Abstracts

Rationale: Memory impairment is a common feature in temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS). HS severity correlates with memory dysfunction. However, memory impairment is not universally observed in HS patients. In addition to macroscopic findings, HS is associated with synaptic reorganization and increased cellular excitability. Intracellular and synaptic mechanisms in memory dysfunction in TLE remain incompletely understood.Genomic studies provide an insight into intracellular and synaptic functioning in healthy and disease states, and may allow a better understanding of the pathological processes associated with memory impairment in TLE. Methods: We evaluated the association between memory impairment in HS patients and hippocampal genomic expression using gene network analysis.Twenty-two patients with medically refractory epilepsy associated with unilateral HS (13 left) undergoing pre-surgical evaluation and 22 healthy controls underwent a memory battery, including two verbal - Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory Test (LM) - and two non-verbal memory tests - Rey-Osterrieth Complex Figure Test (RCFT) and Face Recognition (FR) Test -. Cut-off scores were established using Receiver Operating Curve (ROC) analysis, comparing patients’ and control’s performances to yield best sensitivity and specificity (Youden index J). Patients were classified as normal or impaired on each test, and a memory impairment score was generated.RNA was extracted from histopathologically confirmed CA3 specimens obtained during amygdalohippocampectomy. We used 44k DNA microarrays to obtain transcriptome profiles, and Weighted Gene Co-expression Networks Analysis (WGCNA) package for complex network analysis, based on Gene Ontology annotated genes. Memory performance was correlated with transcriptional network modules, controlling for confounders (antiepileptic drug load, topiramate use, febrile seizure history and lesion side). Results: Patients and controls did not differ in age, gender and education. Patients showed decreased scores in RAVLT and LM - immediate, delayed and recognition recall on both tests -, FR - immediate and delayed recall - and RCFT - immediate, delayed and late recall - compared to controls. The transcriptional analysis of right HS specimens did not reveal significant modules, therefore directing analysis to left HS patients. Impaired performance in FR was associated with altered gene expression in short-term neuronal plasticity, synaptic transmission and central nervous system development; non-verbal score deficit with learning, neuronal migration, synaptic organization and axon response to injury; intermediate verbal score with short-term memory. Conclusions: We found an association between CA3 transcriptional signatures and clinical patterns of memory impairment. A better understanding of cellular mechanisms associated with memory impairment may contribute to elucidate the role of the hippocampus in verbal and non-verbal memory in patients with mesial temporal lobe epilepsy. Funding: FAPESP- Grant#2005/56.446–0-CinapCe Program-CAMF-LHMCCNPq-Grant#475051/2009–2-CAMF