Hebrew Rehabilitation Center

INTERDISCIPLINARY STUDY OF DELIRIUM AND ITS LONG-TERM OUTCOMES

RISK FACTORS FOR AGED RELATED BONE LOSS

BONE MICROARCHITECTURE: THE FRAMINGHAM OSTEOPOROSIS STUDY

DEVELOPMENT AND VALIDATION OF A DELIRIUM SEVERITY TOOLKIT

TRIAL TO REDUCE ANTIMICROBIAL USE IN NURSING HOME RESIDENTS WITH ALZHEIMER'S DISEASE AND OTHER DEMENTIAS (TRAIN-AD)

TRANSLATIONAL RESEARCH IN AGING TRAINING PROGRAM

NETWORK FOR INVESTIGATION OF DELIRIUM ACROSS THE U.S. (NIDUS)

LOW MAGNITUDE MECHANICAL STIMULATION TO IMPROVE BMD

NIDUS II: ADVANCED-STAGE DEVELOPMENT AND UTILIZATION OF THE NIDUS RESEARCH INFRASTRUCTURE TO ADVANCE INTERDISCIPLINARY AGING RESEARCH IN DELIRIUM - DELIRIUM, AN ACUTE DISORDER OF ATTENTION AND COGNITION, IS A COMMON, LIFE-THREATENING, AND COSTLY CONDITION FOR OLDER ADULTS WITH STRONG LINKS TO ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD). IN 2015, RESPONDING TO RFA-AG-16-009, WE CREATED THE NETWORK FOR INVESTIGATION OF DELIRIUM: UNIFYING SCIENTISTS (NIDUS I, R24AG054259), A COLLABORATIVE INTERDISCIPLINARY NETWORK OF 28 INVESTIGATORS SPANNING 27 INSTITUTIONS WHICH HAS PROVIDED RESEARCH RESOURCES, MEETINGS, PILOT GRANTS, AND INTENSIVE MENTORSHIP FOR >90 TRAINEES, LEADING TO >340 FIRST AUTHOR PAPERS AND >46 GRANTS AS PRINCIPAL INVESTIGATOR. DESPITE THIS PROGRESS, A MAJOR KNOWLEDGE GAP IN THE FIELD REMAINS: SAFE AND EFFECTIVE TREATMENTS FOR DELIRIUM. THUS, IN RESPONSE TO PAR-20-071, WE PROPOSE TO EXPAND THE EXISTING INFRASTRUCTURE AS NIDUS II TO ADVANCE THE FUNDAMENTAL SCIENCE NEEDED TO DEVELOP MORE EFFECTIVE TREATMENTS FOR DELIRIUM, AND ULTIMATELY, IMPROVE OUTCOMES FOR DELIRIUM IN ALL OLDER ADULTS AND IN THOSE WITH ADRD. OUR SPECIFIC AIMS ARE: (1) HARMONIZATION CORE. TO DEVELOP AND EXPAND INNOVATIVE MEASUREMENT METHODS RELATED TO HARMONIZATION OF DELIRIUM MEASURES, OUTCOMES, AND PREDICTORS FOR CLINICAL STUDIES AND TREATMENT TRIALS, AND TO REFINE MEASURES OF DELIRIUM DIAGNOSIS AND SEVERITY IN PATIENTS WITH ALL STAGES OF ADRD. THESE APPROACHES WILL ALLOW US TO COMBINE DATA FROM MULTIPLE EXISTING DELIRIUM STUDIES; (2) RESEARCH RESOURCES CORE. TO DEVELOP AND EXPAND THE NIDUS RESEARCH HUB TO CREATE A COLLABORATIVE INFRASTRUCTURE THAT WILL SEED FUTURE INTERDISCIPLINARY STUDIES TO ADVANCE DELIRIUM RESEARCH (E.G., BIOMARKER STUDIES, INTERVENTION DEVELOPMENT STUDIES); (3) PILOT/EXPLORATORY STUDIES CORE. TO AWARD PILOT AND EXPLORATORY GRANTS THAT WILL PROMOTE COLLABORATIVE INTERDISCIPLINARY STUDIES DESIGNED TO UTILIZE OUR INFRASTRUCTURE AND ADVANCE RESEARCH NEEDED TO DEVELOP BETTER TREATMENTS FOR DELIRIUM. FOR THIS AIM, WE WILL ASSEMBLE COLLABORATIVE WORKING GROUPS (WG) WHICH WILL ADDRESS 4 SCIENTIFIC PRIORITY AREAS: (A) MEASUREMENT: HARMONIZE AND REFINE MEASUREMENT OF DELIRIUM AND RELATED OUTCOMES, INCLUDING PATIENTS WITH ADRD, AND TO ENSURE ACCURATE AND SENSITIVE MEASURES FOR TREATMENT TRIALS; (B) PATHOPHYSIOLOGY: BIOMARKER AND MECHANISTIC STUDIES TO ADVANCE OUR UNDERSTANDING AND IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR TREATMENT TRIALS; (C) CLINICAL TRIALS: INTERVENTION DEVELOPMENT FOR NEW MULTICOMPONENT TREATMENT APPROACHES; (D) INTER-RELATIONSHIP OF DELIRIUM AND ADRD: EPIDEMIOLOGIC, RISK FACTOR, PATHOPHYSIOLOGIC, PROGNOSTIC, AND ESPECIALLY TREATMENT STUDIES; (4) CAREER DEVELOPMENT AND OUTREACH CORE: FOR EARLY-STAGE INVESTIGATORS WHO WILL UTILIZE THE NIDUS II INFRASTRUCTURE AND WILL BE INVOLVED IN WORKING GROUPS, PILOT STUDIES, AND TRAINING EVENTS. EVERY ASPECT OF NIDUS II IS DESIGNED TO SEED INNOVATIVE SCIENTIFIC DISCOVERY, AND DRIVE DELIRIUM RESEARCH IN A CRITICALLY IMPORTANT DIRECTION: DEVELOPMENT OF EFFECTIVE TREATMENTS FOR DELIRIUM, INCLUDING DELIRIUM IN ADRD. WHILE WE ARE BUILDING ON THE PREVIOUS NETWORK, THE INNOVATION OF THE NEW NIDUS II NETWORK IS THE PURPOSEFUL APPLICATION AND EXPANSION OF THE INFRASTRUCTURE TO ADVANCE SCIENTIFIC EXPLORATION AND IMPACT IN SPECIFIC PRIORITY AREAS OF GREATEST BENEFIT TO OLDER AMERICANS. .

APPLICATIONS OF CLAIMS-BASED FRAILTY INDEX TO ADVANCE EVIDENCE FOR FRAILTY-GUIDED DECISION-MAKING - PROJECT SUMMARY/ABSTRACT OLDER ADULTS WITH FRAILTY ARE MORE LIKELY TO EXPERIENCE POOR HEALTH OUTCOMES AFTER ACUTE ILLNESSES, DRUG-RELATED ADVERSE EVENTS, AND SURGERIES. HEALTH CARE COSTS FOR FRAIL PATIENTS DOUBLE DUE TO ACUTE HOSPITAL CARE, POST-ACUTE CARE, AND TREATMENTS FOR PREVENTABLE CONDITIONS. DESPITE CLINICAL AND SOCIETAL CONSEQUENCES OF FRAILTY, FRAILTY IS RARELY ASSESSED IN CLINICAL PRACTICE AND LITTLE EVIDENCE EXISTS ON HOW TO INTEGRATE FRAILTY TO INFORM CLINICAL CARE AND POPULATION HEALTH MANAGEMENT. THE CRITICAL STEP TO GENERATE THIS EVIDENCE IS TO MEASURE FRAILTY ON A LARGE SCALE WITH HIGH ACCURACY AND EFFICIENCY. TO ADDRESS THIS NEED, THE INVESTIGATOR TEAM RECENTLY DEVELOPED AND VALIDATED A CLAIMS-BASED FRAILTY INDEX (CFI), WHICH ENABLES MEASUREMENT OF FRAILTY FROM MEDICARE DATA FOR LARGE POPULATIONS WHEN IN-PERSON ASSESSMENT IS NOT FEASIBLE. THE OBJECTIVE OF THIS APPLICATION IS TO GENERATE EVIDENCE NEEDED FOR FRAILTY-GUIDED CLINICAL CARE AND POPULATION HEALTH MANAGEMENT BY APPLYING CFI TO CLAIMS DATA-BASED STUDIES OF DRUG THERAPY; PRAGMATIC CLINICAL TRIALS OF PROCEDURAL THERAPY; AND ELECTRONIC HEALTH RECORDS (EHR)-MEDICARE LINKED DATA OF A HEALTH CARE SYSTEM. THE CENTRAL HYPOTHESIS IS THAT FRAILTY INFORMATION WILL IMPROVE CARE OF OLDER ADULTS BY UNCOVERING MEANINGFUL VARIATIONS IN THE TREATMENT BENEFIT-HARM PROFILE, COSTS, AND RESOURCE NEEDS. TO TEST THIS HYPOTHESIS, THE INVESTIGATOR TEAM WITH EXTENSIVE EXPERTISE IN FRAILTY, PHARMACOEPIDEMIOLOGIC METHODS, AND HEALTH SERVICES RESEARCH WILL ACCOMPLISH THE FOLLOWING SPECIFIC AIMS IN THE NEXT 5 YEARS: 1) DETERMINE HOW FRAILTY CHANGES THE BENEFITS AND HARMS OF 10 PRESCRIPTION DRUGS FOR CHRONIC CONDITIONS IN OLDER ADULTS BY APPLYING CFI TO THE 2014-2022 5% MEDICARE RANDOM SAMPLE; 2) DETERMINE HOW FRAILTY CHANGES THE BENEFITS AND HARMS OF PROCEDURAL THERAPIES IN OLDER ADULTS BY APPLYING CFI TO MEDICARE DATA LINKED TO 2 ONGOING PRAGMATIC CLINICAL TRIALS OF ENDOVASCULAR VS SURGICAL REVASCULARIZATION THERAPY FOR PERIPHERAL ARTERIAL DISEASE AND ACUPUNCTURE VS USUAL CARE FOR CHRONIC LOW BACK PAIN; AND 3) DETERMINE WHETHER IMPLEMENTING CFI TO EHR-MEDICARE LINKED DATA CAN PREDICT HIGH-COST AND HIGH-NEED PATIENTS IN A LARGE HEALTH CARE SYSTEM IN BOSTON, MASSACHUSETTS. THE INNOVATIVE APPLICATIONS OF CFI ARE READILY SCALABLE TO CLAIMS-BASED COMPARATIVE EFFECTIVENESS AND SAFETY STUDIES, CLINICAL TRIALS, AND EHR IN HEALTH CARE SYSTEMS. THE IMPACT OF THIS RESEARCH IS SIGNIFICANT BECAUSE THE CLINICALLY ACTIONABLE EVIDENCE GENERATED FROM THIS RESEARCH CAN ENABLE OPTIMAL CHOICE OF DRUG AND PROCEDURAL THERAPY AND A HEALTH SYSTEM-WIDE RISK STRATIFICATION BASED ON FRAILTY. ULTIMATELY, THESE RESULTS WILL ACCELERATE INTEGRATION OF FRAILTY IN ROUTINE CARE AND FACILITATE FRAILTY-GUIDED CLINICAL CARE AND POPULATION HEALTH MANAGEMENT.

HEALTH OUTCOMES OF TAI CHI IN SUBSIDIZED SENIOR HOUSING

DETERMINANTS AND OUTCOMES OF AGE-RELATED MUSCLE LOSS - ABSTRACT / PROJECT SUMMARY THE UNDERSTANDING OF PROCESSES THAT LEAD TO AGE-RELATED DECLINE IN MUSCLE MASS AND ITS CONSEQUENCES HAS BEEN FUNDAMENTALLY LIMITED BY IMPERFECT METHODS OF ASSESSING TOTAL MUSCLE MASS. THIS HAS SLOWED THE DEVELOPMENT OF INTERVENTIONS TO PREVENT SKELETAL MUSCLE LOSS. THE LONG-TERM GOAL OF THIS RESEARCH IS TO GAIN A BETTER UNDERSTANDING OF THE CAUSES AND CONSEQUENCES OF LOW TOTAL MUSCLE MASS IN OLDER ADULTS. THE OBJECTIVES OF THIS PROJECT ARE TO MEASURE TOTAL MUSCLE MASS VIA THE D3-CREATINE DILUTION METHOD AND DETERMINE ITS ASSOCIATION WITH GENETIC AND NON-GENETIC RISK FACTORS, AND THEIR RELATION WITH FALLS, INJURIOUS FALLS AND FRACTURES IN TWO LARGE, COMMUNITY-BASED COHORTS OF OLDER ADULTS. THIS TECHNIQUE PROVIDES A DIRECT AND ACCURATE ESTIMATE OF TOTAL MUSCLE MASS FROM A SINGLE, FASTING URINE SPECIMEN. THE CENTRAL HYPOTHESES ARE THAT LOWER TOTAL MUSCLE MASS IS ASSOCIATED WITH NOVEL GENETIC VARIANTS, WHICH WHEN USED AS INSTRUMENTAL VARIABLES IN A MENDELIAN RANDOMIZATION ANALYSIS WILL DEMONSTRATE THAT LOWER TOTAL MUSCLE MASS DIRECTLY INCREASES THE RISK OF INCIDENT FALLS, INJURIOUS FALLS AND FRACTURES. FURTHERMORE, ASSOCIATION OF LIFESTYLE PREDICTORS (DIET AND PHYSICAL ACTIVITY) WITH TOTAL MUSCLE MASS AND WITH ACCELERATED LOSS OF TOTAL MUSCLE MASS WILL BE PARTLY MEDIATED BY INFLAMMATION MARKER INTERLEUKIN-6 (IL- 6). GUIDED BY STRONG PRELIMINARY DATA THIS HYPOTHESIS WILL BE TESTED BY PURSUING THREE SPECIFIC AIMS USING UP TO 3,200 PARTICIPANTS FROM TWO WELL-CHARACTERIZED COHORTS, THE FRAMINGHAM HEART STUDY (FHS) AND THE OSTEOPOROTIC FRACTURES IN MEN (MROS) STUDY. AIM 1 WILL IDENTIFY GENETIC VARIANTS ASSOCIATED WITH TOTAL MUSCLE MASS ESTIMATED BY D3-CREATINE DILUTION IN THE FHS AND MROS COHORTS BY PERFORMING A GENOME-WIDE ASSOCIATION STUDY (GWAS).THE AVAILABILITY OF ADDITIONAL COHORTS WITH D3-CREATINE AND GENOTYPING WILL BRING THE SAMPLE SIZE TO 8,400. AIM 2 WILL DETERMINE THE CAUSAL RELATION BETWEEN TOTAL MUSCLE MASS ESTIMATED BY D3-CREATINE DILUTION AND INCIDENT FALLS, INJURIOUS FALLS AND FRACTURES BY USING SNPS IDENTIFIED IN AIM 1 AS INSTRUMENTAL VARIABLES FOR TOTAL MUSCLE MASS IN A MENDELIAN RANDOMIZATION ANALYSIS IN THE FHS AND MROS COHORTS. AIM 3 WILL DETERMINE THE CROSS- SECTIONAL ASSOCIATIONS OF PHYSICAL ACTIVITY, DIETARY PROTEIN, ESSENTIAL AMINO ACIDS (EAA), BRANCHED CHAIN AMINO ACIDS (BCAA) AND N-3 POLYUNSATURATED FATTY ACIDS (N3-PUFA) WITH BASELINE TOTAL MUSCLE MASS IN THE FHS AND MROS COHORTS AS WELL AS ASSOCIATIONS WITH THE CHANGE IN TOTAL MUSCLE MASS OVER AN 18 MONTH PERIOD IN THE FHS COHORT. TO MINIMIZE THE CHANCE OF CONFOUNDING, AIM 3 WILL ALSO USE A PREVIOUSLY PUBLISHED GWAS ON ACCELEROMETRY DERIVED PHYSICAL ACTIVITY TO PERFORM A MENDELIAN RANDOMIZATION ANALYSIS OF ACCELEROMETRY DERIVED PHYSICAL ACTIVITY AND TOTAL MUSCLE MASS. LASTLY, AIM 3B WILL DETERMINE THE IMPLIED INDIRECT EFFECT OF ACTIVITY AND DIET ON MUSCLE MASS ALONG A PATHWAY DELINEATED BY IL-6. THIS STUDY HAS THE POTENTIAL TO TRANSFORM THE FIELD IN TERMS OF DEFINING THE IMPACT OF REDUCED MUSCLE MASS MEASURED USING A VALID TECHNOLOGY, D3-CREATINE DILUTION, WHICH COULD ALSO ULTIMATELY SERVE AS AN ENDPOINT IN DRUG TRIALS.

