Project Grant K23NS133488

MAGNETIC RESONANCE IMAGING BIOMARKERS OF POST-COVID-19 CEREBRAL MICROVASCULAR DYSFUNCTION - ABSTRACT NEUROLOGIC POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION (NEURO-PASC) IS A PRESSING PUBLIC HEALTH ISSUE AND LITTLE IS KNOWN ABOUT THE CAUSE, DURATION, AND POTENTIAL TREATMENTS. IT IS DEFINED AS A NEW HEALTH PROBLEM OCCURRING THREE MONTHS AFTER INITIAL COVID INFECTION AND LASTING FOR AT LEAST TWO MONTHS. COMMON SYMPTOMS OF NEURO- PASC INCLUDE HEADACHE, INATTENTION, COGNITIVE IMPAIRMENT, DIZZINESS, INSOMNIA, AND MOOD CHANGES. EMERGING EVIDENCE SUGGESTS THAT PERSISTENT MICROVASCULAR INFLAMMATION AND DYSFUNCTION PLAY CRITICAL ROLES IN THE PASC OF THE LUNGS AND HEART. NUMEROUS POST-MORTEM STUDIES HAVE DEMONSTRATED SIGNIFICANT MICROVASCULAR DAMAGE AND DYSFUNCTION IN THE BRAINS OF INDIVIDUALS WHO HAVE DIED OF ACUTE COVID-19. IN THE BRAINS OF INDIVIDUALS LIVING WITH NEURO-PASC, CASE-CONTROL STUDIES HAVE FOUND MICROVASCULAR DYSFUNCTION, CEREBRAL HYPOPERFUSION, AND NEW SMALL VESSEL DISEASE. THE LONG-TERM NEUROLOGIC EFFECTS OF MICROVASCULAR DYSFUNCTION AND SUBSEQUENT RISK OF VASCULAR DEMENTIA IS UNKNOWN. I HYPOTHESIZE THAT CEREBRAL MICROVASCULAR DYSFUNCTION PLAYS A CRITICAL ROLE IN NEURO- PASC COGNITIVE IMPAIRMENT AND PUTS INDIVIDUALS AT RISK FOR PROGRESSION OF SMALL VESSEL DISEASE. HERE, I PROPOSE UTILIZING ADVANCED VASCULAR MRI TECHNIQUES TO INVESTIGATE FOR BIOMARKERS OF MICROVASCULAR DYSFUNCTION IN THE BRAIN TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY OF NEURO-PASC AND RISK FOR PROGRESSION OF SMALL VESSEL DISEASE. UNDERSTANDING THE UNDERLYING DISEASE PROCESS WILL BRING US CLOSER TO IDENTIFYING BIOMARKERS AND TREATMENT TARGETS. IN ORDER TO ENRICH THE PROBABILITY OF FINDING MRI ALTERATIONS, I WILL RECRUIT PARTICIPANTS WITH COGNITIVE IMPAIRMENT, WHICH IS THE MOST COMMON AND WELL-DOCUMENTED NEURO-PASC SYMPTOM. I WILL CONDUCT A LONGITUDINAL STUDY AND PERFORM TWO SETS OF MRIS, BLOOD TESTS, AND NEUROPSYCHOLOGICAL TESTS ON EACH PARTICIPANT. I WILL RECRUIT AT LEAST 50 ADULTS WITH A DOCUMENTED COVID-19 INFECTION AND COGNITIVE SYMPTOMS AND COMPARE THEM TO 50 ADULTS WITH A DOCUMENTED COVID-19 INFECTION AND NO RESIDUAL SYMPTOMS (CONTROLS). MY DETAILED MRI PROTOCOL WILL EVALUATE THE VESSEL WALL, ARTERIAL, AND VENOUS VASCULATURE AND EXPLORE TECHNIQUES TO MAP THE LYMPHATIC VASCULATURE. IN THE BLOOD, I WILL TEST MARKERS OF COAGULOPATHY, ENDOTHELIOPATHY, AND NEURODEGENERATION. I AM A NEUROLOGIST AND PHYSICIAN-SCIENTIST WHO HAS DEVELOPED CLINICAL AND SCIENTIFIC EXPERTISE IN NEURO-PASC THROUGH CARING FOR PATIENTS IN THE NEUROCOVID CLINIC AT YALE, AND I AM WORKING IN THE NEURO-INFECTIOUS DISEASE LABORATORY OF MY PRIMARY MENTOR. I RECENTLY GRADUATED FROM FELLOWSHIP, AND I AM NOW AN INSTRUCTOR IN THE DEPARTMENT OF NEUROLOGY. MY LONG-TERM GOAL IS TO BECOME AN INDEPENDENT CLINICIAN-SCIENTIST WITH A FOCUS ON UTILIZING NEUROIMAGING TECHNIQUES TO UNDERSTAND THE PATHOPHYSIOLOGY OF NEURO-PASC AND GENERATE BIOMARKERS OF DISEASE AND TREATMENT TARGETS. TO ACCOMPLISH THIS GOAL, I HAVE ASSEMBLED A WORLD CLASS MENTORSHIP TEAM WITH EXPERTS IN NEURORADIOLOGY, NEUROPSYCHOLOGY, AND NEURO-ID. I WILL TAKE ADVANCED COURSEWORK IN NEUROIMAGING, STATISTICS, AND VASCULAR BIOLOGY. THE COMPLETION OF THIS MENTORED AWARD WILL PREPARE ME TO BECOME AN INDEPENDENT PHYSICIAN-SCIENTIST AND ALLOW ME TO MAKE MEANINGFUL CONTRIBUTIONS TO THE FIELD AND TO PATIENT CARE.