Abstracts

Rationale:
Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remains poorly understood. The objective of this study was to compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory.
Method:
Brain tissue specimens were obtained from 23 adults who underwent dominant temporal lobectomies for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE genotype on memory, only APOE ε3 homozygotes were included. Patients were classified into one of two groups based on preoperative memory performance (impaired=10 vs. intact=13). The groups were well-matched on demographic and disease variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from temporal lobe tissues, and pathway and integrative analyses were conducted.  
Results:
We identified 1092 differentially expressed transcripts (DETs), the majority (71%) of which were underexpressed in brain tissues from patients with impaired memory compared to those with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite identical APOE genotypes (ε3/ ε3), APOE was underexpressed in patients with impaired memory compared to those with intact memory. Four differentially expressed microRNAs (miRNAs) were identified and predicted to target a subset (22%) of all DETs. Integrative analysis showed that the miRNA-predicted DET targets impact brain-related pathways and biological processes pertinent to memory and cognition.
Conclusion:
Our results suggest that episodic memory function in TLE may be influenced by gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE.
Funding:
:Clinical and Translational Science Collaborative of Cleveland (KL2TR000440, UL1TR000439) from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research (to R.M.B.); Cleveland Clinic Epilepsy Center (to R.M.B.); Lerner Research Institute Center of Excellence for Epilepsy and Co-morbidities Research (to R.M.B., I.N. and C.E.).