PERSONALIZED BRAIN ACTIVITY MODULATION TO IMPROVE BALANCE AND COGNITION IN ELDERLY FALLERS

FOOT DISORDERS, PAIN AND PHYSICAL DISABILITY IN ELDERS

IDENTIFYING OSTEOPOROSIS GENES BY WHOLE GENOME SEQUENCING AND FUNCTIONAL VALIDATION IN ZEBRA FISH

AN RCT OF AN EDUCATIONAL VIDEO TO IMPROVE NURSING HOME CARE IN END-STAGE DEMENTIA

VASCULAR MECHANISMS UNDERLYING SKELETAL FRAGILITY IN OLDER ADULTS - THE VASCULAR SUPPLY IS CRITICALLY IMPORTANT TO THE SKELETON, YET THE CLINICAL IMPLICATIONS OF VASCULAR DYSFUNCTION FOR SKELETAL FRAGILITY ARE POORLY UNDERSTOOD. STUDIES DEMONSTRATE ASSOCIATIONS BETWEEN VASCULAR DISEASE AND OSTEOPOROSIS IN OLDER ADULTS. HOWEVER, IT IS UNKNOWN WHETHER VASCULAR DYSFUNCTION ITSELF UNDERLIES THESE ASSOCIATIONS. WE PROPOSE TO USE SUBCLINICAL VASCULAR TONOMETRY AND HEMODYNAMIC MEASURES TO TEST THE HYPOTHESIS THAT VASCULAR IMPAIRMENTS NEGATIVELY AFFECT CORTICAL BONE MICROARCHITECTURE INCREASING FRACTURE RISK IN THE CORTICAL-RICH PERIPHERAL SKELETON. OUR PRELIMINARY DATA DEMONSTRATE THAT VASCULAR CHANGES ARE ASSOCIATED WITH INCREASED FRAGILITY FRACTURES AND DEFICITS IN CORTICAL BONE MICROSTRUCTURE, AS ASSESSED BY HIGH-RESOLUTION PERIPHERAL QUANTITATIVE COMPUTED TOMOGRAPHY (HR-PQCT). THESE DATA PROVIDE STRONG RATIONALE FOR OUR PROPOSED WORK, PARTICULARLY SINCE NO PREVIOUS STUDIES HAVE COMPREHENSIVELY INVESTIGATED MECHANISTIC MEASURES OF BLOOD FLOW IN BOTH LARGE ARTERIES AND MICROCIRCULATION IN RELATION TO SKELETAL FRAGILITY. OUR LONG-TERM GOAL IS TO IMPROVE UNDERSTANDING OF SKELETAL FRAGILITY IN OLDER ADULTS TO REDUCE THE BURDEN OF FRACTURES, BY FOCUSING ON HOW AGING RELATED CHANGES IN THE VASCULATURE AFFECT THE PERIPHERAL SKELETON. OUR CENTRAL HYPOTHESIS IS THAT INDIVIDUALS WITH MORE SEVERE AORTIC STIFFNESS AND BLUNTED PERIPHERAL HYPEREMIC FLOW RESPONSE WILL HAVE MORE SEVERE DETERIORATION IN CORTICAL BONE MICROARCHITECTURE, LOSS OF BONE STRENGTH, AND HIGHER INCIDENCE OF FRACTURE. ADVANCED IMAGING TECHNIQUES, SUCH AS HR-PQCT, PROVIDE VOLUMETRIC SKELETAL COMPARTMENT SPECIFIC MEASURES OF VOLUMETRIC BONE DENSITY AND MICROARCHITECTURE, WHILE NON-INVASIVE VASCULAR TONOMETRY AND HEMODYNAMICS LEND KEY INSIGHT INTO THE ORIGINS OF LARGE ARTERY AND MICROVASCULAR DEFICITS. TOGETHER, THESE INNOVATIONS PROVIDE NECESSARY TOOLS TO ADVANCE KNOWLEDGE OF THE VASCULAR MECHANISMS UNDERLYING SKELETAL FRAGILITY, AND WILL IDENTIFY NOVEL TARGETS FOR FRACTURE PREVENTION. THUS, IN THE UNIQUE SETTING OF THE FRAMINGHAM HEART STUDY, WE WILL ADDRESS THE FOLLOWING SPECIFIC AIMS: (1) DETERMINE THE CONTRIBUTION OF VASCULAR FUNCTION TO INCIDENCE OF FRACTURE, AND (2) DETERMINE THE CONTRIBUTION OF VASCULAR FUNCTION TO LONGITUDINAL CHANGES IN BONE DENSITY, MICROARCHITECTURE, AND STRENGTH. USING STATE-OF-THE-ART ASSESSMENTS OF VASCULAR DYSFUNCTION AND CORTICAL BONE DEFICITS, THE INVESTIGATIVE TEAM HAS THE EXPERIENCE AND COMPLEMENTARY AREAS OF EXPERTISE TO SUCCESSFULLY CARRY OUT THE SPECIFIC AIMS. BY IDENTIFYING THE VASCULAR MECHANISMS UNDERLYING SKELETAL FRAGILITY, THIS PROJECT HAS THE POTENTIAL TO BE PARADIGM SHIFTING, PROVIDING NEW TARGETS FOR INTERVENTIONS TO REDUCE THE TREMENDOUS PUBLIC HEALTH BURDEN OF FRACTURES IN OUR OLDER POPULATION.

DETERMINANTS, DECISION-MAKING AND OUTCOMES OF ANTIBIOTIC USE IN ADVANCED DEMENTIA

ADVANCE: ASSESSMENT OF DISPARIRIES AND VARIATION FOR ALZHEIMER'S DISEASE IN NURSING HOME CARE AT END OF LIFE

MECHANSIMS AND CLINICAL IMPORTANCE OF HYPERKYPHOSIS:THE FRAMINGHAM STUDY

SAFE CARDIOMETABOLIC DRUG PRESCRIBING TO PREVENT INJURY IN NURSING HOME RESIDENTS

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CLINICAL TRIAL OF A PROBIOTIC/PREBIOTIC SUPPLEMENT FOR THE DIETARY MANAGEMENT OF AGE-RELATED BONE LOSS. - ABSTRACT / PROJECT SUMMARY CURRENTLY RECOMMENDED STRATEGIES FOR PRIMARY MAINTENANCE OF BONE MASS WITH AGE ARE LIMITED TO CONSUMING A DIET RICH IN VITAMINS AND MINERALS AND PERFORMING WEIGHT BEARING ACTIVITY. WITHOUT MORE SPECIFIC AND EFFECTIVE WAYS TO MAINTAIN BONE MASS WITH AGE, OLDER ADULTS WILL DEVELOP OSTEOPOROSIS AND ELEVATED FRACTURE RISK NECESSITATING PRESCRIPTION DRUGS, WITH SIDE EFFECTS AND RESTRICTIVE COSTS. HENCE, THERE IS AN UNMET NEED FOR SAFE AND EFFECTIVE DIETARY INTERVENTIONS FOR THE METABOLIC PROCESSES UNDERLYING BONE LOSS. OUR LONG TERM GOAL IS TO DEVELOP SAFE AND EFFECTIVE PREBIOTIC/PROBIOTIC COMBINATION SUPPLEMENTS FOR THE DIETARY MANAGEMENT OF THE METABOLIC PROCESSES UNDERLYING OSTEOPENIA AND OSTEOPOROSIS. THE OBJECTIVE OF THIS PROJECT IS TO TEST THE EFFICACY OF AN PROBIOTIC/PREBIOTIC COMBINATION (“SYNBIOTIC”) ON THE SKELETON IN A CLINICAL TRIAL THAT IS DESIGNED TO PROVIDE MECHANISTIC INSIGHTS INTO THE ACTION OF THE SYNBIOTIC. OUR CENTRAL HYPOTHESIS IS THAT A NOVEL PLANT-DERIVED MEDICAL FOOD SYNBIOTIC (“SBD111”) WILL IMPROVE DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA) DERIVED LUMBAR SPINE BONE MINERAL DENSITY (BMD), QUANTITATIVE COMPUTED TOMOGRAPHY (QCT) DERIVED BONE STRENGTH — AKA BIOMECHANICAL COMPUTED TOMOGRAPHY ANALYSIS, OR BCT— AND VOLUMETRIC BMD (VBMD), MARKERS OF BONE TURNOVER, INFLAMMATION, AND GUT MICROBIOME FUNCTION IN OLDER WOMEN (>60 YEARS) COMPARED TO PLACEBO. GUIDED BY STRONG PRELIMINARY DATA THIS HYPOTHESIS WILL BE TESTED BY PERFORMING AN 18-MONTH RANDOMIZED, DOUBLE-BLINDED, PLACEBO- CONTROLLED CLINICAL TRIAL IN 220 OLDER WOMEN. OUR SPECIFIC AIMS ARE: AIM 1A AND 1B TO DETERMINE THE EFFECT OF 18 MONTHS OF DAILY INTAKE OF SBD111 ON THE PRIMARY OUTCOME OF LUMBAR SPINE DXA-BMD AND SECONDARY OUTCOMES (BCT-DERIVED VERTEBRAL COMPRESSIVE BONE STRENGTH, VBMD, AND MARKERS OF BONE TURNOVER) IN WOMEN. AIM 2A AND 2B TO DETERMINE THE EFFECT OF 18 MONTHS OF DAILY INTAKE OF SBD111 ON MARKERS OF INFLAMMATION AND GUT MICROBIOME FUNCTION IN WOMEN. WE WILL EMPLOY WHOLE METAGENOME AND META-TRANSCRIPTOME SHOTGUN SEQUENCING TO DISSECT CHANGES IN GUT MICROBIOME FUNCTION [DEFINED AS CHANGES IN GLYCOSYL HYDROLASE, MENAQUINONE 7, SHORT CHAIN FATTY ACID (SCFA), AND MICROBIAL DIVERSITY], WHICH CAN MEDIATE THE EFFECT OF SBD111 ON BONE TURNOVER AND INFLAMMATION. WE WILL ALSO CONSIDER INTAKE OF TOTAL DIETARY FIBER, PREBIOTIC FIBER, AND PROBIOTIC FOODS THAT COULD MODIFY THE EFFECT OF SBD111 ON BONE, INFLAMMATION, AND GUT MICROBIOME. IF SUCCESSFUL, THIS PROPOSED TRIAL WILL LEAD TO DEVELOPING POTENTIALLY SAFE, INEXPENSIVE HEALTH PROMOTING STRATEGIES FOR THE DIETARY MANAGEMENT OF THE METABOLIC PROCESSES UNDERLYING OSTEOPENIA AND OSTEOPOROSIS. 1

CEREBROVASCULAR MECHANISMS OF SLOW GAIT AND FALLS

MULTIFOCAL TRANSCRANIAL CURRENT STIMULATION FOR COGNITIVE AND MOTOR DYSFUNCTION IN DEMENTIA - PROJECT SUMMARY: IN OLDER ADULTS WITH MILD DEMENTIA, DISRUPTION IN THE ABILITY TO COMPLETE INSTRUMENTAL ACTIVITIES OF DAILY LIVING STEMS NOT ONLY FROM MEMORY DEFICITS, BUT ALSO FROM EXECUTIVE DYSFUNCTION WHICH ALSO IMPACTS GAIT AND BALANCE. THERE IS THUS AN URGENT NEED TO DEVELOP SAFE, MULTI-COMPONENT INTERVENTIONS DESIGNED TO MAXIMIZE FUNCTIONAL CAPACITY IN THIS VULNERABLE POPULATION BY SIMULTANEOUSLY TARGETING MEMORY, EXECUTIVE FUNCTION, AND THE COMPLEX CONTROL OF GAIT AND BALANCE. IT IS NOW WELL-ESTABLISHED THAT MEMORY AND EXECUTIVE-MOTOR DEFICITS ARISE FROM ALTERED FUNCTION WITHIN SPECIFIC AND SPATIALLY DISTINCT BRAIN NETWORKS, AND, THAT DIFFERENT FORMS OF TRANSCRANIAL CURRENT STIMULATION CAN TARGET THESE NETWORKS TO PROVIDE SYMPTOMATIC RELIEF TO THIS POPULATION. PARALLEL LINES OF PRELIMINARY EVIDENCE SPECIFICALLY SUGGEST THAT 1) TRANSCRANIAL ALTERNATING CURRENT STIMULATION TARGETING THE LEFT ANGULAR GYRUS (TACS) AT GAMMA FREQUENCY CAN IMPROVE EPISODIC AND AUTOBIOGRAPHICAL MEMORY; AND 2) TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) TARGETING THE LEFT DORSOLATERAL PREFRONTAL CORTEX CAN IMPROVE EXECUTIVE FUNCTION AND GAIT PERFORMANCE, ESPECIALLY WHEN OLDER ADULTS ARE WALKING WHILE PERFORMING ADDITIONAL COGNITIVE TASKS (I.E., DUAL TASKING). AT THE SAME TIME, IMPORTANT TECHNOLOGICAL ADVANCES HAVE RECENTLY ENABLED RESEARCHERS TO: STUDY AND OPTIMIZE MULTI-CHANNEL STIMULATION MONTAGES (I.E., ELECTRODE PLACEMENT AND CURRENT PARAMETERS) BASED UPON INDIVIDUALIZED MODELING OF GENERATED CORTICAL ELECTRIC FIELDS; TARGET MORE THAN ONE BRAIN NETWORK AT THE SAME TIME WITHIN THE SAME MONTAGE; IMPLEMENT ACTIVE-SHAM PROTOCOLS THAT FACILITATE DOUBLE-BLINDING AND CONTROL OF THE POTENTIAL EFFECTS OF PERIPHERAL STIMULATION; AND SAFELY DELIVER INTERVENTIONS TO PARTICIPANTS WITHIN THEIR OWN HOMES VIA REMOTELY-SUPERVISED, CAREGIVER-LED ADMINISTRATION OF STIMULATION. BUILDING UPON THESE PRELIMINARY STUDIES AND ADVANCES, WE PROPOSE TO CONDUCT A PHASE II, RANDOMIZED, SHAM- CONTROLLED, DOUBLE-BLINDED, PARALLEL-ARM TRIAL TO ASSESS THE SEPARATE AND COMBINED EFFECTS OF TACS TARGETING THE LEFT ANGULAR GYRUS AT GAMMA FREQUENCY AND TDCS TARGETING THE LEFT DORSOLATERAL PREFRONTAL CORTEX ON MEMORY, EXECUTIVE FUNCTION, DUAL TASK GAIT, AND INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN AMBULATORY OLDER ADULTS WITH MILD DEMENTIA (SPECIFIC AIM 1). WITHIN THIS TRIAL, WE WILL ALSO DETERMINE HOW MUCH OF THE CLINICAL EFFECTS OF INTERVENTION ON MEMORY ON THE ONE HAND, AND EXECUTIVE FUNCTION AND DUAL TASK GAIT PERFORMANCE ON THE OTHER HAND, DEPEND UPON THE AMOUNT OF THE ELECTRIC FIELD INDUCED RESPECTIVELY IN THE LEFT ANGULAR GYRUS AND THE LEFT DORSOLATERAL PREFRONTAL CORTEX, AS ASSESSED BY INDIVIDUALIZED E-FIELD HIGH-RESOLUTION MODELLING (SPECIFIC AIM 2). THIS PROJECT IS EXPECTED TO DEMONSTRATE THAT TACS AND TDCS CAN BE COMBINED INTO ONE SINGLE INTERVENTION TO OPTIMIZE THE FUNCTIONAL IMPACT OF A HOME-BASED INTERVENTION FOR OLDER ADULTS SUFFERING FROM MILD DEMENTIA. IT WILL ALSO PROVIDE INSIGHTS INTO THE SPECIFICITY OF MAPPING BETWEEN BRAIN NETWORKS AND SYMPTOMS, AND OFFER CRITICAL FOUNDATION TO ENABLE PERSONALIZED OPTIMIZATION OF STIMULATION INTERVENTIONS WITHIN FUTURE TRIALS.

UTILIZATION AND CLINICAL OUTCOMES OF LEFT ATRIAL APPENDAGE OCCLUSION IN OLDER ADULTS WITH ATRIAL FIBRILLATION AND FRAILTY - PROJECT SUMMARY ONE IN EVERY 3 PERSONS DEVELOPS ATRIAL FIBRILLATION (AF) IN THEIR LIFETIME, AND AF AFFECTS AT LEAST 10% OF ADULTS AGED ≥65 YEARS. STROKE PROPHYLAXIS WITH ORAL ANTICOAGULANTS (OAC) IS RECOMMENDED, BUT HALF OF OLDER ADULTS WHO ARE ELIGIBLE FOR OAC ARE NOT TREATED BECAUSE OF CONCERNS FOR MAJOR BLEEDING. TREATMENT WITH OAC IS EVEN LESS FREQUENT IN ADULTS WITH FRAILTY, WHO HAVE EXCESS RISK FOR MAJOR BLEEDING BUT ALSO FOR ISCHEMIC STROKE. TO REDUCE AF RISKS IN VULNERABLE POPULATIONS, LEFT ATRIAL APPENDAGE OCCLUSION (LAAO) WAS APPROVED BY CENTERS FOR MEDICARE & MEDICAID SERVICES (CMS) AND IS RECOMMENDED BY PRACTICE GUIDELINES TO PROVIDE AF STROKE PREVENTION FOR INDIVIDUALS DEEMED UNSAFE FOR LONG-TERM OAC. HOWEVER, GIVEN ITS SHORT-TERM PROCEDURAL COMPLICATIONS AND LIFE- LONG REQUIREMENT FOR ANTIPLATELET THERAPY, THE OVERALL BENEFIT OF LAAO AMONG ADULTS WITH FRAILTY IS UNKNOWN. IN FACT, BECAUSE LAAO’S EFFICACY AND SAFETY WERE ESTABLISHED AGAINST OAC IN RANDOMIZED CONTROLLED TRIALS (RCT) OF OAC-ELIGIBLE PATIENTS, LAAO’S EFFECTIVENESS AND SAFETY REMAIN UNCERTAIN FOR THE POPULATION MOST LIKELY TO BENEFIT—PATIENTS WITH FRAILTY OR OAC INELIGIBILITY—RESULTING IN A CRITICAL EVIDENCE-PRACTICE GAP. THE LONG-TERM GOAL OF OUR AF OUTCOMES RESEARCH PROGRAM IS TO IMPROVE EVIDENCE-BASED, PATIENT-CENTERED CARE FOR OLDER ADULTS WITH AF. TO THIS END, OUR CURRENT OBJECTIVE IS TO EVALUATE UTILIZATION AND OUTCOMES OF LAAO COMPARED TO THERAPEUTIC ALTERNATIVES IN OLDER ADULTS WITH FRAILTY. WE WILL UTILIZE MULTIPLE REAL-WORLD DATA SOURCES AND APPLY ADVANCED CAUSAL INFERENCE METHODS TO ENHANCE GENERALIZABILITY AND THE VALIDITY OF INFERENCE. IN AIM 1 WE WILL DETERMINE CHARACTERISTICS OF OLDER ADULTS WHO RECEIVED LAAO AND CHARACTERIZE CONCORDANCE OF LAAO USE WITH CMS APPROVED AND GUIDELINE RECOMMENDED INDICATION. IN AIMS 2 AND 3 WE WILL DETERMINE EFFECTIVENESS, SAFETY, AND NET BENEFIT (HOME TIME) OF LAAO COMPARED TO OAC AND NO OAC, RESPECTIVELY. IN ABSENCE OF RCTS, THE PROPOSED RESEARCH WILL BE THE MAIN SOURCE OF EVIDENCE FOR GUIDING RATIONAL USE OF LAAO IN VULNERABLE POPULATIONS.

LONG-TERM HOME-BASED TRANSCRANIAL ELECTRICAL STIMULATION FOR COGNITIVE AND MOTOR FUNCTION IN OLDER ADULTS WITH AN INCREASED RISK OF DEMENTIA: A RANDOMIZED CONTROLLED TRIAL - MOTORIC COGNITIVE RISK (MCR) IS A TRANSITION STATE BETWEEN “NORMAL” AGING AND ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD). OLDER ADULTS WITH MCR HAVE AN INCREASED RISK OF DEVELOPING AD/ADRD. THEY SUFFER FROM BRAIN ATROPHY IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC)—A BRAIN REGION SUBSERVING EXECUTIVE FUNCTION—AND HAVE ABNORMAL DLPFC ACTIVATION WHEN WALKING AND PERFORMING A COGNITIVE TASK (I.E., DUAL-TASKING, DT), AN EXECUTIVE FUNCTION THAT PREDICTS INCIDENT AD/ADRD. MCR THUS IDENTIFIES AN OPPORTUNITY TO INTERVENE (UPSTREAM) TO ALTER THE TRAJECTORY OF COGNITIVE DECLINE AND THE RISK OF AD/ADRD IN LATER LIFE. IN A SERIES OF PILOT STUDIES, WE HAVE SHOWN THAT TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) IMPROVES DUAL-TASKING GAIT, EXECUTIVE FUNCTION, AND RELATED OUTCOMES. THESE SHORT-TERM STUDIES ARE ENCOURAGING. YET, THE EXTENT TO WHICH TDCS CAN INDUCE LONGER-TERM BENEFITS IS UNCLEAR. WE HAVE ALSO SHOWN THAT TDCS CAN BE ADMINISTERED SAFELY IN THE HOME AND THAT A SMARTPHONE APP CAN BE USED FOR HOME-BASED TESTING OF DT GAIT. WE WILL ENROLL 128 OLDER ADULTS INTO A SHAM-CONTROLLED, DOUBLE-BLINDED, DELAYED-START, MULTI-SITE CLINICAL TRIAL OF HOME-BASED TDCS, WITH STIMULATION PARAMETERS TAILORED TO TARGET THE ANATOMICALLY DEFINED LEFT DLPFC OF EACH PARTICIPANT. AFTER AN INITIAL OPEN-LABEL 2-WEEK TDCS INTERVENTION, PARTICIPANTS WILL BE RANDOMIZED INTO A TDCS ARM (5 WEEKLY TDCS SESSIONS FOR 6 MONTHS), OR A DELAYED-START SHAM ARM (5 WEEKLY SHAM SESSIONS FOR 3 MONTHS BEFORE SWITCHING TO 5 WEEKLY SESSIONS OF TDCS FOR 3 MONTHS). IN-LAB ASSESSMENTS WILL BE CONDUCTED AT BASELINE, AFTER THE INITIAL 2-WEEK INTERVENTION, AFTER 3 AND 6 MONTHS OF STIMULATION, AND 3 MONTHS LATER. STRUCTURAL AND FUNCTIONAL MRIS WILL BE ACQUIRED AT BASELINE AND 3 MONTHS. THE PRIMARY ENDPOINT WILL BE DT COST (DTC) TO GAIT SPEED, A COGNITIVE-MOTOR MARKER OF PREFRONTAL FUNCTION AND PREDICTOR OF FUTURE COGNITIVE DECLINE. OUR PRIMARY HYPOTHESIS IS THAT COMPARED TO SHAM, THE TDCS ARM WILL EXHIBIT LOWER (BETTER) DTC TO GAIT SPEED AFTER 3 MONTHS OF CONTINUED STIMULATION. WE ALSO EXPECT THAT TDCS, COMPARED TO SHAM, WILL LEAD TO BETTER PERFORMANCE ON OTHER TESTS OF EXECUTIVE AND COGNITIVE FUNCTION, REDUCED (MORE EFFICIENT) DLPFC ACTIVATION WHEN WALKING, AND MEASURABLE CHANGES IN PREFRONTAL STRUCTURE AND FUNCTIONAL CONNECTIVITY AS MEASURED BY MRI. THE DELAYED-START TRIAL DESIGN WILL FURTHER ENABLE US TO TEST THE HYPOTHESES THAT THE BENEFITS OF TDCS ACCUMULATE OVER TIME, AND THAT THE RATE OF DECLINE OF BENEFITS IS SLOWER AFTER SIX MONTHS, AS COMPARED TO ONLY THREE MONTHS OF USE. FINALLY, WE WILL UTILIZE WEEKLY, HOME-BASED GAIT ASSESSMENTS USING OUR APP THROUGHOUT THE RCT—AND FOR 3 MONTHS AFTER—TO ESTABLISH INDIVIDUAL AND GROUP TRAJECTORIES OF CHANGE IN THE DTC TO GAIT SPEED OVER TIME, ALLOWING US TO ADDRESS MANY CRITICAL UNKNOWNS (E.G., IF AND WHEN DO THE BENEFITS OF 2-WEEKS, 3-MONTHS, AND 6-MONTHS OF TDCS WEAR OFF, AND IF SO, AT WHAT RATE?). WE ANTICIPATE SHOWING THAT HOME-BASED TDCS IS AN EFFECTIVE, LONG-TERM THERAPEUTIC OPTION CAPABLE OF INDUCING SUSTAINED IMPROVEMENTS IN COGNITIVE AND MOTOR FUNCTION, AS WELL AS LEFT DLPFC STRUCTURE AND FUNCTION, IN OLDER ADULTS AT RISK OF DEVELOPING AD/ADRD.

MIDCAREER MENTORING AWARD FOR PATIENT-ORIENTED RESEARCH IN AGING

SYSTEMIC CONTRIBUTION OF AGE-ASSOCIATED EPIGENETIC MECHANISMS TO OSTEOARTHRITIS

A CLINICAL PREDICTION TOOL TO GUIDE TREATMENT OF OSTEOPOROSIS IN THE NURSING HOME

MULTIFOCAL TRANSCRANIAL CURRENT STIMULATION FOR COGNITIVE AND MOTOR DYSFUNCTION IN DEMENTIA - PROJECT SUMMARY: IN OLDER ADULTS WITH MILD DEMENTIA, DISRUPTION IN THE ABILITY TO COMPLETE INSTRUMENTAL ACTIVITIES OF DAILY LIVING STEMS NOT ONLY FROM MEMORY DEFICITS, BUT ALSO FROM EXECUTIVE DYSFUNCTION WHICH ALSO IMPACTS GAIT AND BALANCE. THERE IS THUS AN URGENT NEED TO DEVELOP SAFE, MULTI-COMPONENT INTERVENTIONS DESIGNED TO MAXIMIZE FUNCTIONAL CAPACITY IN THIS VULNERABLE POPULATION BY SIMULTANEOUSLY TARGETING MEMORY, EXECUTIVE FUNCTION, AND THE COMPLEX CONTROL OF GAIT AND BALANCE. IT IS NOW WELL-ESTABLISHED THAT MEMORY AND EXECUTIVE-MOTOR DEFICITS ARISE FROM ALTERED FUNCTION WITHIN SPECIFIC AND SPATIALLY DISTINCT BRAIN NETWORKS, AND, THAT DIFFERENT FORMS OF TRANSCRANIAL CURRENT STIMULATION CAN TARGET THESE NETWORKS TO PROVIDE SYMPTOMATIC RELIEF TO THIS POPULATION. PARALLEL LINES OF PRELIMINARY EVIDENCE SPECIFICALLY SUGGEST THAT 1) TRANSCRANIAL ALTERNATING CURRENT STIMULATION TARGETING THE LEFT ANGULAR GYRUS (TACS) AT GAMMA FREQUENCY CAN IMPROVE EPISODIC AND AUTOBIOGRAPHICAL MEMORY; AND 2) TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) TARGETING THE LEFT DORSOLATERAL PREFRONTAL CORTEX CAN IMPROVE EXECUTIVE FUNCTION AND GAIT PERFORMANCE, ESPECIALLY WHEN OLDER ADULTS ARE WALKING WHILE PERFORMING ADDITIONAL COGNITIVE TASKS (I.E., DUAL TASKING). AT THE SAME TIME, IMPORTANT TECHNOLOGICAL ADVANCES HAVE RECENTLY ENABLED RESEARCHERS TO: STUDY AND OPTIMIZE MULTI-CHANNEL STIMULATION MONTAGES (I.E., ELECTRODE PLACEMENT AND CURRENT PARAMETERS) BASED UPON INDIVIDUALIZED MODELING OF GENERATED CORTICAL ELECTRIC FIELDS; TARGET MORE THAN ONE BRAIN NETWORK AT THE SAME TIME WITHIN THE SAME MONTAGE; IMPLEMENT ACTIVE-SHAM PROTOCOLS THAT FACILITATE DOUBLE-BLINDING AND CONTROL OF THE POTENTIAL EFFECTS OF PERIPHERAL STIMULATION; AND SAFELY DELIVER INTERVENTIONS TO PARTICIPANTS WITHIN THEIR OWN HOMES VIA REMOTELY-SUPERVISED, CAREGIVER-LED ADMINISTRATION OF STIMULATION. BUILDING UPON THESE PRELIMINARY STUDIES AND ADVANCES, WE PROPOSE TO CONDUCT A PHASE II, RANDOMIZED, SHAM- CONTROLLED, DOUBLE-BLINDED, PARALLEL-ARM TRIAL TO ASSESS THE SEPARATE AND COMBINED EFFECTS OF TACS TARGETING THE LEFT ANGULAR GYRUS AT GAMMA FREQUENCY AND TDCS TARGETING THE LEFT DORSOLATERAL PREFRONTAL CORTEX ON MEMORY, EXECUTIVE FUNCTION, DUAL TASK GAIT, AND INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN AMBULATORY OLDER ADULTS WITH MILD DEMENTIA (SPECIFIC AIM 1). WITHIN THIS TRIAL, WE WILL ALSO DETERMINE HOW MUCH OF THE CLINICAL EFFECTS OF INTERVENTION ON MEMORY ON THE ONE HAND, AND EXECUTIVE FUNCTION AND DUAL TASK GAIT PERFORMANCE ON THE OTHER HAND, DEPEND UPON THE AMOUNT OF THE ELECTRIC FIELD INDUCED RESPECTIVELY IN THE LEFT ANGULAR GYRUS AND THE LEFT DORSOLATERAL PREFRONTAL CORTEX, AS ASSESSED BY INDIVIDUALIZED E-FIELD HIGH-RESOLUTION MODELLING (SPECIFIC AIM 2). THIS PROJECT IS EXPECTED TO DEMONSTRATE THAT TACS AND TDCS CAN BE COMBINED INTO ONE SINGLE INTERVENTION TO OPTIMIZE THE FUNCTIONAL IMPACT OF A HOME-BASED INTERVENTION FOR OLDER ADULTS SUFFERING FROM MILD DEMENTIA. IT WILL ALSO PROVIDE INSIGHTS INTO THE SPECIFICITY OF MAPPING BETWEEN BRAIN NETWORKS AND SYMPTOMS, AND OFFER CRITICAL FOUNDATION TO ENABLE PERSONALIZED OPTIMIZATION OF STIMULATION INTERVENTIONS WITHIN FUTURE TRIALS.

PREDICTING HIP FRACTURE USING A BIOMECHANICAL APPROACH

NURSING HOME PREVENTION OF INJURY IN DEMENTIA (NH PRIDE)

NONLINEAR DYNAMICS OF FRAILTY IN AGING

ACTIVE PHASE III: HRC FIELD SITE

IMPROVING THE QUALITY OF CARE IN NURSING HOMES

THE MECHANISTIC EFFECTS OF COMBINED TESTOSTERONE THERAPY AND EXERCISE ON AXIAL BONE AND MUSCLE POST-HIP FRACTURE

NOVEL FACTORS FOR MUSCLE MASS AND STRENGTH IN ADULTS

ENHANCING ELDER SHELTER WITH APS COLLABORATION, TRAUMA-INFORMED HOUSING SERVICES, AND PERSON-LED GOAL-SETTING

INTENSIVE PALLIATIVE CARE: IMPROVING THE PROCESS OF PALLIATIVE VENTILATOR WITHDRAWAL AMONG CRITICALLY ILL OLDER ADULTS

TARGETED SEQUENCING OF 3 LOCI ASSOCIATED WITH BMD IN THE FRAMINGHAM OSTEOPOROSIS

RISK-GUIDED ATRIAL FIBRILLATION SURVEILLANCE IN ISCHEMIC STROKE - PROJECT SUMMARY ATRIAL FIBRILLATION (AF) IS AN IMPORTANT ISCHEMIC STROKE RISK FACTOR, INCREASING THE RISK 5-FOLD AND ACCOUNTING FOR 1 IN EVERY 4 ISCHEMIC STROKES. EXTENDED RHYTHM MONITORING FOR AF FOLLOWING ISCHEMIC STROKE IS RECOMMENDED BECAUSE 10-20% EXPERIENCE RECURRENT STROKE DUE TO UNDETECTED AF AND UP TO 30% OF PATIENTS WITH ISCHEMIC STROKE ARE DIAGNOSED WITH NEW AF AFTER HOSPITAL DISCHARGE. SINCE 25-50% OF AF CASES ARE DUE TO PAROXYSMAL AF, OPPORTUNISTIC SCREENING WITH BEDSIDE ELECTROCARDIOGRAM WILL MISS A SUBSTANTIAL PORTION OF AF CASES. IMPLANTABLE LOOP RECORDERS (ILRS) ARE GUIDELINE-ENDORSED, LONG-TERM RHYTHM MONITORS THAT DETECT PAROXYSMAL AF. BUT UNIVERSAL ILR PLACEMENT IS SUBOPTIMAL BECAUSE ILRS ARE RESOURCE-INTENSIVE AND ONLY 30% OF PATIENTS WHO RECEIVE ILR AFTER STROKE ARE DIAGNOSED WITH AF. AN ALTERNATIVE, YET UNTESTED, STRATEGY IS TO CALCULATE PATIENT RISK OF AF IN ORDER TO IDENTIFY PATIENTS WHO ARE MOST LIKELY TO HAVE UNDETECTED AF AND WILL DERIVE THE MOST CLINICAL BENEFIT FROM ILR MONITORING. USING INDIVIDUAL AF RISK ESTIMATES CAN IMPROVE THE APPROPRIATENESS OF OVERALL ILR USE IN A RESOURCE-EFFECTIVE MANNER. TO TEST OUR HYPOTHESIS, THE SPECIFIC OBJECTIVES OF THE CURRENT APPLICATION ARE TO IDENTIFY HEALTHCARE SETTINGS IN WHICH A RISK-GUIDED APPROACH WILL BE MOST IMPACTFUL, DEVELOP A POST-STROKE AF RISK ESTIMATION TOOL, AND PILOT TEST THE TOOL TO ASSESS ACCEPTABILITY, ADOPTION, AND VALIDITY OF OUR INTERVENTION PRIOR TO ITS TESTING IN A RANDOMIZED TRIAL. THROUGH THE MENTORED CAREER DEVELOPMENT AWARD, THE CANDIDATE WILL UNDERGO TRAINING IN RESEARCH WITH LARGE HEALTHCARE DATABASES, ADVANCED PREDICTION MODELING, AND CLINICAL TRIAL METHODOLOGY TO FACILITATE TRANSITION TO AN INDEPENDENT INVESTIGATOR WITH EXPERTISE IN PREVENTION AND TREATMENT OF AF AND ITS COMPLICATION. THE INFORMATION PRODUCED FROM THE PROPOSED PROJECT WILL ADDRESS IMPORTANT KNOWLEDGE GAPS IN HEALTHCARE UTILIZATION FOR PREVENTION OF AF-RELATED STROKE AND INFORM FUTURE EFFECTIVENESS TRIALS DESIGNED TO DIRECTLY INFORM SELECTION OF APPROPRIATE AF MONITORING STRATEGY FOLLOWING ISCHEMIC STROKE.

EVALUATION OF CMS TRANSITIONAL CARE AND CHRONIC CARE MANAGEMENT SERVICES: BRIDGING THE GAP AND MAXIMIZING POTENTIAL - PROJECT SUMMARY WITH INCREASING LIFE EXPECTANCY OF US POPULATION, HEALTHCARE SYSTEMS ARE FACED WITH THE CHALLENGE OF IMPROVING THE HEALTH OF OLDER ADULTS WHILE CONTAINING HEALTHCARE COSTS. THE HEALTH OUTCOMES AND HEALTHCARE COSTS OF OLDER ADULTS ARE SIGNIFICANTLY INFLUENCED BY MULTIMORBIDITY, FRAILTY, AND POOR SOCIAL DETERMINANTS OF HEALTH. THERE IS AN INCREASING EFFORT TO SHIFT DISEASE-BASED CARE TOWARD PATIENT-CENTERED CARE THAT ADDRESSES PATIENTS' MEDICAL AND PSYCHOSOCIAL NEEDS AND ENHANCES CARE COORDINATION. TO THIS END, THE CENTERS FOR MEDICARE & MEDICAID SERVICES INTRODUCED TRANSITIONAL CARE MANAGEMENT (TCM) IN 2013 AND CHRONIC CARE MANAGEMENT (CCM) SERVICES IN 2015. DESPITE THE PREMISE OF THESE SERVICES, THEY ARE NOT DELIVERED TO PATIENTS WHO NEED THESE SERVICES MOST. THE OBJECTIVE OF THIS PROPOSED RESEARCH IS TO NARROW THIS PRACTICE GAP BY EVALUATING THE EFFECTIVENESS OF TCM AND CCM AND DEVELOP STRATEGIES TO INCREASE ADOPTION OF THESE SERVICES. THE CENTRAL HYPOTHESIS OF THIS PROJECT IS THAT TCM AND CCM SERVICES ARE MORE EFFECTIVE IN INCREASING DAYS AT HOME (HOME TIME), SURVIVAL, AND REDUCING TOTAL MEDICARE COSTS THAN USUAL CARE IN OLDER ADULTS, PARTICULARLY THOSE WITH FRAILTY, DEMENTIA, AND POOR SOCIAL DETERMINANTS OF HEALTH; THE UPTAKE OF THESE SERVICES IS AFFECTED BY PATIENT-LEVEL, CAREGIVER-LEVEL, AND PRACTICE- LEVEL FACTORS. A TEAM OF EXPERTS IN GERIATRICS, HEALTH SERVICES RESEARCH, CAUSAL INFERENCE, HEALTH ECONOMICS, AND QUALITATIVE RESEARCH WILL ACCOMPLISH THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE THE EFFECTIVENESS OF TCM AND CCM ON HOME TIME, SURVIVAL, AND HEALTHCARE COSTS BY EMULATING TARGET TRIALS OF TCM AND CCM IN MEDICARE FEE-FOR- SERVICE AND MEDICARE ADVANTAGE BENEFICIARIES; 2) DEVELOP AND VALIDATE PREDICTION MODELS TO IDENTIFY PATIENTS WHO ARE MORE LIKELY TO BENEFIT FROM TCM AND CCM; AND 3) IDENTIFY PATIENT-LEVEL, CAREGIVER-LEVEL, AND PRACTICE- LEVEL FACILITATORS AND BARRIERS IN ADOPTING TCM AND CCM BY CONDUCTING A LARGE, MULTIREGIONAL QUALITATIVE STUDY OF 30 PRACTICES OF HIGH-VOLUME, LOW-VOLUME, AND FORMER USE OF TCM AND CCM. THE INNOVATION OF THIS RESEARCH INCLUDES ITS TARGET TRIAL EMULATION APPROACH TO EVALUATE THE EFFECTIVENESS OF TCM AND CCM COMPARED WITH USUAL CARE; USE OF PATIENT-CENTERED OUTCOME HOME TIME; INCLUSION OF CONTEMPORARY MEDICARE FEE-FOR-SERVICE AND MEDICARE ADVANTAGE BENEFICIARIES; AND MIXED METHODS APPROACH OF CONDUCTING A MULTI-REGIONAL QUALITATIVE STUDY INFORMED BY A QUANTITATIVE ANALYSIS OF THE NATIONAL MEDICARE DATA. THIS RESEARCH IS SIGNIFICANT BECAUSE THE RESULTS CAN INFORM DEVELOPMENT OF STRATEGIES TO INCREASE CLINICAL ADOPTION OF TCM AND CCM SERVICES IN BENEFICIARIES WHO ARE MOST LIKELY TO BENEFIT FROM EACH SERVICE. ULTIMATELY, APPROPRIATE USE OF TCM AND CCM WILL ENHANCE PATIENT-CENTERED COORDINATED CARE AND REDUCE HEALTHCARE COSTS IN AGING POPULATIONS.

MENTORING PATIENT-ORIENTED RESEARCH TO PREVENT INJURY IN OLDER ADULTS - THERE IS A REAL SHORTAGE OF CLINICIANS TRAINED IN GERIATRIC PRINCIPLES, WITH EVEN FEWER CLINICIANS WITH GERIATRIC COMPETENCIES ALSO TRAINED IN PATIENT-ORIENTED RESEARCH. MY OVERARCHING GOAL IS TO GROW THE FIELD OF YOUNG INVESTIGATORS PROPERLY TRAINED IN PATIENT-ORIENTED AGING RESEARCH, AND TO IMPROVE THE HEALTH OF FRAIL, OLDER ADULTS THROUGH MY RESEARCH EFFORTS FOCUSED ON UNINTENTIONAL INJURY. FOR MORE THAN TEN YEARS I HAVE HAD FUNDING FROM THE NIA TO STUDY INJURIOUS FALLS IN FRAIL, OLDER ADULTS, AND FOR THE PAST SIX YEARS I HAVE SERVED AS THE PROGRAM DIRECTOR FOR THE HARVARD MULTICAMPUS GERIATRIC MEDICINE FELLOWSHIP. THE CURRENT PROPOSAL WILL CAPITALIZE ON MY STRENGTHS AS AN INDEPENDENT CLINICAL INVESTIGATOR WITH EXPERTISE IN INJURIOUS FALLS AND PROGRAM LEADER TO ENHANCE MY CAPACITY TO MENTOR EARLY INVESTIGATORS IN AGING RESEARCH. THE SPECIFIC AIMS OF THE CURRENT PROPOSAL ARE TO 1) CONDUCT HIGH-QUALITY RESEARCH ON PREVENTING UNINTENTIONAL INJURIES IN FRAIL, OLDER ADULTS THAT WILL SERVE AS A PLATFORM TO ENGAGE EARLY INVESTIGATORS IN PATIENT-ORIENTED AGING RESEARCH; 2) GROW THE NUMBER OF WELL-TRAINED INVESTIGATORS SKILLED IN STUDYING UNINTENTIONAL INJURY IN OLDER ADULTS; AND 3) ENHANCE MY SKILLS TO LEAD AND MENTOR EARLY CLINICAL INVESTIGATORS BY COMPLETING FORMAL DIDACTIC TRAINING FOCUSED ON IMPLEMENTATION SCIENCE AND LEADERSHIP. ONGOING FUNDED RESEARCH PROJECTS THAT COULD SERVE AS A PLATFORM TO ENGAGE RESEARCH TRAINEES INCLUDE A LARGE OBSERVATIONAL STUDY TO DETERMINE THE RISKS AND BENEFITS OF ANTIHYPERTENSIVE, ANTIHYPERGLYCEMIC, AND ANTICOAGULANT DRUGS IN OLDER ADULTS WITH ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD), AS WELL AS A FEASIBILITY TRIAL TO DEVELOP AND IMPLEMENT AN INTERVENTION TO PREVENT INJURIOUS FALLS IN OLDER NURSING HOME RESIDENTS. ADDITIONALLY I HAVE CONDUCTED RESEARCH AND CONTINUE TO COLLABORATE WITH INVESTIGATORS USING SEVERAL LARGE DATASETS THAT WILL SERVE AS AN EXCELLENT RESOURCE FOR TRAINEES. POTENTIAL MENTEES WILL BE IDENTIFIED FROM A PIPELINE OF EXISTING TRAINING PROGRAMS AT HARVARD MEDICAL SCHOOL INCLUDING THE GERIATRIC MEDICINE FELLOWSHIP, TRANSLATIONAL RESEARCH IN AGING PROGRAMS (T32), AND OTHERS. I WILL DEVELOP AN INDIVIDUALIZED MENTORING PLAN WITH ALL TRAINEES, INCLUDING THE DESIGN OF AN ORIGINAL HYPOTHESIS-DRIVEN RESEARCH PROJECT, PLAN FOR INDIVIDUALIZED AND GROUP MENTORSHIP, AND OPPORTUNITIES FOR COURSEWORK/DIDACTICS TO ENHANCE RESEARCH TRAINING. FINALLY, I WILL BOOST MY OWN MENTORING SKILLS THROUGH 1) FORMAL DIDACTICS AND DIRECTED READING ON IMPLEMENTATION SCIENCE; 2) DIRECTED READING/COURSEWORK ON MENTORSHIP; 3) A LEADERSHIP COURSE; 4) A COURSE ON PREVENTING BURNOUT; AND 5) ADDITIONAL COURSEWORK (E.G., INTRODUCTION TO GENETICS) TO EXPAND MY SCIENTIFIC INQUIRY. A SENIOR ADVISORY PANEL WILL PROVIDE FEEDBACK ON MY PERFORMANCE AS A MENTOR AND LEADER. IN SUMMARY, THIS CAREER DEVELOPMENT AWARD WILL PROVIDE ME WITH THE PRACTICAL EXPERIENCE AND FORMAL DIDACTIC TRAINING TO EXPAND MY CAPACITY AS A RESEARCHER, LEADER, AND MENTOR IN PATIENT-ORIENTED RESEARCH ON UNINTENTIONAL INJURY, INCLUDING PATIENTS WITH ADRD. AT THE END OF THIS 5-YEAR AWARD, I WILL HAVE EQUIPPED AT LEAST 18 EARLY INVESTIGATORS IN THE STUDY OF UNINTENTIONAL INJURY, MANY OF WHOM WILL ENTER THE FIELD OF AGING RESEARCH.

THE ADEPT STUDY: ESTIMATING PROGNOSIS IN ADVANCED DEMENTIA

MID-CAREER MENTORING AWARD FOR PATIENT-ORIENTED RESEARCH IN FRAILTY AND HEALTH OUTCOMES - PROJECT SUMMARY INCREASING EVIDENCE SUGGESTS THAT FRAILTY—A COMMON PROBLEM OF OLD AGE CHARACTERIZED BY REDUCED PHYSIOLOGIC RESERVE AND INABILITY TO TOLERATE ACUTE STRESSORS—MAY DETERMINE INTER-INDIVIDUAL VARIABILITY IN OUTCOMES AFTER DRUG THERAPY AND SURGICAL PROCEDURES AMONG OLDER ADULTS. WHILE THIS UNDERSTANDING SUPPORTS THE IDEA OF PERSONALIZING TREATMENTS BASED ON A PATIENT'S FRAILTY LEVEL, THERE IS LITTLE EMPIRICAL EVIDENCE ON HOW TO USE FRAILTY INFORMATION TO MAXIMIZE BENEFITS OR AVOID HARMS IN OLDER PATIENTS. THERE IS A PRESSING NEED TO UNDERSTAND HOW FRAILTY AFFECTS THE OUTCOMES OF VARIOUS MEDICAL AND SURGICAL TREATMENTS. THE CANDIDATE IS A GERIATRICIAN AND EPIDEMIOLOGIST WHO HAS ESTABLISHED A ROBUST PATIENT-ORIENTED RESEARCH PROGRAM ON FRAILTY, GERIATRIC PHARMACOEPIDEMIOLOGY, AND PREDICTION OF FUNCTIONAL OUTCOMES AFTER SURGERY AT HEBREW SENIORLIFE MARCUS INSTITUTE FOR AGING RESEARCH. HE IS ALSO A DEDICATED MENTOR OF TRAINEES AND JUNIOR FACULTY, WHO HAVE PUBLISHED A NUMBER OF PEER-REVIEWED PAPERS AND HAVE SUCCESSFULLY COMPETED FOR TRAINING AND CAREER DEVELOPMENT AWARDS IN AGING RESEARCH. THE CANDIDATE'S RESEARCH PROGRAM HAS A LONG-TERM OBJECTIVE TO IMPROVE CARE OF OLDER ADULTS WITH FRAILTY BY GENERATING HIGH-QUALITY EVIDENCE, TRAINING FUTURE CLINICIANS AND RESEARCHERS, AND CHANGING HEALTH SYSTEMS AND POLICY. TOWARD THIS GOAL, HIS CURRENT NIA-FUNDED RESEARCH FOCUSES ON USE OF A FRAILTY INDEX FOR MEDICARE DATA TO DETERMINE WHO SHOULD BE TREATED WITH A DRUG THERAPY OR A SURGICAL PROCEDURE AND WHO SHOULD NOT DUE TO LACK OF BENEFIT OR INCREASED LIKELIHOOD OF HARM. THIS K24 MID-CAREER INVESTIGATOR AWARD PROPOSAL WILL ALLOW THE CANDIDATE TO DEVELOP A FORMAL MENTORING PROGRAM, EXPAND HIS RESEARCH, AND BECOME A MORE EFFECTIVE MENTOR AND LEADER. THE SPECIFIC AIMS ARE TO: 1) DEVELOP A MENTORING PROGRAM IN FRAILTY RESEARCH FOR EARLY-STAGE AND NEW INVESTIGATORS FROM DIVERSE CLINICAL AND RESEARCH BACKGROUNDS; 2) CONDUCT HIGH-QUALITY RESEARCH TO DETERMINE HETEROGENEITY OF TREATMENT EFFECTS BY FRAILTY FOR A BROAD RANGE OF MEDICAL AND SURGICAL INTERVENTIONS; AND 3) ACQUIRE NEW RESEARCH SKILLS IN IMPLEMENTATION SCIENCE AND ENHANCE CAPACITY IN MENTORSHIP AND LEADERSHIP WITHIN AND OUTSIDE GERIATRICS. THE OUTSTANDING COLLABORATIVE ENVIRONMENT OF HEBREW SENIORLIFE AND OTHER HARVARD-AFFILIATED INSTITUTIONS WILL PROVIDE RESOURCES (E.G., VARIOUS DATA SOURCES, INCLUDING MEDICARE DATA, COMPUTING ENVIRONMENT, AND CAREER DEVELOPMENT TRAINING COURSES) AND SUPPORT (E.G., DATA SCIENTISTS AND RESEARCH METHODOLOGY EXPERTS) NEEDED TO ACCOMPLISH THE PROPOSED ACTIVITIES. THE ADVANCEMENT OF THE CANDIDATE'S MENTORING AND RESEARCH PROGRAM, SUPPORTED BY THIS K24 AWARD, WILL FOSTER GROWTH OF WELL-TRAINED CLINICIAN INVESTIGATORS IN AGING RESEARCH AND ACCELERATE ADOPTION OF PERSONALIZED MEDICINE FOR OLDER ADULTS ACROSS MEDICAL AND SURGICAL SPECIALTIES BASED ON A PATIENT'S FRAILTY LEVEL.

UNRAVELING MUSCULOSKELETAL PLEIOTROPY USING GENOME-WIDE ASSOCIATION

K07 LEADERSHIP GRANT

FOOT DISORDERS AND FALLS IN A POPULATION-BASED COHORT

ASSESSMENT OF CHOLINERGIC AND COGNITIVE FUNCTION USING PHARMACOLOGIC ASL-PERFUSIO

CORTICAL MECHANISMS AND MODULATION OF SOMATOSENSATION IN OLDER ADULTS WITH FOOT SOLE SOMATOSENSORY IMPAIRMENTS - PROPOSAL SUMMARY MY CAREER GOALS ARE TO 1) UNDERSTAND THE SUPRASPINAL SENSORIMOTOR PATHWAYS THROUGH WHICH AGE- AND AGE- RELATED CONDITIONS DIMINISH THE FUNCTIONALITY OF THE LOCOMOTOR CONTROL SYSTEM, AND 2) USE THIS INFORMATION TO DEVELOP NEW THERAPIES TO IMPROVE GAIT AND BALANCE IN OLDER ADULTS. I HOPE TO ACHIEVE THIS GOAL BY TRANSITIONING INTO AN INDEPENDENT SCIENTIST AND LEADING AN RESEARCH PROGRAM IN THE FIELDS OF AGING AND BALANCE CONTROL. IN OLDER ADULTS, DIMINISHED LOWER-EXTREMITY SOMATOSENSATION IS HIGHLY PREVALENT AND A PRIMARY CONTRIBUTOR TO POOR BALANCE, REDUCED MOBILITY, AND INCREASED RISK OF FALLING. THE VAST MAJORITY OF RESEARCH AND CLINICAL EFFORTS TO DATE HAVE ATTEMPTED TO IMPROVE SOMATOSENSATION BY RESTORING THE FUNCTION OF PERIPHERAL ELEMENTS OF THE SOMATOSENSORY SYSTEM. HOWEVER, SOMATOSENSATION IS ALSO DEPENDENT UPON THE CAPACITY TO ACTIVATE THE APPROPRIATE CORTICAL NETWORKS IN RESPONSE TO A GIVEN STIMULUS, WHICH IS ALSO ALTERED IN OLDER ADULTS. THERAPEUTIC STRATEGIES AIMED AT ENHANCING THE EXCITABILITY OF THE SOMATOSENSORY CORTICAL NETWORK THUS OFFER UNTAPPED POTENTIAL TO IMPROVE FOOT-SOLE SOMATOSENSATION IN THIS POPULATION. OUR PRELIMINARY STUDIES SUGGEST THAT A SINGLE SESSION OF TRADITIONAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS), WHICH PRODUCES A DIFFUSE ELECTRIC FIELD OVER THE PRIMARY SOMATOSENSORY CORTEX, IMPROVES FOOT-SOLE SOMATOSENSATION IN OLDER ADULTS. IN THIS K01 AWARD, WE WILL FIRST WORK TO IDENTIFY THE SPECIFIC CORTICAL NETWORK THAT IS RESPONSIVE TO WALKING-RELATED FOOT-SOLE STIMULATION IN OLDER ADULTS WITH AND WITHOUT FOOT-SOLE SOMATOSENSATION (AIM 1). WE WILL USE A BLOCK-DESIGN FUNCTIONAL MRI PARADIGM WITH A CUSTOM-DESIGNED, MRI-COMPATIBLE FOOT SOLE STIMULATION SYSTEM TO APPLY INDIVIDUALIZED PRESSURES TO THE PARTICIPANT’S FOOT SOLES THAT MIMIC THOSE EXPERIENCED WHEN THEY WALK, YET WHILE THEY LAY MOTIONLESS IN THE SCANNER. BASED UPON THIS KNOWLEDGE OBTAINED FROM AIM 1, WE WILL DEVELOP A NOVEL MULTI- TARGET TDCS INTERVENTION TARGETING THE IDENTIFIED CORTICAL NETWORK AND TEST THE EFFECTS OF A SINGLE SESSION OF THIS INTERVENTION ON FOOT-SOLE SOMATOSENSATION, BALANCE AND MOBILITY IN OLDER ADULTS WITH MILD-TO-MODERATE FOOT-SOLE SOMATOSENSORY IMPAIRMENTS (AIM 2). WE WILL THEN USE PARTICIPANT BRAIN MRIS AND ELECTRIC FIELD MODELING TO ESTABLISH THE “DOSE-RESPONSE” RELATIONSHIP BETWEEN ON-TARGET CURRENT INTENSITY INDUCED BY TDCS AND ITS ACUTE EFFECT ON THE CORTICAL RESPONSE TO FOOT SOLE STIMULATION (AIM 3). THROUGH THIS WORK WE WILL LEARN ABOUT HOW CHRONIC LOWER-EXTREMITY SOMATOSENSORY IMPAIRMENTS INFLUENCE THE CORTICAL PROCESSING OF SENSORY FEEDBACK INVOLVED IN THE CONTROL OF BALANCE AND MOBILITY, DEMONSTRATE THAT SUCH PROCESSING CAN BE MODULATED BY TDCS, AND THUS, OBTAIN CRITICAL INFORMATION NEEDED TO DESIGN A LARGER MORE DEFINITIVE TRIAL TO TEST THE POTENTIAL FOR TDCS TO IMPROVE FOOT SOLE SENSATION, BALANCE, AND MOBILITY IN THIS POPULATION. THIS CAREER DEVELOPMENT AWARD WILL PROVIDE ME WITH UNIQUE TRAINING EXPERIENCES IN NEUROPHYSIOLOGY OF SOMATOSENSATION IN AGING, THE CLINICAL CARE OF THESE OLDER ADULTS, AND INCREASE MY EXPERTISE IN ADVANCED NEUROIMAGING AND BRAIN STIMULATION TECHNIQUES, WHICH, TAKEN TOGETHER, WILL GREATLY FACILITATE MY EFFORTS TO TRANSITION INTO AN INDEPENDENT ACADEMIC SCIENTIST.

