Abstracts

Rationale: Executive functioning (EF) deficits are common in patients with temporal lobe epilepsy (TLE), despite relatively focal temporal lobe seizure onset (Stretton & Thompson, 2012; Oyegbile et al., 2004). Several genetic polymorphisms (APOE ε4, BDNF Met, and COMT Val) have been demonstrated to play a role in EF in healthy individuals and patients with neurologic disease, but have not been investigated in TLE. The objective of this study was to explore these known polymorphisms in EF performance in patients with pharmacoresistant TLE.  Methods: Ninety-three adults (51 female, Mage=39 years) with TLE completed at least some of the following EF measures as part of presurgical evaluations: Trail Making Test – Parts A & B (TMT-A, TMT-B), Wisconsin Card Sorting Test – Perseverative Errors (WCST-PE), Color Word Interference (CWI) from the Delis Kaplan Executive Function System, Controlled Oral Word Association Test (COWAT), and semantic  fluency (Animals). Demographically corrected standard scores were used for all measures. Genotyping was conducted using DNA extracted from peripheral blood or brain tissue. A series of ANCOVAs was conducted with carrier status (for each gene separately) as independent variable and EF measure (for each measure separately) as dependent variable. The following covariates (CVs) were considered: age at seizure onset, duration of epilepsy, and etiology. Interactions between genotypes could not be adequately examined due to small sample sizes for some carrier combinations. Results: Age at seizure onset was eliminated as a CV due to multicollinearity with duration of epilepsy, and etiology was eliminated as a CV using a model selection procedure based on Akaike’s Information Criteria. After adjustment for duration, COMT Val carriers showed poorer performance on Animals (p < .001, ηp2=.17) and CWI (p < .05, ηp2=.10), and BDNF Met carriers showed poorer performance on COWAT (p < .01, ηp2=.08) with medium to large effects. Trends, with generally moderate range effect sizes, were observed on several other executive functioning measures as well. Specifically, APOE ε4 carriers demonstrated poorer performance on TMT-B (p=.06, ηp2=.04) and CWI (p=.05, ηp2=.06). Conclusions: Results suggest that COMT, BDNF, and APOE polymorphisms are significantly associated with performance on a range of EF measures (response inhibition, lexical fluency, semantic fluency) with trends on other EF abilities (mental flexibility) in patients with TLE , accounting for up to 17% of the variance in test performance. Twin studies suggest that EF is highly heritable, with estimates as high as 99% (Friedman et al., 2008). As such, additional research is clearly needed to further examine the genetic underpinnings of executive dysfunction in temporal lobe epilepsy. Funding: Cleveland Clinic Epilepsy Center, NIH/NCATS, CTSC/CTSA, Cleveland, Ohio KL2TR000440 and UL1TR000439 (R.M.B.), Cleveland Clinic Neurological Institute Center for Outcomes Research and Evaluation (R.M.B.), and Clinical Research Unit (R.M.B.)