Project Grant R03AG082988

DELIRIUM, ACUTE INFLAMMATION, AND RHYTHMIC TRANSCRIPTOMICS (DART) - PROJECT SUMMARY POSTOPERATIVE DELIRIUM IN OLDER ADULTS IMPOSES MASSIVE BURDENS ON PATIENTS, FAMILY MEMBERS, AND HOSPITAL SYSTEMS WITH UNITED STATES COSTS UPWARDS OF $32 BILLION. DESPITE THIS, THE PATHOPHYSIOLOGY OF POSTOPERATIVE DELIRIUM REMAINS POORLY UNDERSTOOD AND NO THERAPIES EXIST. DISRUPTION OF THE CIRCADIAN CLOCK SYSTEM IS A PUTATIVE CONTRIBUTOR TO POSTOPERATIVE DELIRIUM. THE CIRCADIAN CLOCK SYSTEM COORDINATES THE TIMING OF MOST PHYSIOLOGIC PROCESSES INCLUDING THE SYSTEMIC INFLAMMATORY RESPONSE, WHOSE DYSFUNCTION HAS BEEN LINKED TO POSTOPERATIVE DELIRIUM INCIDENCE AND SEVERITY. IT IS UNKNOWN WHETHER ACUTE, PERIOPERATIVE DISRUPTION OF THE CIRCADIAN CLOCK SYSTEM LEADS TO AN ABERRANT SYSTEMIC INFLAMMATORY RESPONSE TO PRECIPITATE POSTOPERATIVE DELIRIUM. ELUCIDATION OF THESE DYNAMIC, BIDIRECTIONAL RELATIONSHIPS MAY YIELD NOVEL PREDICTIVE BIOMARKERS AND THERAPIES TO REDUCE DELIRIUM RISK. WE HAVE RECENTLY VALIDATED A MACHINE-LEARNING ALGORITHM, TIMESIGNATURE (TS), THAT USES TRANSCRIPTOMIC DATA FROM WHOLE BLOOD TO MEASURE INTERNAL CIRCADIAN TRANSCRIPTOMIC TIME IN A COHORT OF OLDER ADULTS. TS CAN BE USED TO DETERMINE THE TRANSCRIPTOMIC ANGLE, OR THE MAGNITUDE OF DISCREPANCY BETWEEN INTERNAL TRANSCRIPTOMIC TIME AND TRUE TIME OF BLOOD SAMPLING IN AN INDIVIDUAL. IN THIS PROPOSAL, WE AIM TO DETERMINE TEMPORAL LINKS BETWEEN CHANGES IN TRANSCRIPTOMIC ANGLE, SYSTEMIC INFLAMMATION, AND DELIRIUM SEVERITY IN A COHORT OF OLDER ADULTS UNDERGOING ELECTIVE CARDIAC SURGERY. THE CENTRAL HYPOTHESIS IS THAT PATIENTS STRATIFIED BY DELIRIUM SEVERITY WILL EXHIBIT DISTINCT LONGITUDINAL MOLECULAR PATTERNS OF CIRCADIAN RHYTHMS AND SYSTEMIC INFLAMMATION PERIOPERATIVELY. IN AIM 1, WE WILL DETERMINE WHETHER PATIENTS STRATIFIED BY DELIRIUM SEVERITY EXHIBIT DISTINCT LONGITUDINAL PATTERNS OF TRANSCRIPTOMIC ANGLE ACROSS THE PERIOPERATIVE CONTINUUM. OLDER ADULTS STRATIFIED BY DELIRIUM SEVERITY WILL UNDERGO SERIAL MEASUREMENT OF TRANSCRIPTOMIC ANGLE AT THREE PERIOPERATIVE TIMEPOINTS: ON THE DAY BEFORE CARDIAC SURGERY, ON POSTOPERATIVE DAY (POD) 1, AND POD 4. IN AIM 2, WE WILL EVALUATE WHETHER INCORPORATING PROTEOMIC BIOMARKER DATA ENHANCES DISTINGUISHING LONGITUDINAL PATTERNS AMONG DELIRIUM SEVERITY GROUPS. THE SAME PATIENTS FROM AIM 1 WILL UNDERGO SERIAL MEASUREMENT OF A COMPREHENSIVE PANEL OF PROTEIN BIOMARKERS RELATED TO ACUTE INFLAMMATION AND NEUROBIOLOGICAL INJURY. THE CONTRIBUTION OF THIS PROPOSAL IS SIGNIFICANT BECAUSE IT REPRESENTS CRITICAL FIRST STEP IN ESTABLISHING THE CLINICAL RELEVANCE OF MOLECULAR CIRCADIAN RHYTHM DISRUPTIONS DURING THE PERIOPERATIVE PERIOD. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT WILL SHIFT CURRENT DELIRIUM RESEARCH PARADIGMS TOWARDS A PRECISION-BASED APPROACH IDEALLY SUITED FOR HOSPITALIZED AND CRITICALLY-ILL OLDER ADULTS UNDERGOING MAJOR SURGERY.