Late-onset unexplained seizures are associated with cognitive impairment and lower amygdala volumes
Authors: Sarkis Rani A , Orozco Janet , Lemus Hernan Nicolas , Hankerson Alexis , Liu Lei , Lam Alice D , Johnson Emily , Stufflebeam Steven , Viswanathan Anand , Amariglio Rebecca E , Purandare Mallika , Trouten Patrick , Young Geoffrey S , Locascio Joseph J , Pennell Page B , Marshall Gad A 
Published: January 2025

Abstract
Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition (z-score ≤ −1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite -5, 23.2% for delayed verbal recall, 15.6% for processing speed and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex and race, late-onset unexplained epilepsy group had lower left AV (%; β = −0.003, P = 0.0016), right AV (%) (β = −0.003, P = 0.01), and log-transformed WMV (mm3; β = −0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer’s disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline.