Project Grant F31AG101814

IMPACT OF CARDIOVASCULAR HEALTH ON BRAIN AGING IN HUMANS AND GREAT APES - PROJECT SUMMARY/ABSTRACT: AS THE U.S. POPULATION INCREASINGLY AGES, CARDIOVASCULAR (CAVD) AND CEREBROVASCULAR (CEVD) DISEASES REMAIN LEADING CAUSES OF DEMENTIA AND DEATH. AGING IS A MAJOR RISK FACTOR FOR BOTH CAVD AND CEVD, WHICH SHARE ADDITIONAL RISK FACTORS WITH AGE-RELATED NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE (AD). THE LINK BETWEEN VASCULAR DISEASES AND COGNITIVE DECLINE IS WELL-RECOGNIZED- NEURODEGENERATIVE DISEASES ARE A KNOWN CONTRIBUTOR TO CARDIAC ARRHYTHMIA AND EPIDEMIOLOGICAL STUDIES ADDITIONALLY ASSOCIATE DEMENTIA AND CAVD AMONG PATIENT POPULATIONS. HOWEVER, OUR UNDERSTANDING OF HOW VASCULAR DISEASES CONTRIBUTE TO OVERALL BRAIN AGING AND COGNITIVE DECLINE AT THE CELLULAR LEVEL, IS POORLY UNDERSTOOD; FURTHER, IT IS NOT CLEAR WHAT FEATURES OF AGING AND DISEASE ARE UNIQUE TO HUMANS. THIS PROJECT WILL BE A COMPARATIVE STUDY WITH HUMANS, CHIMPANZEES, AND GORILLAS, EXAMINING THE CELLULAR AND MACROSCOPIC STRUCTURAL CHANGES IN THE BRAIN IN THE CONTEXT OF CAVD, CEVD, AND AGE- RELATED COGNITIVE DECLINE. GREAT APES SERVE AS A VALUABLE MODEL FOR STUDYING AGING AND DISEASE, AS THEY ARE OUR CLOSEST LIVING RELATIVES AND HAVE FAIRLY LONG LIFE SPANS, ESPECIALLY IN COMPARISON TO OTHER MODEL ANIMALS FREQUENTLY USED IN NEUROSCIENCE RESEARCH. ADDITIONALLY, GREAT APES EXHIBIT INCREASING HEART DISEASE AND COGNITIVE DEFICITS WITH AGE, AS WELL AS THE AMYLOID-BETA PLAQUES AND TAU NEUROFIBRILLARY TANGLES OBSERVED IN HUMAN AD. THE CENTRAL HYPOTHESIS OF THE PRESENT STUDY IS THAT CAVD AND CEVD NEUROPATHOLOGY INCREASES WITH AGE AND EXACERBATES THE NEURONAL LOSS, GLIOSIS, AND COGNITIVE DECLINE THAT OTHERWISE OCCUR MILDLY WITH NORMAL AGING, AND THAT THESE CHANGES WILL BE GREATER IN HUMANS COMPARED TO GREAT APES. THIS PROJECT WILL UTILIZE MULTIPLEXED IMMUNOFLUORESCENCE (MXIF) TO SIMULTANEOUSLY VISUALIZE FOURTEEN BRAIN CELL TYPES AND PATHOLOGY AT THE SINGLE CELL LEVEL. THIS METHOD WILL ALLOW FOR THE PRECISE MEASUREMENT OF THE NEURONAL LOSS (AIM 1), CHANGES IN OLIGODENDROCYTE, AXON, AND VESSEL DENSITY (AIM 2), AND MICRO- AND ASTROGLIOSIS (AIM 3) THAT OCCURS WITH CAVD AND CEVD. EX VIVO MAGNETIC RESONANCE IMAGING (MRI) SCANS HAVE ALSO BEEN ACQUIRED FOR THE VOLUMETRIC ANALYSIS OF CORTICAL AND SUBCORTICAL STRUCTURES (AIM 1), AS WELL AS WHITE MATTER HYPERINTENSITIES (AIM 2). IN CHIMPANZEES, ANTEMORTEM COGNITIVE DATA WILL ALSO BE COMPARED AGAINST ALL MXIF AND MRI MEASUREMENTS. THE RESULTS FROM THIS STUDY WILL IMPROVE OVERALL UNDERSTANDING OF LIFESPAN AND CARDIOVASCULAR AND COGNITIVE HEALTH, BY DETERMINING IF NEUROLOGICAL CHANGES ASSOCIATED WITH AGING ARE MADE WORSE BY CAVD OR CEVD AND WHETHER EFFECTS DIFFER BETWEEN HUMANS AND GREAT APES. IMPORTANTLY, THIS PROJECT WILL ALSO BE AN EXCEPTIONAL TRAINING OPPORTUNITY AND WILL SUPPORT THE DEVELOPMENT OF MENTORSHIP, TECHNICAL, AND PROFESSIONAL SKILLS TO PROVIDE A STRONG FOUNDATION FOR A CAREER AS AN INDEPENDENT ACADEMIC RESEARCHER.