Project Grant F30AG101849

EXAMINING CEREBROVASCULAR MECHANISMS OF CANCER-RELATED COGNITIVE DECLINE: A MULTIMODAL FRAMEWORK FOR STUDYING COGNITIVE AGING - THE BROAD GOAL OF THIS APPLICATION IS TO DEVELOP AN INNOVATIVE PARADIGM FOR CANCER-RELATED COGNITIVE DECLINE (CRCD) RESEARCH THAT IDENTIFIES CEREBROVASCULAR RISK AS A KEY MODIFIABLE FACTOR CONTRIBUTING TO COGNITIVE AGING IN OLDER CANCER SURVIVORS, WITH TRANSLATIONAL IMPLICATIONS FOR OTHER AGING-RELATED COGNITIVE DISORDERS. AS CANCER SURVIVAL RATES INCREASE ALONGSIDE POPULATION AGING, MORE OLDER ADULTS ARE LIVING WITH THE CONSEQUENCES OF CANCER AND ITS TREATMENTS, INCLUDING COGNITIVE AGING (CRCD) AFFECTING UP TO 75% OF SURVIVORS. THOUGH CRCD'S ETIOLOGY REMAINS UNCLEAR, OLDER CANCER SURVIVORS OFTEN HAVE SEVERAL COMORBIDITIES LIKE HYPERTENSION AND DIABETES THAT INCREASE CEREBROVASCULAR DISEASE RISK AND COGNITIVE DECLINE. HOWEVER, THERE IS LIMITED RESEARCH EXAMINING THE ROLE OF THESE MODIFIABLE CEREBROVASCULAR RISK FACTORS IN CRCD. THIS PROPOSED PROJECT AIMS TO FILL THIS GAP. MY PRELIMINARY WORK REVEALED THAT OLDER BREAST CANCER SURVIVORS WITH A HIGH COMORBIDITY BURDEN HAD GREATER LOSS OF BRAIN GRAY MATTER VOLUME OVER TIME THAN CONTROLS WITH SIMILAR COMORBIDITY BURDEN AND SURVIVORS WITH LOW COMORBIDITY BURDEN. THIS MOTIVATES THE CENTRAL HYPOTHESIS THAT GREATER CEREBROVASCULAR RISK, MEASURED BY THE CLINICALLY-AVAILABLE AND VALIDATED REVISED FRAMINGHAM RISK SCORE, WILL INTERACT SYNERGISTICALLY WITH CANCER AND ITS TREATMENTS TO INDUCE VASCULAR-RELATED BRAIN AGING AND COGNITIVE DECLINE IN OLDER SURVIVORS RELATIVE TO AGE-MATCHED CONTROLS. THIS LONGITUDINAL STUDY WILL LEVERAGE THE EXISTING THINKING AND LIVING WITH CANCER (TLC) DATASET OF 1,141 PARTICIPANTS AGED 60 WITH A BASELINE VISIT (PRE-SYSTEMIC THERAPY IN SURVIVORS) AND ANNUAL FOLLOW-UP FOR UP TO 60 MONTHS. A SUBSET OF THIS COHORT HAD NEUROIMAGING DATA COLLECTED ON THE SAME SCANNER FOLLOWING AN ALZHEIMER'S DISEASE RESEARCH CENTER PROTOCOL. AIM 1 INVESTIGATES THE RELATIONSHIP BETWEEN CEREBROVASCULAR RISK, AS MEASURED BY THE REVISED FRAMINGHAM RISK SCORE, AND COGNITIVE DECLINE OVER TIME. AIMS 2 AND 3 USE ADVANCED NEUROIMAGING TECHNIQUES (PSEUDO-CONTINUOUS ARTERIAL SPIN LABELING, DIFFUSION TENSOR IMAGING, AND 3D FLUID-ATTENUATED INVERSION RECOVERY IMAGING) TO ASSESS CEREBRAL BLOOD FLOW CHANGES AND DISRUPTIONS IN WHITE MATTER INTEGRITY RELATED TO COGNITION AND CEREBROVASCULAR RISK. TO ENSURE SUCCESS IN THESE GOALS, FOUR TRAINING AIMS HAVE BEEN IDENTIFIED INCLUDING 1) ENHANCING NEUROIMAGING EXPERTISE, WITH A FOCUS ON VASCULAR-BASED IMAGING TECHNIQUES, 2) DEVELOPING EXPERTISE IN COGNITIVE ASSESSMENT AND NEUROPSYCHOLOGICAL METHODS, 3) ACQUIRING KNOWLEDGE ABOUT NEW CLINICAL RESEARCH METHODS, INCLUDING BIOINFORMATICS, BIOSTATISTICS, AND INCORPORATION OF MULTI-OMIC DATA TO DESIGN MY FUTURE STUDIES, AND 4) DEVELOPING CROSS-DISCIPLINARY CLINICAL EXPOSURE TO SUCCESSFULLY INTEGRATE KNOWLEDGE ABOUT CEREBROVASCULAR RISK, CANCER AND COGNITIVE AGING INTO FUTURE RESEARCH AND PRACTICE. TAKEN TOGETHER, THIS PROJECT WILL CONTRIBUTE AN INNOVATIVE PARADIGM TO THE CRCD LITERATURE THAT CAN BE APPLIED TO OTHER DISEASES OF COGNITIVE AGING, LIKE ALZHEIMER'S DISEASE AND VASCULAR DEMENTIA, WHILE OFFERING UNPARALLELED TRAINING EXPERIENCES FOR MY CAREER GOAL OF BECOMING A PHYSICIAN-SCIENTIST WHO DEVELOPS PERSONALIZED MEDICINE APPROACHES FOR AGING-RELATED COGNITIVE DISORDERS.