SENOLYTICS TO IMPROVE COGNITION AND MOBILITY IN OLDER ADULTS AT RISK OF ALZHEIMER?S DISEASE - PROJECT SUMMARY: ABNORMALITIES IN COGNITION AND MOBILITY ARE COMMON ACCOMPANIMENTS OF AGING THAT OFTEN PRECEDE THE DEVELOPMENT OF ALZHEIMER'S DISEASE. AMONG THEIR MANY ETIOLOGIES, THESE ABNORMALITIES ARE ASSOCIATED WITH ALTERATIONS IN THE REGULATION OF CEREBRAL BLOOD FLOW TO FRONTAL REGIONS OF THE BRAIN THAT SUBSERVE EXECUTIVE FUNCTIONS AND GAIT SPEED. WE HAVE PREVIOUSLY SHOWN THAT TREATMENT WITH COCOA FLAVANOLS CAN IMPROVE BLOOD FLOW IN RESPONSE TO A COGNITIVE TASK (NEUROVASCULAR COUPLING [NVC]), AS WELL AS EXECUTIVE FUNCTION IN OLDER PEOPLE WITH IMPAIRED NVC. THESE COMPOUNDS CAN ALSO REDUCE THE NUMBER OF SENESCENT CELLS AND THEIR TOXIC SECRETORY PRODUCTS (SASP) IN A VARIETY OF TISSUES. IN MICE, “SENOLYTIC” COMPOUNDS SUCH AS FLAVANOLS AND TYROSINE KINASE INHIBITORS, HAVE BEEN SHOWN TO REDUCE NEUROFIBRILLARY TANGLE DENSITY, NEURON LOSS, AND VENTRICULAR ENLARGEMENT, AND IN HUMANS WITH IDIOPATHIC PULMONARY FIBROSIS, IMPROVE GAIT SPEED AND OTHER FUNCTIONAL ABILITIES. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT THE FLAVANOL, QUERCETIN, AND TYROSINE KINASE INHIBITOR, DASATINIB, (Q+D) WILL IMPROVE NVC IN RESPONSE TO AN EXECUTIVE TASK, REDUCE CIRCULATING SASP COMPONENTS, AND IN SO DOING, IMPROVE COGNITION AND MOBILITY IN OLDER ADULTS WHO ARE AT RISK OF ALZHEIMER'S DISEASE.

EXPERIENCES OF FAMILY MEMBERS OF NURSING HOME PATIENTS WITH ADVANCED DEMENTIA

MEDICATIONS AS ACUTE PRECIPITANTS OF FALLS IN THE NURSING HOME SETTING

BLOOD-BASED BIOMARKERS OF NEURONAL INJURY AND ALZHEIMER'S DISEASE: PREDICTORS OF DELIRIUM AND LONG-TERM COGNITIVE DECLINE, AND POTENTIAL SHARED PATHOPHYSIOLOGY

A PILOT STUDY OF AN RCT TO IMPROVE INFECTION MANAGEMENT IN ADVANCED DEMENTIA

RESTRICTED MEAN SURVIVAL TIME TO INTERPRET CLINICAL TRIALS FOR TREATMENT DECISION-MAKING IN OLDER ADULTS

CAREGIVER'S ROLE IN HOSPITALIZING NURSING HOME RESIDENTS WITH ADVANCED DEMENTIA

OPTIMIZING TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) TO IMPROVE DUAL TASK GAIT AND BALANCE IN OLDER ADULTS

HARVARD OLDER AMERICANS INDEPENDENCE CENTER GRANT

VOLUMETRIC BONE DENSITY AND VASCULAR CALCIFICATION: THE FRAMINGHAM QCT STUDY

OSTEOCALCIN AND METABOLIC RISK FACTORS. THE FRAMINGHAM STUDY

MODULATING BRAIN ACTIVITY TO PRESERVE GAIT IN OLDER ADULTS.

MODULATING BRAIN NETWORKS TO REDUCE GAIT VARIABILITY IN OLDER ADULTS AT RISK OF FALLING - PROJECT SUMMARY MY CAREER GOAL IS TO LEAD EFFORTS TO IMPROVE GAIT REHABILITATION AND MITIGATE FALLS RISK IN OLDER ADULTS BY CONDUCTING INNOVATIVE RESEARCH FOCUSED ON THE NEURAL CONTROL AND ENHANCEMENT OF GAIT AND MOBILITY. I AM PARTICULARLY INTERESTED IN DEVELOPING INDIVIDUALIZED, MULTI-MODAL, AND PATIENT-CENTERED INTERVENTIONS THAT CAN BOTH STAND ALONE AND BE COMBINED WITH CURRENT EVIDENCED-BASED GERIATRICS REHABILITATION PROGRAMMING. THOUGH WALKING IS A REPETITIVE TASK, ONE’S TEMPOROSPATIAL PATTERNS OF MOVEMENT DURING WALKING VARY FROM STRIDE TO STRIDE. THIS GAIT VARIABILITY, IF SUFFICIENTLY HIGH, IS PREDICTIVE OF BOTH FALLS AND COGNITIVE DECLINE IN OLDER ADULTS. STILL, THE NEURAL MECHANISMS THAT GIVE RISE TO GAIT VARIABILITY ARE NOT COMPLETELY UNDERSTOOD. WE THUS LACK EFFECTIVE INTERVENTIONS TO MINIMIZE GAIT VARIABILITY IN OLDER ADULTS. HOWEVER, OUR TEAM HAS DEMONSTRATED THAT IN OLDER ADULTS, THOSE WITH ELEVATED GAIT VARIABILITY EXHIBIT WORSE ABILITY TO SUSTAIN PERFORMANCE ON A CONTINUOUS COGNITIVE TASK OVER TIME (I.E., SUSTAINED ATTENTION). MY WORK HAS ALSO LINKED GAIT VARIABILITY TO THE FUNCTIONAL CONNECTIVITY BETWEEN THE TWO LARGE-SCALE BRAIN NETWORKS BELIEVED TO UNDERSERVE SUSTAINED ATTENTION—NAMELY, THE DORSAL ATTENTION NETWORK (DAN) AND THE DEFAULT NETWORK (DN)—IN MULTIPLE COHORTS OF OLDER ADULTS. BASED UPON THESE DISCOVERIES, WE DESIGNED A NOVEL MULTI-CHANNEL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) INTERVENTION TO SIMULTANEOUSLY FACILITATE THE EXCITABILITY OF THE DAN AND INHIBIT THE EXCITABILITY OF THE DN. OUR PRELIMINARY DATA SUGGESTS THAT A SINGLE EXPOSURE TO THIS TDCS, AS COMPARED TO SHAM, REDUCES GAIT VARIABILITY WHEN TESTED JUST FOLLOWING STIMULATION. MY OVERARCHING HYPOTHESIS IS THAT THIS FORM OF TDCS CAN MODULATE THE FUNCTIONAL CONNECTIVITY BETWEEN THE DAN AND DN AND THUS REDUCE GAIT VARIABILITY IN OLDER ADULTS. IN THIS PROJECT, WE WILL TEST THIS HYPOTHESIS BY EXAMINING THE ACUTE AFTER-EFFECTS OF A SINGLE SESSION OF TDCS ON RESTING-STATE FUNCTIONAL CONNECTIVITY (AIM 1), AS WELL AS DETERMINING THE EFFECTS OF A MULTI-SESSION TDCS INTERVENTION ON GAIT VARIABILITY AND RELATED OUTCOMES (AIM 2). WE WILL RECRUIT 30 OLDER ADULTS FREE OF MAJOR DISEASE THAT EXHIBIT HIGHER-THAN-TYPICAL GAIT VARIABILITY. PARTICIPANTS WILL FIRST COMPLETE A BASELINE ASSESSMENT AND TWO FMRI VISITS. THE SAME PARTICIPANTS WILL THEN BE RANDOMIZED TO A TDCS INTERVENTION ARM (TEN, ONCE-DAILY, 20-MIN SESSIONS) OR A SHAMATDCS INTERVENTION ARM (FIVE, ONCE-DAILY, 20-MIN SESSIONS OF SHAM IN WEEK ONE FOLLOWED BY FIVE, ONCE- DAILY, 20-MIN SESSIONS OF TDCS IN WEEK 2). THE PRIMARY OUTCOME OF GAIT VARIABILITY WILL BE ASSESSED DAILY USING A VALIDATED SMARTPHONE APP FOR THE ENTIRE STUDY PERIOD. WE EXPECT TO DEMONSTRATE THAT TDCS CAN MODULATE FUNCTIONAL CONNECTIVITY AND REDUCE GAIT VARIABILITY IN OLDER ADULTS. THE RESULTS FROM THIS PROJECT ARE EXPECTED TO INFORM THE DESIGN OF A LARGER, MORE DEFINITIVE TRIAL OF TDCS DESIGNED TO OPTIMIZE BRAIN CONNECTIVITY AS IT RELATES TO GAIT VARIABILITY IN OLDER ADULTS. THIS RESEARCH, COMBINED WITH SPECIFIC TRAINING IN ADVANCED NEUROIMAGING AND NEUROMODULATION, COGNITIVE NEUROSCIENCE IN AGING, AND THE CONDUCT A CLINICAL RESEARCH IN VULNERABLE OLDER ADULTS, WILL GREATLY FACILITATE MY EFFORTS TO TRANSITION INTO AN INDEPENDENCE CLINICIAN SCIENTIST.

MENTORSHIP PROGRAM PATIENT-ORIENTED RESEARCH ON AGING

PREDICTING AND IDENTIFYING RISK FACTORS FOR SHORT TIME AT HOME IN OLDER ADULTS AFTER HOSPITALIZATION - ABSTRACT THE TIME AFTER HOSPITALIZATION IS A CRITICAL WINDOW FOR OLDER ADULTS RECOVERING FROM ACUTE MEDICAL PROBLEMS. ROUGHLY 1 IN 5 MEDICARE BENEFICIARIES ARE DISCHARGED FROM HOSPITAL TO SKILLED NURSING FACILITIES (SNFS) FOR POST- ACUTE CARE AND REHABILITATION, ACCOUNTING FOR OVER 2 MILLION STAYS ANNUALLY. ALTHOUGH SNF STAYS ARE INTENDED TO RESTORE INDEPENDENCE AND FUNCTION, MANY PATIENTS CYCLE BETWEEN RE-HOSPITALIZATIONS AND SNF IN A DOWNWARD SPIRAL. TIME AT HOME QUANTIFIES THIS PHENOMENON OF BEING ‘REHABBED TO DEATH’ BY COUNTING THE NUMBER OF DAYS SPENT ALIVE IN THE COMMUNITY, OUT OF THE HOSPITAL OR SNF. HOWEVER, TOOLS THAT ASSESS RISK FOR SHORT TIME AT HOME HAVE NOT BEEN DEVELOPED IN THE SNF SETTING, AND IDENTIFYING THESE CAN INFORM THE DESIGN OF INTERVENTIONS. FRAILTY IS A COMMON STATE OF VULNERABILITY KNOWN TO INCREASE RISKS OF HOSPITALIZATIONS AND MORTALITY AMONG OLDER ADULTS. ALTHOUGH REHABILITATION INTERVENTIONS IMPROVE FUNCTION AND OUTCOMES AMONG NON-FRAIL ADULTS IN OUTPATIENT SETTINGS, FRAIL COMPARED TO MORE ROBUST OLDER ADULTS DO NOT BENEFIT FROM THE SAME REHABILITATION APPROACHES. MOREOVER, WHETHER MODIFIABLE RISK FACTORS SUCH AS DELIRIUM, DEPRESSION, AND POTENTIALLY INAPPROPRIATE MEDICATIONS (PIMS), INDEPENDENTLY IMPACT SHORT TIME AT HOME IN THE SETTING OF FRAILTY IS UNCLEAR. THUS, FRAILTY MEASURES HAVE THE POTENTIAL TO RISK-STRATIFY REHABILITATION PATIENTS FOR SHORT TIME AT HOME WHILE INFORMING TARGETING OF MEANINGFUL AND EFFICACIOUS INTERVENTIONS. THIS PROPOSAL AIMS TO ELUCIDATE PREDICTORS OF SHORT TIME AT HOME AFTER SNF DISCHARGE AMONG WELL- ESTABLISHED FRAILTY MEASURES AND MODIFIABLE RISK FACTORS. THIS RESEARCH WILL LEVERAGE AN EXISTING DATASET OF A NATIONALLY REPRESENTATIVE COHORT OF MEDICARE BENEFICIARIES, THE NATIONAL HEALTH AND AGING TRENDS STUDY (NHATS) LINKED TO MEDICARE CLAIMS. THE SPECIFIC AIMS ARE TO: 1) ASSESS AND COMPARE THE ABILITY OF TWO MEASURES OF PRE-HOSPITALIZATION FRAILTY TO PREDICT SHORT TIME AT HOME AFTER POST-ACUTE SNF REHABILITATION, IN A NATIONALLY REPRESENTATIVE COHORT OF MEDICARE BENEFICIARIES, AND 2) IDENTIFY MODIFIABLE RISK FACTORS (DELIRIUM, DEPRESSION, PIMS, REHABILITATION CHARACTERISTICS) THAT ARE INDEPENDENTLY ASSOCIATED WITH SHORT TIME AT HOME AFTER POST-ACUTE SNF REHABILITATION. IMPACT: THIS AWARD WILL SUPPORT THE PRINCIPAL INVESTIGATOR’S (PI’S) EARLY CAREER DEVELOPMENT AND PATHWAY TO BECOMING A NATIONAL LEADER IN GERIATRIC POST-ACUTE SNF REHABILITATION. AS A GERIATRICIAN WITH EXPERIENCE IN AGING RESEARCH, DR. SHI WILL ACQUIRE NEW INSIGHT AND PERSPECTIVE FROM REHABILITATION MEDICINE AND DEVELOP THE SKILLS TO DESIGN AND LEAD MULTIDISCIPLINARY SNF REHABILITATION INTERVENTIONS. THIS PROPOSAL IS SUPPORTED BY A COLLABORATIVE TEAM OF HIGHLY EXPERIENCED MENTORS AND A RICH RESEARCH ENVIRONMENT. THE RESEARCH AND TRAINING WILL PROVIDE THE PI WITH FOUNDATIONAL KNOWLEDGE IN LONGITUDINAL DATA ANALYSIS, RISK STRATIFICATION, AND MODIFIABLE RISK FACTORS FOR SHORT TIME AT HOME AFTER SNF REHABILITATION. IN DOING SO, IT WILL LEAD TO THE NEXT LOGICAL STEP: DESIGNING AND EVALUATING A TAILORED INTERVENTION GUIDED BY THE FRAILTY STATUS OF OLDER PATIENTS, MAXIMIZING THEIR TIME AT HOME.

