxide dismutase (SOD) and catalase (CAT) activity in the hippocampus and cortex were measured. Results: All doses of captopril postponed the onset of MCS and GTCS. Accumulation of MDA in the brain tissues of PTZ group was higher than control group, while total thiol content and CAT activity were lower. Pretreatment with captopril (100 mg/kg) diminished MDA concentration compared with PTZ group. Captopril (50 and 100 mg/kg) also increased the level of total thiol groups versus PTZ group. Captopril injection (50 and 100 mg/kg) elevated the activity of SOD and CAT in the brain tissues. In addition captopril administration diminished mortality rat...

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Seizures as an early symptom of autosomal dominant Alzheimer's disease

Abstract: Authors' contributions: JV contributed to writing the article, study concept and design, acquisition of data, analysis, and interpretation of data. SN contributed to analysis and interpretation of data and critical revision of the article for intellectual content.

Cited by 34 publications

References 25 publications

Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution

Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution

Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

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