Project Grant R01AG091184

PROTEIN CO-PATHOLOGIES IN ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - ABSTRACT DEMENTIA IS ASSOCIATED WITH STAGGERING ECONOMIC, SOCIAL, AND PERSONNEL COSTS. STRIKINGLY, MOST DEMENTIA CASES HAVE CO-PATHOLOGIES BEYOND THE DOMINANT TYPE. RESEARCH SUGGESTS THESE NON-DOMINANT PROTEIN AGGREGATES CAN IMPACT COGNITION, SYMPTOMS, AND PROGRESSION. THESE FINDINGS MOTIVATE OUR CENTRAL HYPOTHESIS THAT INDIVIDUAL PATHOLOGIES UNIQUELY CONTRIBUTE TO THE DEGENERATIVE TRAJECTORY OF CLINICAL DEMENTIA. OUR LONG-TERM GOAL IS TO BUILD A MODEL OF DEGENERATIVE DEMENTIA THAT IS INCLUSIVE OF CO-PATHOLOGY. ACCOMPLISHING THIS GOAL REQUIRES IDENTIFYING PATHOLOGIES AND DETERMINING HOW EACH PATHOLOGY CONTRIBUTES TO NEURODEGENERATION, INCLUDING SYNAPSE LOSS, CELL LOSS, AND CLINICAL SYMPTOMS. TO ACCOMPLISH THIS GOAL, WE WILL FIRST DETERMINE THE RELATIONSHIP BETWEEN PATHOLOGY IN CUTANEOUS NERVES AND PATHOLOGY IN THE BRAIN OF INDIVIDUALS THAT DIED WITH DEMENTIA, INCLUDING ALZHEIMER'S DISEASE OR RELATED DISORDERS. THERE IS STRONG EVIDENCE TYING ALPHA-SYNUCLEIN AGGREGATES IN PERIPHERAL NERVES WITH PARKINSON'S DISEASE. HOWEVER, IT IS UNKNOWN HOW THIS CLINICALLY AVAILABLE BIOMARKER RELATES TO BRAIN PATHOLOGY IN PATIENTS WITH DEMENTIAS. IN AIM 2, WE WILL USE BOTH UNBIASED STEREOLOGY AS WELL AS HIGH THROUGHPUT SCREENING METHODS TO EVALUATE THE RELATIONSHIP BETWEEN BRAINSTEM PATHOLOGY AND CELL LOSS. PATHOLOGY IN BRAINSTEM PROJECTION NEURONS SUCH AS NOREPINEPHRINE PRODUCING LOCUS COERULEUS, SEROTONIN PRODUCING DORSAL RAPHE, AND ACETYLCHOLINE PRODUCING PEDUNCULOPONTINE NUCLEUS HAVE THE POTENTIAL TO SUBSTANTIALLY IMPACT THE BRAIN AND ITS RESPONSE TO PHARMACOLOGICAL TREATMENT. ALTHOUGH SUBSTANTIAL EVIDENCE SUPPORTS THE PREMISE THAT THESE REGIONS SHOW PATHOLOGY, FEW STUDIES HAVE COMPARED HOW DIFFERENT PATHOLOGIES IMPACT CELL MORPHOLOGY OR DEATH. FINALLY, IN AIM 3 WE WILL DIRECTLY QUANTIFY HOW SPECIFIC PATHOLOGIES IMPACT CORTICAL SYNAPSE LOSS. SYNAPSE LOSS IS CONSIDERED ONE OF THE STRONGEST PREDICTORS OF COGNITIVE DEFICITS. HOWEVER, STUDIES ARE NOT DEFINITIVE ON WHICH PATHOLOGIES BEST PREDICT THIS LOSS. WE WILL USE CONVERGING TECHNIQUES, INCLUDING GOLGI-STAINING AND HIGH- RESOLUTION IMMUNOFLUORESCENCE TO INCREASE GENERALIZABILITY AND REPRODUCIBILITY WHEN ADDRESSING THIS CRITICAL QUESTION. UNDERDIAGNOSIS OF CO-PATHOLOGIES IMPACTS CARE AND RESEARCH AND UNDERMINES OUR UNDERSTANDING OF NEURODEGENERATIVE DEMENTIAS. THESE AIMS ADDRESS THE ROLE AND PATTERN OF CO-PATHOLOGY AND BEGIN TO BRIDGE THE GAP FROM THE GOLD STANDARD BRAIN AUTOPSY TO CLINICALLY AVAILABLE PERIPHERAL BIOMARKERS.