SYSTEM BIOLOGY APPROACH TO DECODE MOLECULAR MECHANISM OF GLUCOSE METABOLISM IN AD AND DEMENTIA - PROJECT SUMMARY/ABSTRACT ALZHEIMER’S DISEASE (AD) AND DEMENTIA AFFECT 50 MILLION WORLDWIDE AND NUMBERS EXPECTED TO TRIPLE BY 2050. AD IS THE 6TH LEADING CAUSE OF DEATH AND AFFECTS MORE THAN 5 MILLION IN THE USA ALONE. DESPITE SUBSTANTIAL EFFORTS, THE BIOCHEMICAL AND CELLULAR CHANGES IN THE BRAIN OF AD REMAIN INCOMPLETELY UNDERSTOOD AND NO DISEASE- MODIFYING DRUGS ARE AVAILABLE YET. HOWEVER, A GROWING NUMBER OF STUDIES REVEAL A LINK BETWEEN DISRUPTED GLUCOSE METABOLISM AND NEURONAL CELL DEATH IN AD/DEMENTIA. HIGH GLUCOSE LEVELS INCREASED BRAIN CELL DAMAGE AND PROMOTED THE FORMATION OF AMYLOID PLAQUES AND TAU TANGLES, AND A REDUCTION IN GLYCOLYSIS LEAD TO SEVERE FORM OF DEMENTIA. THE ALTERATION OF GLUT (GLUCOSE TRANSPORTER), SGLT (SODIUM-DEPENDENT CO-TRANSPORTERS), AND INSULIN SIGNALING PATHWAY WERE REPORTED IN THE BRAIN OF AD/DEMENTIA. HOWEVER, THE CONSEQUENCES OF THESE ALTERATIONS IN THE BRAIN AND THE ASSOCIATION WITH PERIPHERAL GLUCOSE METABOLISM AND AD/DEMENTIA REMAIN CONTROVERSIAL. GIVEN THE HIGH PREVALENCE OF TYPE 2 DIABETES IN THE OLDER ADULTS (28% IN THE USA), THIS TOPIC IS TIMELY AND SIGNIFICANT FOR FURTHER IN-DEPTH KNOWLEDGE. THUS, WE PROPOSE TO INTERROGATE THE SYSTEMIC MOLECULAR MECHANISM OF GLUCOSE METABOLISM IN AD/DEMENTIA USING A WELL-ESTABLISHED LARGE COHORT, UK BIOBANK (N=500,000) VIA TRANSCRIPTOME-WIDE ASSOCIATION STUDY (TWAS) AND CO-EXPRESSION NETWORK BIOLOGICAL PATHWAY ANALYSIS WITH PROTEOMICS. TWAS INTEGRATES GWAS AND EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) INCREASING THE POWER TO PREDICT GENE EXPRESSION LEVELS AND TO ENABLE SOLID INTERPRETATIONS OF GENE-TRAIT ASSOCIATIONS. WE HAVE TWO SPECIFIC AIMS; 1) ESTIMATE PREDICTED GLUCOSE METABOLISM GENE EXPRESSIONS ASSOCIATED WITH AD/DEMENTIA. WE WILL USE A TWAS APPROACH VIA GLUT, SGLT, AND INSULIN SIGNALING PATHWAYS IN THE BRAIN AND WHOLE GENOME-WIDE ANALYSIS ACROSS ALL TISSUES USING PREDIXCAN ALGORITHM WHICH USES GTEX RNA-SEG AND EQTL DATA FOR ITS MODEL DEVELOPMENT. 2) DETERMINE GLUCOSE METABOLISM MOLECULAR PATHWAYS AND TARGETS ASSOCIATED WITH AD/DEMENTIA. WE WILL CONSTRUCT CO-EXPRESSION NETWORKS OF PROTEOMICS THAT ARE ASSOCIATED WITH GLUCOSE METABOLISM GENES VIA WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA) AND PRESENT HIGHLY SIGNIFICANT HUB MODULE AND DRIVER PROTEINS TO ELUCIDATE MULTI-LAYERED BIOLOGICAL AND MOLECULAR THERAPEUTIC TARGETS FOR AD/DEMENTIA. OUR PROPOSAL CAN PROVIDE FUNDAMENTAL KNOWLEDGE IN ENHANCING THE UNDERSTANDING OF EARLY DISEASE INITIATION AND PROGRESSION OF AD/DEMENTIA AND TO ENLIST RELIABLE MOLECULAR TARGETS FOR THE ACCELERATION OF DRUG DISCOVERY OR REPURPOSING.

EFFECT OF BASELINE AND INTERCURRENT MEDICAL FACTORS ON 6-YEAR COGNITIVE TRAJECTORY: SECONDARY ANALYSIS OF THE SAGES STUDY - RESPONDING TO PAS-19-391, THIS PROPOSAL WILL LEVERAGE EXISTING DATA TO ADVANCE OUR UNDERSTANDING OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD) AND TO NURTURE THE CAREER OF A PROMISING EARLY STAGE INVESTIGATOR, DR. TAMMY HSHIEH. THIS PROPOSAL WILL USE DATA DRAWN FROM A CLINICALLY RICH COHORT, THE SUCCESSFUL AGING AFTER ELECTIVE SURGERY (SAGES), INVOLVING 560 OLDER ADULTS (AGE 70+) WITHOUT CLINICAL DEMENTIA EVALUATED PRIOR TO MAJOR ELECTIVE SURGERY AND FOLLOWED FOR 6 YEARS WITH REPEATED NEUROPSYCHOLOGICAL TESTING. WE PLAN TO EXPLORE A PRIORITY AREA IN THE PA: ‘TO ADVANCE OUR UNDERSTANDING OF HOW COGNITIVE FUNCTION MAY CHANGE FROM NORMAL TO PATHOLOGICAL COGNITIVE AGING’, WHICH WE HERE DEFINE BROADLY AS INCLUDING BOTH AD- AND ADRD-RELATED PROCESSES. SAGES HAS COLLECTED DATA ON INTERCURRENT ILLNESSES, HOSPITALIZATIONS, SURGERIES, AND MAJOR TREATMENTS (E.G., CHEMOTHERAPY, HEMODIALYSIS) FOR UP TO 6 YEARS. WE PROPOSE TO EVALUATE THE EFFECTS OF THESE INTERCURRENT FACTORS ON COGNITIVE TRAJECTORY, ALONG WITH THE MODERATING EFFECTS OF DELIRIUM AND/OR APOE-E4 STATUS, WHICH MAY SERVE AS MARKERS OF BRAIN VULNERABILITY. OUR SPECIFIC AIMS ARE: (1) TO EVALUATE THE EFFECT OF INTERCURRENT MEDICAL FACTORS ON COGNITIVE TRAJECTORY FOR UP TO 6 YEARS: WE WILL EXAMINE FACTORS FIRST SINGLY THEN CUMULATIVELY WITH THE HYPOTHESIS THAT CERTAIN FACTORS WILL HAVE GREATER DECREMENTS CONSIDERED SINGLY AND THAT A HIGHER NUMBER OF FACTORS WILL RESULT IN A STEEPER SLOPE OF DECLINE OVER TIME, ACHIEVING RATES OF DECLINE COMPARABLE TO MCI OR EARLY AD/ADRD. (2) TO EXAMINE THE EFFECT OF ABNORMAL BASELINE LABORATORY RESULTS AND INFLAMMATORY BIOMARKERS (E.G., C-REACTIVE PROTEIN, INTERLEUKIN-6) ON COGNITIVE TRAJECTORY: WE HYPOTHESIZE THAT A HIGHER NUMBER OF ABNORMAL LABORATORY VALUES AND/OR BIOMARKERS WILL HAVE A HIGHEST RATE OF COGNITIVE DECLINE, ACHIEVING RATES OF DECLINE COMPARABLE TO MCI OR EARLY AD/ADRD. (3) TO ELUCIDATE WHETHER DEVELOPMENT OF DELIRIUM AND/OR GENETIC RISK (APOE-E4 STATUS) MODERATES THE ASSOCIATION OF MAJOR INTERCURRENT FACTORS OR ABNORMAL LABORATORY- OR BIO- MARKERS, EITHER SINGLY OR CUMULATIVELY, ON COGNITIVE TRAJECTORY. OUR ANALYSES WILL UTILIZE AN INNOVATIVE LONGITUDINAL DATA ANALYSIS APPROACH WITH TIME-VARYING PREDICTORS TO GENERATE A WEIGHTING ALGORITHM FOR A DYNAMIC INDEX (AN INDEX THAT CAN CHANGE WITHIN A PERSON OVER TIME), REPRESENTING THE CUMULATIVE EFFECT OF POTENTIAL COGNITIVE INSULTS. WE HAVE DEMONSTRATED ADEQUATE STATISTICAL POWER TO ACHIEVE OUR AIMS. SUCCESS OF THE PROPOSED WORK IS FURTHER ASSURED BY A HIGHLY SKILLED INTERDISCIPLINARY TEAM WHO HAVE BEEN CLOSE COLLABORATORS FOR OVER 10 YEARS, AND WHO WILL MENTOR DR. HSHIEH. THIS PROJECT WILL HELP TO IDENTIFY INTERCURRENT FACTORS OR ABNORMAL LABORATORY- OR BIO- MARKERS THAT MAY LEAD TO COGNITIVE DECLINE, PARTICULARLY IN THOSE INDIVIDUALS WITH MORE VULNERABLE BRAINS, AS SIGNALED BY APOE-E4 OR BY DEVELOPMENT OF DELIRIUM. UNDERSTANDING THESE FACTORS WILL HELP US TO IDENTIFY POTENTIAL PATHWAYS WHICH MIGHT TRANSFORM NORMAL TO PATHOLOGICAL COGNITIVE AGING. SUCH UNDERSTANDING WILL ADVANCE OUR PATHOPHYSIOLOGIC UNDERSTANDING, AND LAY THE GROUNDWORK FOR FUTURE TARGETED INTERVENTION STRATEGIES.

EPIDEMIOLOGY AND LONG-TERM EFFECT OF CARDIOMETABOLIC MEDICATION SUBSTITUTION DURING POST-ACUTE CARE - PROJECT SUMMARY/ABSTRACT NEARLY 70% OF OLDER ADULTS EXPERIENCE MEDICATION DISCREPANCY–INCONSISTENCIES IN MEDICATION REGIMENS WHEN THEY TRANSITION FROM ACUTE HOSPITAL TO SKILLED NURSING FACILITIES (SNF). MEDICATION DISCREPANCY IN THIS PERIOD OFTEN RESULTS FROM INADEQUATE RECONCILIATION PROCESSES AND FORMULARY OR FINANCIAL RESTRICTIONS IN HOSPITALS OR SNFS. MEDICATION DISCREPANCY CAN TAKE THE VARIOUS FORMS, INCLUDING OMISSION, ADDITION, DUPLICATION, AND SUBSTITUTION. AMONG THESE TYPES, SUBSTITUTION ACCOUNTS FOR UP TO 20% AND FREQUENTLY INVOLVES CARDIOVASCULAR MEDICATIONS. CLINICAL OBSERVATIONS SUGGEST THAT NEWER, HIGH-COST CARDIOMETABOLIC MEDICATIONS (E.G., ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITOR, SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS, AND GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS) ARE OFTEN SUBSTITUTED WITH LESS EXPENSIVE AND LESS EFFICACIOUS ALTERNATIVES IN SNFS. SUCH SUBSTITUTIONS MAY IMPACT CHRONIC DISEASE OUTCOMES IF THE MODIFIED REGIMEN IS CONTINUED AFTER SNF STAY. DESPITE THE COMMON OCCURRENCE OF MEDICATION SUBSTITUTION DURING SNF STAYS AND ITS POTENTIAL CLINICAL SIGNIFICANCE, SYSTEMATIC INVESTIGATION HAS BEEN HINDERED BY THE LACK OF A COMPREHENSIVE DATABASE CONTAINING MEDICATION ADMINISTRATION RECORDS FROM A LARGE NUMBER OF SNFS. THE OBJECTIVE OF THIS STUDY IS TO DETERMINE THE EPIDEMIOLOGY AND CLINICAL CONSEQUENCES OF CARDIOMETABOLIC MEDICATION SUBSTITUTION IN SNF. THE INVESTIGATORS’ HYPOTHESIS IS THAT PERSISTENT MEDICATION SUBSTITUTION BEYOND SNF STAY IS ASSOCIATED WITH WORSE OUTCOMES COMPARED WITH NO SUBSTITUTION OR RESOLVED SUBSTITUTION DURING SNF STAY. TO TEST THIS HYPOTHESIS, THEY WILL USE THE LONG-TERM CARE DATA COOPERATIVE PLATFORM, WHICH PROVIDES ELECTRONIC HEALTH RECORDS DATA FROM NATIONWIDE SNFS LINKED WITH MEDICARE DATA. THE SPECIFIC AIMS ARE: 1) TO DETERMINE THE FREQUENCY AND FACTORS ASSOCIATED WITH CARDIOMETABOLIC MEDICATION SUBSTITUTION DURING POST-ACUTE SNF STAY AMONG OLDER ADULTS AFTER ELECTIVE ORTHOPEDIC SURGERY; AND 2) TO DETERMINE LONG-TERM CHRONIC DISEASE OUTCOMES ASSOCIATED WITH CARDIOMETABOLIC MEDICATION SUBSTITUTION DURING POST-ACUTE SNF STAY. THE PROJECT IS INNOVATIVE BECAUSE IT IS THE FIRST NATIONAL-SCALE STUDY OF MEDICATION SUBSTITUTION DURING THE POST- ACUTE SNF STAY. THE IMPACT OF THIS RESEARCH IS SIGNIFICANT BECAUSE THE EVIDENCE GENERATED FROM THIS RESEARCH CAN ENABLE OPTIMAL MEDICATION MANAGEMENT OF CARDIOMETABOLIC CONDITIONS IN THE TRANSITIONAL PERIOD. MOREOVER, THE GEMSSTAR AWARD WILL PROVIDE MENTORSHIP, TRAINING, AND EXPERIENCE FOR THE PRINCIPAL INVESTIGATOR TO EMERGE AS A LEADER IN OPTIMIZING MEDICATION USE FOR OLDER ADULTS.

