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Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

ABSTRACT: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition.We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years.Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p?=?0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p?=?0.006), and in executive function (p?=?0.01).Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.

SUBMITTER: Vossel KA

PROVIDER: S-EPMC5177487 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

Vossel Keith A KA Ranasinghe Kamalini G KG Beagle Alexander J AJ Mizuiri Danielle D Honma Susanne M SM Dowling Anne F AF Darwish Sonja M SM Van Berlo Victoria V Barnes Deborah E DE Mantle Mary M Karydas Anna M AM Coppola Giovanni G Roberson Erik D ED Miller Bruce L BL Garcia Paul A PA Kirsch Heidi E HE Mucke Lennart L Nagarajan Srikantan S SS

Annals of neurology 20161107 6

<h4>Objective</h4>Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition.<h4>Methods</h4>We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no hi ...[more]

PMID: 27696483

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Project description:BackgroundEpileptic seizures are an established comorbidity of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD.Aims1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls. 2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD. 3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters.MethodsSubjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs.ResultsWe found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher's exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall-Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann-Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without.ConclusionWe confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes.Trial registrationClinicaltrials.gov, NCT04131491. 12/02/2020.

Project description:Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco.We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n?=?35), and AD plus subclinical epileptiform activity (n?=?7).Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications.Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P?=?.02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P?=?.001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P?<?.001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin.Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

Project description:BACKGROUND:Physical activity might reduce the risk of developing dementia. However, it is still unclear whether the protective effect differs depending on the subtype of dementia. We aimed to investigate if midlife physical activity affects the development of vascular dementia (VaD) and Alzheimer's disease (AD) differently in two large study populations with different designs. METHODS:Using a prospective observational design, we studied whether long-distance skiers of the Swedish Vasaloppet (n?=?197,685) exhibited reduced incidence of VaD or AD compared to matched individuals from the general population (n?=?197,684) during 21?years of follow-up (median 10, interquartile range (IQR) 5-15?years). Next, we studied the association between self-reported physical activity, stated twice 5?years apart, and incident VaD and AD in 20,639 participants in the Swedish population-based Malmo Diet and Cancer Study during 18?years of follow-up (median 15, IQR 14-17?years). Finally, we used a mouse model of AD and studied brain levels of amyloid-?, synaptic proteins, and cognitive function following 6?months of voluntary wheel running. RESULTS:Vasaloppet skiers (median age 36.0?years [IQR 29.0-46.0], 38% women) had lower incidence of all-cause dementia (adjusted hazard ratio (HR) 0.63, 95% CI 0.52-0.75) and VaD (adjusted HR 0.49, 95% CI 0.33-0.73), but not AD, compared to non-skiers. Further, faster skiers exhibited a reduced incidence of VaD (adjusted HR 0.38, 95% CI 0.16-0.95), but not AD or all-cause dementia compared to slower skiers. In the Malmo Diet and Cancer Study (median age 57.5?years [IQR 51.0-63.8], 60% women), higher physical activity was associated with reduced incidence of VaD (adjusted HR 0.65, 95% CI 0.49-0.87), but not AD nor all-cause dementia. These findings were also independent of APOE-?4 genotype. In AD mice, voluntary running did not improve memory, amyloid-?, or synaptic proteins. CONCLUSIONS:Our results indicate that physical activity in midlife is associated with lower incidence of VaD. Using three different study designs, we found no significant association between physical activity and subsequent development of AD.

Project description:BackgroundWinter-seasonal epidemics of pneumococcal disease provide an opportunity to understand the drivers of incidence. We sought to determine whether seasonality of invasive pneumococcal disease is caused by increased nasopharyngeal transmission of the bacteria or increased susceptibility to invasive infections driven by cocirculating winter respiratory viruses.MethodsWe analyzed pneumococcal carriage and invasive disease data collected from children <7 years old in the Navajo/White Mountain Apache populations between 1996 and 2012. Regression models were used to quantify seasonal variations in carriage prevalence, carriage density, and disease incidence. We also fit a multivariate model to determine the contribution of carriage prevalence and RSV activity to pneumococcal disease incidence while controlling for shared seasonal factors.ResultsThe seasonal patterns of invasive pneumococcal disease epidemics varied significantly by clinical presentation: bacteremic pneumococcal pneumonia incidence peaked in late winter, whereas invasive nonpneumonia pneumococcal incidence peaked in autumn. Pneumococcal carriage prevalence and density also varied seasonally, with peak prevalence occurring in late autumn. In a multivariate model, RSV activity was associated with significant increases in bacteremic pneumonia cases (attributable percentage, 15.5%; 95% confidence interval [CI], 1.8%-26.1%) but was not associated with invasive nonpneumonia infections (8.0%; 95% CI, -4.8% to 19.3%). In contrast, seasonal variations in carriage prevalence were associated with significant increases in invasive nonpneumonia infections (31.4%; 95% CI, 8.8%-51.4%) but not with bacteremic pneumonia.ConclusionsThe seasonality of invasive pneumococcal pneumonia could be due to increased susceptibility to invasive infection triggered by viral pathogens, whereas seasonality of other invasive pneumococcal infections might be primarily driven by increased nasopharyngeal transmission of the bacteria.

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Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

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Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

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