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

Abstract

OBJECTIVE 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. METHODS 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 and a one-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. RESULTS 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). INTERPRETATION 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.

ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

“…A growing body of evidence suggests that network dysfunction in the form of epileptiform activity contributes to cognitive deficits in AD, even in early stages of the disease (Bakker et al, 2012; Vossel et al, 2013; Vossel et al, 2016). Understanding how specific neuronal alterations contribute to cognitive deficits may therefore highlight additional therapeutic avenues to improve the quality of life for AD patients.…”

“…This rate may be underestimated due to the incidence of subclinical epileptiform activity and non-convulsive seizures, which in a majority of cases precede or coincide with the diagnosis of amnestic mild cognitive impairment or AD (Vossel et al, 2013). A recent prospective study found that 42.4% of AD patients with no clinical history of seizures exhibited subclinical epileptiform activity, and the presence of such activity was associated with faster rates of cognitive decline (Vossel et al, 2016). Furthermore, multiple mouse models of AD exhibit epileptiform activity (Chin and Scharfman, 2013; Kam et al, 2016; Minkeviciene et al, 2009; Palop et al, 2007; Palop and Mucke, 2009).…”

Relative Incidence of Seizures and Myoclonus in Alzheimer’s Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia

“…[8, 40] The genes included AD-causing mutations (amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), and presenilin 2 ( PSEN2 )) and FTD-causing mutations (chromosome 9 open reading frame 72 ( C9ORF72 ), FUS RNA binding protein ( FUS ), granulin precursor ( GRN ), microtubule-associated protein tau ( MAPT ), and TAR DNA binding protein ( TDP43 )). Genetic variants associated with dementia risk and potential genetic disease modifiers were also assessed including apolipoprotein E ( APOE ) alleles,[8], MAPT Ala152Thr (A152T) substitution,[41] granulin precursor rs5848 allele,[42] MAPT H1/H2 haplotype,[8] transmembrane protein 106B ( TMEM106B ) rs1990622 allele,[43] and triggering receptor expressed on myeloid cells 2 ( TREM2 ) rs75932628 allele. [44] Genotype data was available in 25–30% of all 1,846 subjects.…”

“…Additionally, subclinical epileptiform activity, the occurrence of epileptiform activity in the absence of seizures, can be detected in over 40% of AD patients when they undergo extended neurophysiological monitoring [8]. Both seizures and subclinical epileptiform activity in AD are associated with accelerated cognitive decline [8–10], a phenomenon that could relate to increased amyloid-beta (Aβ) and tau production due to periodic increases in synaptic activity [11–13] as well as chronic compensatory remodeling of neuronal circuits [14, 15]. Previous studies suggest that seizures and myoclonus, which are both signs of network hyperexcitability, could predict shortened survival in AD [16, 17].…”

“…Comparisons were also conducted between clinical subtypes of each dementia group, including DLB and concurrent AD (DLB-AD) and FTD-spectrum disorders including behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), PSP, corticobasal syndrome due to CBD, and non-fluent variant primary progressive aphasia (nfvPPA). Since network hyperexcitability is associated with faster cognitive decline in patients with AD [8–10] and possibly non-AD dementias, recognizing the risk and typical presentations of new-onset seizures across multiple forms of dementia is important. Correct diagnosis and early treatment of epilepsy in patients with dementia could improve quality of life, and trials will determine if such strategies could help stabilize or delay disease progression [26, 27].…”