Project Grant R01NS135080

MOLECULAR PROFILING AND BIOMARKERS OF MEMORY PHENOTYPES IN TEMPORAL LOBE EPILEPSY - PROJECT SUMMARY TEMPORAL LOBE EPILEPSY (TLE) IS A LEADING CAUSE OF SEIZURE DISORDERS IN ADULTS AND IS ASSOCIATED WITH HIGH RISK OF MEMORY DEFICITS THAT CAN NEGATIVELY IMPACT DAY-TO-DAY FUNCTIONING AND QUALITY OF LIFE. MEMORY DEFICITS ARE MOST PREVALENT IN THOSE WITH PHARMACORESISTANT MESIAL TLE AND HIPPOCAMPAL SCLEROSIS (MTLE-HS). HOWEVER, A LARGE SUBSET OF PATIENTS WITH MTLE-HS PARADOXICALLY HAVE INTACT MEMORY PERFORMANCE, EVEN WITH HISTOPATHOLOGICAL EVIDENCE OF MARKED HIPPOCAMPAL CELL LOSS. DESPITE THE HIGH PREVALENCE OF MEMORY IMPAIRMENT IN PATIENTS WITH TLE, VERY LITTLE IS KNOWN ABOUT THE UNDERLYING PATHOPHYSIOLOGICAL ETIOLOGIES OF SUCH MEMORY DYSFUNCTION AND THERE ARE NO PREDICTIVE BIOMARKERS. OUR LONG-TERM OBJECTIVES ARE TO IDENTIFY PERIPHERAL BIOMARKERS AND TO DEVELOP INDIVIDUALIZED PROGNOSTICATION MODELS FOR MEMORY IMPAIRMENT IN ADULTS WITH TLE, WHICH WILL AID THE DEVELOPMENT OF EVIDENCE-BASED CLINICAL TRIALS TO TREAT OR PREVENT MEMORY IMPAIRMENT IN TLE. PREVIOUSLY, WE IDENTIFIED GENES AND PROTEINS ASSOCIATED WITH IMPORTANT NEUROLOGICAL FUNCTIONS, INCLUDING PROCESSES ESSENTIAL FOR NEW MEMORY FORMATION AND IMPLICATED IN NEURODEGENERATIVE DISEASES. THESE GENES AND PROTEINS ARE OVEREXPRESSED IN THE TEMPORAL LOBE OF PATIENTS WITH TLE AND IMPAIRED MEMORY COMPARED TO THOSE WITH INTACT MEMORY, DESPITE THE SAME PATHOLOGICAL SUBSTRATE AND DISEASE SEVERITY. IN THIS PROPOSAL, WE WILL IDENTIFY MOLECULAR BIOMARKERS FOR EPISODIC MEMORY DYSFUNCTION IN TLE BY PERFORMING DEEP MOLECULAR PROFILING OF A WELL-MATCHED AND CAREFULLY CLINICALLY-PHENOTYPED PROSPECTIVE SERIES OF PATIENTS WITH LANGUAGE-DOMINANT MTLE-HS. GUIDED BY OUR STRONG PRELIMINARY DATA, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: AIM 1) TO IDENTIFY REGIONAL DIFFERENCES IN TRANSCRIPT AND PROTEIN EXPRESSION IN HIPPOCAMPAL AND TEMPORAL NEOCORTICAL TISSUES BETWEEN PATIENTS WITH AND WITHOUT EPISODIC MEMORY IMPAIRMENT; AIM 2) TO ASCERTAIN CELL-TYPE- SPECIFIC DIFFERENCES IN RNA EXPRESSION IN TEMPORAL LOBE TISSUES BETWEEN PATIENTS WITH AND WITHOUT MEMORY IMPAIRMENT; AND AIM 3) TO IDENTIFY PERIPHERAL BLOOD BIOMARKERS FOR EPISODIC MEMORY IMPAIRMENT IN TLE THROUGH INTEGRATIVE ANALYSES. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE WE WILL BROADLY AND DEEPLY CHARACTERIZE THE BRAIN TRANSCRIPTOME AND TARGETED PROTEOME IN TLE, WHICH HAS NOT BEEN INVESTIGATED PREVIOUSLY, USING RESOURCES AND EXPERTISE THAT ARE UNIQUE TO THE CLEVELAND CLINIC EPILEPSY CENTER, ONE OF THE LARGEST SURGICAL EPILEPSY CENTERS IN THE US. THE IMPACT OF THIS PROJECT INCLUDES 1) THE ELUCIDATION OF MOLECULAR UNDERPINNINGS FOR EPISODIC MEMORY IMPAIRMENT IN PHARMACORESISTANT TLE AND 2) THE IDENTIFICATION OF PREDICTIVE PERIPHERAL BIOMARKERS OF MEMORY DYSFUNCTION IN TLE. THESE ARE CRUCIAL FIRST STEPS IN THE EFFORT TO IDENTIFY MEASURABLE MARKERS AND MECHANISMS OF MEMORY IMPAIRMENT IN TLE. THE ULTIMATE FUTURE GOAL IS THE DEVELOPMENT OF PERSONALIZED PROGNOSTICATION MODELS AND EVIDENCE- BASED CLINICAL TRIALS TO TREAT OR PREVENT MEMORY IMPAIRMENT IN TLE, IN ORDER TO IMPROVE DAY-TO-DAY FUNCTIONING AND QUALITY OF LIFE. IN ADDITION, OUR FINDINGS WILL HAVE IMPORTANT IMPLICATIONS FOR OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH MEMORY IMPAIRMENT DUE TO PREDICTABLY OVERLAPPING BIOLOGICAL MECHANISMS.