Epilepsy is associated with the accelerated aging of brain activity in sleep

Abstract

Objective: Although seizures are the cardinal feature, epilepsy is associated with other forms of brain dysfunction including impaired cognition, abnormal sleep, and increased risk of developing dementia. We hypothesized that, given the widespread neurologic dysfunction caused by epilepsy, accelerated brain aging would be seen. We measured the sleep-based brain age index (BAI) in a diverse group of patients with epilepsy. The BAI is a machine learning-based biomarker that measures how much the brain activity of a person during overnight sleep deviates from chronological age-based norms.

Methods: This case-control study drew information of age-matched controls without epilepsy from home sleep monitoring volunteers and from non-epilepsy patients with Sleep Lab testing. Patients with epilepsy underwent in-patient monitoring and were classified by epilepsy type and seizure burden. The primary outcomes measured were BAI, processed from electroencephalograms, and epilepsy severity metrics (years with epilepsy, seizure frequency standardized by year, and seizure burden [number of seizures in life]). Subanalyses were conducted on a subset with NIH Toolbox cognitive testing for total, fluid, and crystallized composite cognition.

Results: 138 patients with epilepsy (32 exclusively focal and 106 generalizable [focal seizures with secondary generalization]) underwent in-patient monitoring, and age-matched, non-epilepsy controls were analyzed. The mean BAI was higher in epilepsy patients vs controls and differed by epilepsy type: -0.05 years (controls) versus 5.02 years (all epilepsy, p < 0.001), 5.53 years (generalizable, p < 0.001), and 3.34 years (focal, p = 0.03). Sleep architecture was disrupted in epilepsy, especially in generalizable epilepsy. A higher BAI was positively associated with increased lifetime seizure burden in focal and generalizable epilepsies and associated with lower crystallized cognition. Lifetime seizure burden was inversely correlated with fluid, crystallized, and composite cognition.

Significance: Epilepsy is associated with accelerated brain aging. Higher brain age indices are associated with poorer cognition and more severe epilepsy, specifically generalizability and higher seizure burden. These findings strengthen the use of the sleep-derived, electroencephalography-based BAI as a biomarker for cognitive dysfunction in epilepsy.

Keywords: EEG; Epilepsy; brain age; cognition; sleep.

FIGURE 1

Correlation between epilepsy vs. sleep stage and EEG features. (A) Sleep macrostructure features, specifically sleep stages Nl, N2, N3, and REM, were identified for the Sleep Lab control group, as well as for generalizable epilepsy patients, focal epilepsy patients, and the combined all epilepsy patients. Of note, there is a statistically significant decrease in N3 sleep in all epilepsy patients relative to controls, while the differences between the remaining sleep stages are not statistically significant. (B) The top 15 microstructural features based on sleep EEG that differed between the patients with epilepsy and Dreem controls were noted, with the most prominent features including average central delta–theta ratio in N2 sleep, average central delta–alpha ratio in N2 sleep, and average frontal delta–alpha ratio in N2 sleep.

FIGURE 2

Brain age is positively associated with chronological age for patients with epilepsy. Brain age was calculated using our algorithm and compared to chronological age in patients with epilepsy, in subgroups of patients with generalizable epilepsy and focal epilepsy, and in control groups consisting of the Dreem cohort and Sleep Lab cohort. Seizure frequency was determined for all epilepsy patients and depicted using a color gradient. (A) Brain age index (BAI) by group indicated a higher BAI in epilepsy, most notably in the generalizable group. The DREEM (n = 1,077) and Sleep Lab (n = 112) cohorts serve as controls with ^* < .05; ^**p < .01; ^***p < .001. (B) Brain age and chronological age for all patients with epilepsy were compared, demonstrating a positive linear relationship with the intercept of 10.64 and a slope of 0.86, but no clear association based on the seizure frequency. (C) Brain age and chronological age for patients with generalizable epilepsy showed a positive linear relationship with an intercept of 9.47 and a slope of 0.90, but no clear association based on the seizure frequency. (D) Brain age and chronological age for patients with focal epilepsy showed a positive linear relationship with an intercept of 12.59 and slope of 0.78, but no clear association based on the seizure frequency.

FIGURE 3

Brain age index is positively associated with lifetime seizure burden. The logarithm of the lifetime seizure burden was calculated based on the seizure frequency (per year) multiplied by the years of epilepsy and was then compared to the brain age index (BAI), demonstrating a weakly positive association. (A) For all epilepsy patients, a regression showed an R-squared of 0.0416 with an intercept of 2.16 and a slope of 0.45 with an associated p-value of 0.016. (B) For generalizable epilepsy patients, a regression showed an R-squared of 0.120 with an intercept of 3.30 and a slope of 0.59 with an associated p-value <0.001. (C) For non-generalizable (focal) seizure patients, a regression showed an R-squared of 0.0844 with an intercept of −0.76 and a slope of 0.92 with an associated p-value of 0.099.

FIGURE 4

Cognitive functioning decreases with worsening lifetime seizure burden. The logarithm of the lifetime seizure burden was calculated based on the seizure frequency (per year) multiplied by the years of epilepsy and was then compared to scores on the NIH Toolbox cognitive function battery, demonstrating a negative association. (A) For total composite cognition, a regression demonstrated an R-squared of 0.130 with an intercept of 109.93 and a slope of −2.21 with an associated p-value of 0.011. (B) For total fluid cognition, a regression demonstrated an R-squared of 0.104 with an intercept of 107.70 and a slope of −2.30 with a p-value of 0.024. (C) For total crystallized cognition, a regression demonstrated an R-squared of 0.125 with an intercept of 110.58 and a slope of −1.46 with a p-value of 0.012.

FIGURE 5

Higher crystalized cognitive functioning is negatively associated with brain age index. Brain age index (BAI) for all epilepsy patients was compared to scores on the NIH Toolbox cognitive function battery, demonstrating a negative association. (A) For total composite cognition, a regression demonstrated an R-squared of 0.0467 with an intercept of 103.00 and a slope of −0.66 with an associated p-value of 0.19. (B) For fluid cognition, a regression demonstrated an R-squared of 0.0146 with an intercept of 99.86 and a slope of −0.42 with an associated p­ value of 0.46. (C) For crystallized cognition, a regression demonstrated an R-squared of 0.102 with an intercept of 106.26 and a slope of −0.69 with a p-value of 0.048.