**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** THERE ARE TRILLION OF MICROBES THAT LIVE IN THE INSTESTINES (I.E., GUT MICROBES), WHICHDIRECTLY IMPACT THE HEALTH OF AN INDIVIDUAL. RECENT EVIDENCE SUGGESTS SOME GUTMICROBES MAY BE ABLE TO PREVENT THE DEVELOPMENT OFDEPRESSION (E.G., NEURO-INFLAMMATION AND NEUROTRANSMITTERS). ONE OF THE MOST EFFICENT WAYS TO MODULATE THE GUT MICROBIOTA IS THROUGH DIET. THE LONG-TERM GOAL OF THIS PROJECT IS TO IDENTIFY NUTRIENTS THAT INTERACT WITH THE GUT MICROBES AND INFLUENCE THE PROCESSES/PATHWAYS RELEVANT TO DEPRESSION. OUR PRELIMINARY DATA SUGGESTS THAT INTAKE OF DIETARY FIBER AND ANTHOCYANINS (A DIETARY ANTIOXIDANTFOUND IN BERRIES) ARE ASSOCIATED WITH REDUCTIONS IN DEPRESSIVE SYMPTOMS. COINCIDENTALLY, FIBER AND ANTHOCYANINS ARE METABOLIZED BY GUT MICROBES. THESE GUT MICROBES THEN PRODUCE CERTAIN METABOLITES THAT MAY PREVENT DEPRESSION (I.E., SHORT CHAIN FATTY ACIDS, SCFA). OUR OBJECTIVE IS TO DETERMINE IF DAILY CONSUMPTION OFA WHOLE-FOOD SOURCE OF DIETARY FIBER AND ANTHOCYANINS (VIA FREEZE-DRIED BLUEBERRY POWDER) INCREASES CERTAIN SPECIES OF GUT MICROBES, INCREASES GUT-DERIVED METABOLITES RELEVANT TO DEPRESSION, AND IMPROVES DEPRESSIVE SYMPTOMS. THIS STUDY IS AN ANCILLARY PROJECT TO A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL THAT CONSISTS OF A 12-WEEK INTERVENTION IN OLDER, SEDENTARY ADULTS WITH DEPRESSIVE SYMPTOMS. THIS STUDY WILL PROVIDE EVIDENCE ON THE UTILITY OF FIBER- AND ANTHOCYANIN-RICH AGRICULTURAL FOODS AS A NEW THERAPEUTIC OPPORTUNITY TO IMPROVE HUMAN HEALTH BY MODULATING THE GUT MICROBES AND METABOLITES RELEVANT TO DEPRESSION.

NEW WAYS TO FIND HUMAN BMD GENES USING MOUSE QTL MAPPING

EFFECT OF DIETARY PROTEIN ON BONE MASS, SUBSEQUENT BONE LOSS AND FRACTURE

HEALTH CARE EXPENDITURES FOR NURSING HOME RESIDENTS WITH ADVANCED DEMENTIA

THE EFFECT OF THE HOME ENVIRONMENT ON HEALTH AND WELLBEING OF LOW-INCOME OLDER ADULTS - PROJECT ABSTRACT IN THE FACE OF A CHANGING CLIMATE, THERE EXISTS AN URGENT NEED TO STUDY THE EFFECTS OF THE SUMMERTIME HOME THERMAL ENVIRONMENT ON THE HEALTH AND WELLBEING OF LOW-INCOME OLDER ADULTS. WE RECENTLY DEVELOPED A PLATFORM FOR CONTINUOUS MEASUREMENTS OF HOME THERMAL ENVIRONMENT AND DAILY MEASUREMENTS OF SLEEP, GAIT, AND SUBJECTIVE WELLBEING—ALL OF WHICH ARE EITHER DIRECTLY OR INDIRECTLY INFLUENCED BY THERMAL ENVIRONMENT. OUR FIRST AIM IS TO DETERMINE COHORT-LEVEL RELATIONSHIPS BETWEEN AMBIENT TEMPERATURE AND OUTCOMES RELATED TO SLEEP, GAIT, AND COMFORT, AND EXAMINE THE EXTENT TO WHICH THESE RELATIONSHIPS VARY AT THE INDIVIDUAL LEVEL. OUR SECOND AIM IS TO EXPLORE FRAILTY AND SEX AS POTENTIAL EFFECT MODIFIERS OF THE RELATIONSHIPS BETWEEN HOME AMBIENT TEMPERATURE AND OUTCOMES RELATED TO SLEEP, GAIT, AND WELL-BEING IN OLDER ADULTS LIVING IN SUBSIDIZED HOUSING. BOTH AIMS WILL BE COMPLETED BY CONTINUOUSLY MEASURING THE HOME THERMAL ENVIRONMENT OF 50 LOW-INCOME OLDER ADULTS LIVING IN SUBSIDIZED HOUSING FACILITIES IN BOSTON FOR FOUR SUMMERTIME MONTHS. PARTICIPANTS WILL USE A VALIDATED WEARABLE DEVICE TO MEASURE OUTCOMES RELATED TO SLEEP, COMPLETE PERIODIC SMARTPHONE-BASED ASSESSMENTS OF GAIT, AND COMPLETE DAILY QUESTIONNAIRES TO REPORT THEIR PRESENT SUBJECTIVE COMFORT. THE PROPOSED STUDY WILL ESTABLISH THAT THE HOME THERMAL ENVIRONMENT HAS A SUBSTANTIAL IMPACT ON HEALTH AND WELLBEING OF LOW-INCOME OLDER ADULTS AND WILL ENABLE US TO DEVELOP CLINICAL INTERVENTIONS, PUBLIC HEALTH MEASURES, AND ENGINEERING SOLUTIONS THAT MINIMIZE THE IMPACTS OF HOT WEATHER ON THIS VULNERABLE POPULATION. THE CAREER DEVELOPMENT PLAN BUILDS UPON THE APPLICANT’S KNOWLEDGE ABOUT THE BUILT ENVIRONMENT AND HELPS HIM 1) ADVANCE HIS CLINICAL AND PRACTICAL KNOWLEDGE OF THE EFFECTS OF AGING AND AGE-RELATED CONDITIONS (E.G., FRAILTY) ON PHYSIOLOGY AND SYSTEM FUNCTION, ESPECIALLY AS THEY RELATE TO SENSITIVITY OF SLEEP, PHYSICAL FUNCTION, AND OTHER MEANINGFUL PATIENT-REPORTED OUTCOMES TO ENVIRONMENTAL FACTORS; 2) GAIN EXPERIENCE IN THE CONDUCT OF RESEARCH INVOLVING LOW-INCOME AND/OR UNDERSERVED OLDER ADULTS AND UNDERSTAND THEIR SPECIFIC NEEDS; 3) GAIN STATISTICAL, PROFESSIONAL, AND LEADERSHIP SKILLS TO DEVELOP AND LEAD AN INDEPENDENT RESEARCH PROGRAM FOCUSED ON AGING AND THE BUILT ENVIRONMENT. THE APPLICANT WILL BE WORKING WITHIN A WELL-FUNDED INFRASTRUCTURE THAT PROVIDES THE RESOURCES OF NUMEROUS NIH- AND FOUNDATION-FUNDED GRANTS. THE RESOURCES AVAILABLE AT THE MARCUS INSTITUTE FOR AGING RESEARCH PROVIDE THE INTELLECTUAL EXPERTISE AND SUPPORT NEEDED TO CONDUCT LONG-TERM AT-HOME MONITORING OF OLDER ADULTS, SUBJECT RECRUITMENT, AND STATISTICAL ANALYSIS THAT ARE NEEDED FOR THE SUCCESSFUL COMPLETION OF AIMS. ADDITIONALLY, HARVARD MEDICAL SCHOOL PROVIDES NUMEROUS RESOURCES FOR CAREER DEVELOPMENT, INCLUDING CAREER DEVELOPMENT SEMINARS AND COUNSELING, GRANT-WRITING COURSES, THE SCIENTIFIC CORES OF CLINICAL TRANSLATIONAL SCIENCE CENTER (HARVARD CATALYST); ONE OF THE WORLD’S LARGEST MEDICAL LIBRARIES, AND OPPORTUNITIES TO APPLY FOR PILOT GRANTS AND SPECIAL COURSES TO ENABLE JUNIOR FACULTY TO EXPAND THEIR EXPERTISE.

THE CLINICAL COURSE AND OUTCOMES OF OLDER STROKE PATIENTS WITH FEEDING TUBES

STRENGTHENING RECOVERY - INTEGRATING INTRINSIC CAPACITY CARE INTO POST-ACUTE SKILLED NURSING FACILITIES - ABSTRACT THE TIME AFTER HOSPITALIZATION IS CRITICAL FOR OLDER ADULTS RECOVERING FROM ACUTE ILLNESSES. TO RESTORE INDEPENDENCE AND FUNCTION, OVER 20% OF MEDICARE BENEFICIARIES ARE DISCHARGED TO SKILLED NURSING FACILITIES (SNFS) FOR POST- ACUTE CARE AND REHABILITATION. WHILE PATIENTS HOPE TO 'GET STRONGER AND GO HOME,' INSTEAD, HALF OF POST-ACUTE SNF CARE PATIENTS HAVE RE-HOSPITALIZATIONS, LONG-TERM INSTITUTIONALIZATION, OR DIE. INTRINSIC CAPACITY IS THE TOTAL MEASURE OF AN INDIVIDUAL'S PHYSICAL AND MENTAL CAPABILITIES, WHICH DIMINISHES WITH AGING. MOST OF THE OLDER ADULTS WHO EXPERIENCE POOR OUTCOMES AFTER POST-ACUTE SNF CARE HAVE UNDERLYING FRAILTY, A VULNERABLE STATE OF DIMINISHED INTRINSIC CAPACITY. TO ADDRESS NEGATIVE HEALTH OUTCOMES CAUSED BY DECLINES IN INTRINSIC CAPACITY, THE WORLD HEALTH ORGANIZATION CREATED INTEGRATED CARE FOR OLDER PERSONS (ICOPE). ICOPE OPERATIONALIZES INTRINSIC CAPACITY INTO 6 ACTIONABLE DOMAINS TO SCREEN AND MANAGE: MOBILITY, VITALITY, VISION, HEARING, COGNITION, AND PSYCHOLOGICAL FUNCTION. THIS APPROACH HAS SUCCESSFULLY IMPROVED COMMUNITY FUNCTION AND MAY STRENGTHEN RECOVERY FOR FRAIL OLDER ADULTS IN POST-ACUTE SNF CARE. THE RESEARCH OBJECTIVE OF THIS PROPOSAL IS TO ADAPT AND PILOT ICOPE FOR INTEGRATION INTO POST-ACUTE SNF CARE. FIRST, EXISTING COMMUNITY-BASED ICOPE PROTOCOLS WILL BE ADAPTED TO ALIGN WITH POST-ACUTE SNF WORKFLOWS, GUIDED BY SEMI-STRUCTURED INTERVIEWS WITH SNF STAFF. THE ADAPTED PROTOCOL FOR ICOPE-SNF WILL THEN BE TESTED IN A FEASIBILITY PILOT WITHIN A MASSACHUSETTS SNF. IN THIS PILOT, THE PROTOCOL WILL BE ITERATIVELY REFINED EVERY 5 PATIENTS BASED ON SNF STAFF FEEDBACK AND FIDELITY TO AN ICOPE-SNF CORE TASK CHECKLIST. AFTER ESTABLISHING THE FEASIBILITY OF IMPLEMENTING ICOPE-SNF, THE FEASIBILITY OF A CLUSTER RANDOMIZED TRIAL PROTOCOL WILL BE TESTED IN 4 MASSACHUSETTS SNFS. THE SPECIFIC AIMS ARE TO: 1) ADAPT THE ICOPE PROGRAM INTO ICOPE-SNF – A COMPREHENSIVE APPROACH ADDRESSING INTRINSIC CAPACITY IN POST-ACUTE SNF CARE (NIH STAGE 1A); 2) ESTABLISH THE FEASIBILITY OF IMPLEMENTING THE ICOPE-SNF APPROACH (NIH STAGE 1B); 3) ESTABLISH THE FEASIBILITY OF CONDUCTING A 12-MONTH PARALLEL CLUSTER RANDOMIZED TRIAL OF AN ICOPE-SNF INTERVENTION (NIH STAGE 1B). IMPACT: THIS PROPOSAL DIRECTLY RESPONDS TO IMPERATIVES OUTLINED BY THE NATIONAL INSTITUTE ON AGING TO PRIORITIZE AND FUND RIGOROUS, TRANSLATIONAL RESEARCH, IDENTIFYING EFFECTIVE CARE-DELIVERY MODELS FOR NURSING HOME PATIENTS WITH FRAILTY. THIS AWARD WILL SUPPORT THE PRINCIPAL INVESTIGATOR'S (PI) LONG-TERM GOAL OF BECOMING A NATIONAL LEADER IN DEVELOPING AND TESTING INNOVATIVE GERIATRIC POST-ACUTE SNF REHABILITATION CARE. THIS PROPOSAL IS WELL-SUPPORTED BY A COLLABORATIVE TEAM OF HIGHLY EXPERIENCED MENTORS AND A RICH RESEARCH ENVIRONMENT. AS A GERIATRICIAN FOCUSED IN POST-ACUTE SNF CARE, THE PI WILL ACQUIRE KNOWLEDGE IN IMPLEMENTATION SCIENCE AND SKILLS AS AN INTERVENTIONALIST WITH EXPERTISE IN THE NURSING HOME SETTING. DOING SO WILL LEAD TO THE NEXT LOGICAL STEP: A CLUSTER RANDOMIZED CONTROLLED TRIAL OF ICOPE-SNF FOR FRAIL OLDER PATIENTS IN THE POST-ACUTE SNF SETTING.

GERIATRIC ACADEMIC CAREER AWARDS

THE RELATION OF FAT DISTRIBUTION WITH MUSCLE HEALTH AND THE ROLE OF ADIPOKINES

PREVENTABLE DEATHS DUE TO DELIRIUM

URIC ACID, VITAMIN C AND BONE HEALTH: THE FRAMINGHAM STUDY